WO2017170933A1 - Adhesive patch product - Google Patents

Adhesive patch product Download PDF

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Publication number
WO2017170933A1
WO2017170933A1 PCT/JP2017/013403 JP2017013403W WO2017170933A1 WO 2017170933 A1 WO2017170933 A1 WO 2017170933A1 JP 2017013403 W JP2017013403 W JP 2017013403W WO 2017170933 A1 WO2017170933 A1 WO 2017170933A1
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WO
WIPO (PCT)
Prior art keywords
patch
packaging bag
layer
resin
sensitive adhesive
Prior art date
Application number
PCT/JP2017/013403
Other languages
French (fr)
Japanese (ja)
Inventor
永実子 豊島
Original Assignee
ニチバン株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by ニチバン株式会社 filed Critical ニチバン株式会社
Priority to JP2018509465A priority Critical patent/JPWO2017170933A1/en
Priority to CN201780021397.4A priority patent/CN108883025A/en
Publication of WO2017170933A1 publication Critical patent/WO2017170933A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A61J1/10—Bag-type containers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • 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

Definitions

  • the present invention relates to a patch product comprising a transdermal patch and a packaging bag.
  • nalfraphine which is a ⁇ -type opioid receptor agonist compound
  • Pruritus in hemodialysis patients and chronic liver disease patients is not a life-threatening complication, but it occurs frequently during sleep and causes problems in daily life such as causing sleep disorders, and cannot be neglected in maintaining QOL of dialysis patients It is a complication.
  • oral drugs are the most common method, but oral drugs of nalfrafin have insomnia, constipation, and sleepiness as side effects, and the incidence of side effects is dose-dependent.
  • Patent Documents 2 to 4 As means for improving the temporal stability of nalfurafine in these patches, a method using a specific tackifying resin in the adhesive layer (Patent Document 2), a method using a free form of nalfurafine (Patent Document 3), and a free narfrafin A method using a body or a salt thereof and a specific pressure-sensitive adhesive (Patent Document 4) has been proposed.
  • the present invention is a patch product comprising a nalfurafine-containing patch and a packaging bag, thereby improving the aging stability of nalfurafine in the patch by a packaging container containing the nalfurafine-containing patch.
  • the present invention provides a patch product having excellent temporal stability of nalflaphine in a patch.
  • the present inventors have conducted intensive research and studied the configuration of a packaging bag having excellent temporal stability of a patch containing nalfraphine. As a result, the present inventors have found that the above problems can be solved by using means for reducing the oxygen concentration and / or the amount of water in the packaging bag, and have completed the present invention.
  • the present invention A patch product comprising a packaging bag and a nalflaphine-containing patch housed in the packaging bag,
  • the present invention relates to a patch product comprising means for reducing the oxygen concentration and / or the amount of water in the packaging bag.
  • the patch product of the following embodiments is further provided.
  • the packaging bag is selected from the group consisting of a layer formed of a hygroscopic resin and a layer containing an oxygen absorbent.
  • the above-mentioned patch product comprising the above and comprising a laminate of at least two layers.
  • the patch product wherein the inside of the packaging bag is replaced with nitrogen as means for reducing the oxygen concentration and / or the amount of water in the packaging bag.
  • the patch product comprising a layer.
  • a patch in which the patch comprises a support, a nalfurafine-containing pressure-sensitive adhesive layer provided on at least one surface of the support, and a release sheet provided on the nalfurafine-containing pressure-sensitive adhesive layer. Said patch product.
  • the patch product wherein the pressure-sensitive adhesive layer contains a rubber-based pressure-sensitive adhesive and a rosin resin.
  • the patch product, wherein the pressure-sensitive adhesive layer contains a salt of narfrafin and a desalting agent.
  • the present invention also relates to a nalflaphine-containing patch formed from a laminate of at least two layers containing at least one selected from the group consisting of a layer formed from a hygroscopic resin and a layer containing an oxygen absorbent. Related to packaging bags.
  • the present invention can suppress degradation of drug content over time by suppressing the decomposition of nalfrafin by using means for reducing the oxygen concentration and / or the amount of water in the packaging bag containing the nalfurafine-containing patch. There is an effect. Therefore, according to this invention, there exists an effect that the patch product which is excellent in the temporal stability of the narfrafin in a patch can be provided.
  • the packaging bag of the present invention has an effect that the decomposition of chemically unstable compounds can be suppressed. Therefore, the packaging bag of this invention is suitable for the packaging bag which preserve
  • FIG. 1 is a cross-sectional view of a laminate including a layer formed from a hygroscopic resin.
  • FIG. 2 is a cross-sectional view of a laminate including a layer containing an oxygen absorbent.
  • FIG. 3 shows one embodiment (i) of a patch product comprising a packaging bag, a pouch containing a nalfurafine-containing patch and a hygroscopic agent inside the packaging bag, and a cross section of a laminate constituting the packaging bag. It is a figure which shows figure (ii).
  • FIG. 4 shows another embodiment (i) of a patch product comprising a packaging bag, and a pouch containing a patch and an oxygen absorbent inside the packaging bag, and a cross section of the laminate constituting the packaging bag. It is a figure which shows figure (ii).
  • the present invention relates to a patch product comprising a packaging bag and a nalfurafine-containing patch housed in the packaging bag.
  • the packaging bag used in the present invention includes means for reducing the oxygen concentration in the packaging bag, means for reducing the amount of water, or both means, thereby suppressing the decomposition of nalfrafin and its salts. can do.
  • the means for reducing the oxygen concentration and / or moisture content in the packaging bag is not particularly limited as long as the oxygen concentration and / or moisture content in the packaging bag can be reduced, but the layer formed from a hygroscopic resin.
  • a method of using a packaging bag formed of a laminate of at least two layers including at least one selected from the group consisting of layers containing oxygen absorbent, a hygroscopic agent and / or oxygen absorption in the packaging bag A method of enclosing a pouch containing an agent and a method of replacing the inside of the packaging bag with nitrogen are preferred.
  • at least one selected from the group consisting of a layer formed from a hygroscopic resin and a layer containing an oxygen absorbent is included, at least A method of using a packaging bag formed from a laminate of two or more layers and a method of replacing the inside of the packaging bag with nitrogen are more preferable.
  • a plurality of the above methods can be used in combination as means for reducing the oxygen concentration and / or the amount of water in the packaging bag.
  • Method of using a packaging bag formed from a specific laminate As means for reducing the oxygen concentration and / or moisture content in the packaging bag, at least two layers comprising at least one selected from the group consisting of a layer formed from a hygroscopic resin and a layer containing an oxygen absorbent
  • decomposition disassembly of nalfurafine and its salt can be suppressed.
  • the packaging bag used by this invention is formed from the laminated body of an at least 2 layer or more including 1 or more types chosen from the group which consists of the layer formed from the hygroscopic resin, and the layer containing an oxygen absorber.
  • the configuration is not particularly limited, and for example, the following embodiments (1) and (2) can be taken.
  • the packaging bag has a layer structure formed from a hygroscopic resin.
  • the packaging bag used in the present invention can be formed by laminating at least two layers including a layer formed from a hygroscopic resin by heat-sealing.
  • a sealant layer as an innermost layer of a packaging bag
  • a film or sheet formed from a hygroscopic resin examples of the outer layer may include a laminate in which an air blocking layer is provided, and if necessary, an arbitrary resin film or the like is provided as an outer layer from the air blocking layer (see FIG. 1).
  • the innermost layer of the packaging bag is preferably a heat-sealable layer, that is, a sealant layer.
  • the sealant layer may be formed from a conventionally known sealant resin film. Among them, a layer having a high drug non-adsorption ability in addition to easy heat sealing is preferable.
  • the sealant layer examples include polyethylene resin films such as low density polyethylene (LDPE), linear low density polyethylene (L-LDPE), and high density polyethylene (HDPE); acid-modified polyethylene, polypropylene, acid-modified polypropylene, copolymerization Polyolefin resin films such as polypropylene, ethylene-vinyl acetate copolymer (EVA), ethylene- (meth) acrylic acid ester copolymer, ethylene- (meth) acrylic acid copolymer; polyester such as polyethylene terephthalate (PET)
  • PP unstretched polypropylene resin
  • PE unstretched polyethylene resin
  • Beam is preferable.
  • (meth) acrylic acid represents both acrylic acid and methacrylic acid.
  • the sealant layer has a minimum thickness that can be heat sealed to produce a hermetic packaging bag, and is preferably 10 ⁇ m to 50 ⁇ m, for example, 30 ⁇ m.
  • the film or sheet layer formed from a hygroscopic resin is a film or sheet layer formed from a resin in which a hygroscopic agent is dispersed or contained in the resin to express hygroscopicity.
  • the hygroscopic agent is not particularly limited, and barium oxide, calcium chloride, magnesium sulfate, calcium oxide, calcium sulfate, lithium chloride, lithium perchlorate, alumina, silica gel, zeolite, etc. are used, and one or more may be selected. it can.
  • the resin is not particularly limited, but polyolefin, particularly low density polyethylene (LDPE) is preferable because it is excellent in dispersibility of the hygroscopic agent.
  • Examples of the form of the film or sheet formed from the hygroscopic resin include Moist Catch (registered trademark) (manufactured by Kyodo Printing Co., Ltd.).
  • the layer disposed on the outside of the film or sheet layer formed from the hygroscopic resin is preferably an air blocking layer from the viewpoint of preventing moisture in the air from affecting nalfrafin and its salt.
  • the air barrier layer only needs to be a material that can block the entry of air from the outside of the packaging bag.
  • a soft metal foil such as an aluminum foil (hereinafter also referred to as AL)
  • AL aluminum deposition
  • silica deposition alumina deposition
  • a vapor deposition layer such as silica alumina binary vapor deposition can be employed.
  • the packaging bag has a layer structure containing an oxygen absorbent.
  • the packaging bag used in the present invention can be formed by laminating at least two laminated bodies including a layer containing an oxygen absorbent by heat fusion. And as said laminated body, for example, from a sealant layer as an innermost layer of a packaging bag, a film or sheet layer containing an oxygen absorbent as a layer outside the sealant layer, and a film or sheet layer containing an oxygen absorbent Examples of the outer layer include an air barrier layer, and if necessary, a laminate in which an arbitrary resin film or the like is disposed as an outer layer from the air barrier layer (see FIG. 2).
  • the innermost layer of the packaging bag is preferably a heat-sealable layer, that is, a sealant layer.
  • a sealant layer the sealant layer shown in the above (1) can be used.
  • the oxygen absorbent is not particularly limited, but in addition to inorganic oxides, mixtures made of electrolytes, reducing inorganic salts, polyphenols, reducing sugars, reducing agents, unsaturated fatty acid compounds, unsaturated organic compounds Examples thereof include a compound, a thermoplastic polymer, a composition containing an oxygen absorption promoting substance, or a mixed system thereof.
  • Oxygard registered trademark
  • Oxycatch registered trademark
  • AGELESS OMAC Mitsubishi Gas Chemical Co., Ltd.
  • the layer disposed on the outside of the film or sheet layer containing the oxygen absorbent is preferably an air blocking layer from the viewpoint of preventing moisture in the air from affecting nalfrafin and salts thereof.
  • the air blocking layer the air blocking layer shown in the above (1) can be used.
  • the packaging bag used in the present invention includes a layer formed from a hygroscopic resin and / or a layer containing an oxygen absorbent from the viewpoint of further suppressing the decomposition of nalfurafine and its salt.
  • a heat-sealing layer is disposed between at least two laminates.
  • the heat-fusible layer is made of a heat-fusible resin that melts and heat-fuses by heating, and heats between laminates including a layer formed from a hygroscopic resin and / or a layer containing an oxygen absorbent. To be fused.
  • the heat-sealable resin is not particularly limited as long as it is a heat-sealable resin.
  • polyethylene polypropylene, ethylene-vinyl acetate copolymer, ethylene-methacrylic acid copolymer, ethylene-methacrylic acid ester copolymer
  • examples thereof include a polymer, an ethylene-acrylic acid copolymer, and an ethylene-acrylic acid ester copolymer.
  • the packaging bag used in the present invention is composed of a laminate of at least two layers including at least one selected from the group consisting of a layer formed from a hygroscopic resin and a layer containing an oxygen absorbent.
  • the laminated body only needs to have the above-described laminated structure, and may have a laminated structure including an arbitrary resin film or the like as necessary.
  • arbitrary resin film etc. polyolefin-type resin films, such as a polyethylene film, a polypropylene film, a polymethylpentene film, etc.
  • Vinyl resin film such as vinyl film, polyvinylidene chloride film, polyvinyl alcohol film, polystyrene film, polyacrylonitrile film, ionomer film
  • polyester resin film such as polyethylene terephthalate film
  • polyamide resin film such as nylon film
  • Cellulosic resin films polycarbonate resin films; and laminated films thereof.
  • the above-mentioned resin films and their laminated films are laminated with soft aluminum foil (hereinafter sometimes abbreviated as AL).
  • AL soft aluminum foil
  • examples thereof include a film and a pigment-added resin film obtained by adding a black pigment or the like to the above-described resin film.
  • these resin films, laminated films, etc. can be used in various combinations as a laminate.
  • the packaging bag may be formed from a laminate including an ethylene-vinyl alcohol copolymer (hereinafter also referred to as EVOH) or a cyclic polyolefin film (hereinafter also referred to as COC).
  • EVOH ethylene-vinyl alcohol copolymer
  • COC cyclic polyolefin film
  • a specific laminated structure of a preferable laminate used in the packaging bag used in the present invention is formed from the innermost layer of the packaging bag from polyethylene (PE) / hygroscopic resin. Or a layer containing an oxygen adsorbent / AL / polyester.
  • the laminate can be produced by dry lamination, extrusion lamination, or coextrusion lamination, and the thickness of the laminate can be about 10 ⁇ m to 100 ⁇ m.
  • Each layer is laminated directly or via an adhesive or the like. When the layers are bonded with an adhesive, it is desirable to use an adhesive with little drug adsorption.
  • an isocyanate such as toluene diisocyanate (TDI) or diphenylmethane diisocyanate (MDI) can be used as an adhesive, or a polyurethane adhesive containing a polyol or the like can be used.
  • the package is formed to be slightly larger than the patch containing nalflavine.
  • the area of the patch can be determined as appropriate, but it is preferably 1 cm 2 to 25 cm 2 in view of minimizing the amount of the drug volatilized in the packaging material and adhering to the support as much as possible and considering the ease of application. is there.
  • the laminated body which comprises the packaging bag used by this invention when the plastic laminate film raw material containing aluminum is employ
  • Method of enclosing a pouch in a packaging bag As a means for reducing the oxygen concentration and / or the amount of water in the packaging bag, a method of enclosing a pouch containing a hygroscopic agent, a pouch containing an oxygen absorbent, or both in the packaging bag.
  • the pouch containing the hygroscopic agent and / or the oxygen absorbent enclosed in the packaging bag can suppress the decomposition of nalfurafine and its salt.
  • the following embodiments (3) and (4) can be taken as a form in which a pouch containing a hygroscopic agent and / or an oxygen absorbent is enclosed in the packaging bag.
  • a nalfrafin-containing patch (hereinafter also simply referred to as a patch) 3 and a pouch 4 containing a hygroscopic agent inside the packaging bag [FIG. i) See.
  • the atmosphere inside the packaging bag is omitted.
  • the packaging bag include a sealant layer as the innermost layer of the packaging bag, an air barrier layer as an outer layer from the sealant layer, and an optional resin film as a layer outside the air barrier layer as necessary. Can be mentioned [see FIG. 3 (ii)].
  • the innermost layer of the packaging bag is preferably a heat-sealable layer, that is, a sealant layer.
  • a sealant layer the sealant layer shown in the above (1) can be used.
  • the layer disposed on the outer side of the sealant layer is preferably an air barrier layer from the viewpoint of preventing moisture in the air from affecting nalflavine and its salt.
  • the air blocking layer the air blocking layer shown in the above (1) can be used.
  • the arbitrary resin films etc. which were mentioned above can be used for arbitrary resin films.
  • the pouch containing the hygroscopic agent is not particularly limited as long as the hygroscopic agent can absorb moisture inside the packaging bag.
  • the hygroscopic agent mentioned in the above (1) may be a nonwoven fabric or the like. It is preferable to cover it with a bag or to add a hygroscopic agent to a nonwoven fabric or the like to form a sheet.
  • the patch product 10 includes the packaging bag 2 and the pouch 5 containing the patch 3 and the oxygen absorbent inside the packaging bag [see FIG. 4 (i). In FIG. 4, the atmosphere inside the packaging bag is omitted. ].
  • the packaging bag include a sealant layer as the innermost layer of the packaging bag, an air barrier layer as an outer layer from the sealant layer, and an optional resin film as a layer outside the air barrier layer as necessary. Can be mentioned [see FIG. 4 (ii)].
  • the innermost layer of the packaging bag is preferably a heat-sealable layer, that is, a sealant layer.
  • a sealant layer the sealant layer shown in the above (1) can be used.
  • the layer disposed on the outer side of the sealant layer is preferably an air barrier layer from the viewpoint of preventing moisture in the air from affecting nalflavine and its salt.
  • the air blocking layer the air blocking layer shown in the above (1) can be used.
  • the arbitrary resin films etc. which were mentioned above can be used for arbitrary resin films.
  • the pouch containing the oxygen absorbent is not particularly limited as long as the oxygen absorbent can reduce the oxygen concentration in the packaging bag.
  • the agent is preferably covered with a non-woven fabric to form a bag.
  • a known method can be used, for example, a method of injecting nitrogen after evacuating the inside of the packaging bag.
  • the method for producing the patch product of the present invention is not particularly limited.
  • the patch product is selected from the group consisting of a layer formed from a hygroscopic resin used in the packaging bag used in the present invention and a layer containing an oxygen absorbent.
  • One or more of the laminates containing at least two layers are framed larger than the size of the patch, and three sides are bonded together by heat fusion to form a bag, and after the patch is sealed, the remaining one side
  • the patch product of the present invention can be obtained by heat-sealing and encapsulating.
  • preferable laminates used for packaging bags are frames larger than the size of the patch, and three sides are bonded together by heat fusion to form a bag, After enclosing a pouch containing a hygroscopic agent and / or an oxygen absorbent, the remaining one side is heat-sealed and encapsulated, whereby the patch product of the present invention can be obtained.
  • the moisture content or oxygen content in the packaging bag is preferably low, and the moisture concentration or oxygen concentration in the packaging bag can be lowered by a known method.
  • the moisture content and residual oxygen concentration inside the packaging bag can be reduced by substituting and filling the atmosphere inside the packaging bag with a vacuum gas packaging machine or the like.
  • the state of the atmosphere in this step can be measured by measuring the moisture content or oxygen content with a measuring device installed in the step of performing nitrogen substitution, or by using a measuring device that can be directly enclosed in a packaging bag. With the measuring device that can be directly enclosed in the packaging bag, the moisture content and oxygen concentration in the packaging bag can be measured over time for the patch product.
  • the preferable moisture content (concentration) in the packaging bag in the patch product is not more than the amount of moisture corresponding to a relative humidity of 25% at 25 ° C., and the residual oxygen concentration is not more than 10% by volume.
  • the moisture content of the patch can be measured with an infrared moisture meter.
  • the rate of change after storage in a constant temperature room at 60 ° C. for 1 month is: It is preferably 20 to 70%, particularly preferably 25 to 50%.
  • packaging bag that is, a narfrafin formed from a laminate of at least two layers including at least one selected from the group consisting of a layer formed from a hygroscopic resin and a layer containing an oxygen absorbent.
  • Packaging bags for containing patches are also the subject of the present invention.
  • the patch includes a support, a nalfurafine-containing pressure-sensitive adhesive layer provided on at least one surface of the support, and a release sheet provided on the nalfurafine-containing pressure-sensitive adhesive layer.
  • Examples of the support used for the patch in the patch product of the present invention include flexible supports such as films, nonwoven fabrics, Japanese paper, cotton cloth, knitted fabrics, woven fabrics, and laminate composites of nonwoven fabrics and films. These supports are preferably made of a flexible material that can adhere to the skin and can follow the movement of the skin, and a material that can suppress the occurrence of skin irritation after being applied for a long time. Examples of the material of these supports include polyethylene, polypropylene, polyethylene terephthalate, and the like. There is no restriction
  • the pressure-sensitive adhesive constituting the pressure-sensitive adhesive layer is not particularly limited, and rubber-based pressure-sensitive adhesive, acrylic pressure-sensitive adhesive, silicone pressure-sensitive adhesive, urethane pressure-sensitive adhesive, hydrocolloid-based Although an adhesive etc. are mentioned, Especially preferably, it is a rubber-type adhesive.
  • the pressure-sensitive adhesive layer may have a single-layer structure or a multilayer structure. In the case where the pressure-sensitive adhesive layer has a multilayer structure, the narfrafin may be contained in one or more of them.
  • the pressure-sensitive adhesive layer comprises (a) an elastomer, (b) one or more tackifiers selected from terpene resins and rosin resins, (c) at least one of nalflavine and salts thereof, and ( d) It contains a desalting agent and further contains other components as required.
  • the pressure-sensitive adhesive layer in the patch in the patch product of the present invention is composed of a non-aqueous system, and water is not intentionally added in the manufacturing process.
  • (A) Elastomer There is no restriction
  • examples thereof include SIS5002 (manufactured by JSR Corporation) and quinac 3520 (manufactured by Nippon Zeon Corporation), which are styrene-isoprene-styrene block copolymers.
  • the said elastomer may be used individually by 1 type, and may use 2 or more types together.
  • the content of the elastomer in the pressure-sensitive adhesive layer can be appropriately selected according to the purpose, but is preferably 15% by mass or more, more preferably 20% by mass or more, and further preferably 30% by mass or more. Moreover, 60 mass% or less is preferable, 50 mass% or less is more preferable, and 40 mass% or less is further more preferable.
  • Tackifier There are no particular limitations on the tackifier as long as it improves tackiness, but it is preferable to contain one or more tackifiers selected from terpene resins and rosin resins.
  • the terpene resin include ⁇ -pinene resin, ⁇ -pinene resin, terpene-phenol resin, aromatic modified terpene resin, hydrogenated terpene resin and the like.
  • rosin resin examples include rosins such as gum rosin, tall oil rosin, and wood rosin; hydrogenated rosin, disproportionated rosin, polymerized rosin, modified rosin such as maleated rosin; rosin glycerin ester, hydrogenated rosin ester, hydrogenated Rosin ester such as rosin glycerin ester; and the like.
  • tackifier examples include YS resin PX1150N (manufactured by Yasuhara Chemical Co., Ltd.) and Pine Crystal KE-311 (manufactured by Arakawa Chemical Industries, Ltd.). The said tackifier may be used individually by 1 type, and may use 2 or more types together. Moreover, you may combine the tackifier selected from the said terpene resin and the said rosin resin. In particular, rosin resin is preferable from the viewpoint of stability of narfrafin.
  • nalflaphine and its salt As the above-mentioned nalfurafine, a free form of nalfurafine can be used, but it is preferably blended in the pressure-sensitive adhesive layer as a salt of nalfurafine.
  • the salt of narfrafin is converted into a free form by a desalting agent described later.
  • the salt of nalfurafine is not particularly limited as long as it is a pharmaceutically acceptable salt, but an acid addition salt of nalfurafine is preferable from the viewpoint of skin permeability.
  • the acid addition salt include hydrochloride, acetate, maleate, and oxalate. Among these, nalfrafin hydrochloride is preferable from the viewpoint of skin permeability.
  • the nalflaphine salt may be used alone or in combination of two or more.
  • nalflavine As content in the said adhesive layer of the salt of the said nalfurafine, 0.1 mass% or more is preferable, and 0.2 mass% or more is more preferable. Moreover, 5.0 mass% or less is preferable at the point of skin permeability and skin irritation, 4.0 mass% or less is more preferable, and 3.0 mass% or less is further more preferable. Even when a free form of nalfurafine is used in place of the nalflaphine salt, an amount similar to the content of the nalfurafine salt can be added to the pressure-sensitive adhesive layer. In the present invention, when it is described as nalflavine, it refers to both a free form of nalflaphine and a pharmaceutically acceptable salt thereof unless otherwise specified.
  • the desalting agent is not particularly limited as long as it converts the salt of nalflaphine into a free form, and can be appropriately selected according to the purpose.
  • monoethanolamine e.g., monoethanolamine , Sodium bicarbonate, and a polymer compound having an amino group are preferred.
  • the content of the desalting agent can be appropriately selected according to the purpose, but in terms of skin irritation and skin permeability, the content is 5 mol or more with respect to 1 mol of the salt of narfrafin. Preferably, it is 10 mol or more. Moreover, it is preferable that it is 30 mol or less, and it is more preferable that it is 25 mol or less.
  • As a blending method of the desalting agent it may be performed once during the production process or may be performed in several steps.
  • the content in the pressure-sensitive adhesive layer is preferably 0.01% by mass or more, more preferably 0.1% by mass or more, and further preferably 0.3% by mass or more. . Moreover, 10 mass% or less is preferable, 5.0 mass% or less is more preferable, and 1.0 mass% or less is further more preferable.
  • polymer compound having an amino group in terms of skin permeability, dialkyl (meth) acrylate (methyl or ethyl) aminoalkyl (methyl or ethyl) and alkyl (meth) acrylate (methyl, ethyl, Propylene or butyl), copolymers composed of monomer units selected from monohydroxyalkyl (meth) acrylates (ethyl, propyl or butyl) and combinations thereof are preferred.
  • Examples of such a polymer compound having an amino group include Eudragit (registered trademark) EPO (manufactured by Evonik), which is a methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer.
  • the desalting agent is a polymer compound having an amino group
  • 1.0% by mass or more is preferable in the pressure-sensitive adhesive layer, and 2.0% by mass or more is more preferable.
  • 40 mass% or less is preferable in the said adhesive layer at the point of skin permeability and skin irritation.
  • the said desalting agent may be used individually by 1 type, and may use 2 or more types together.
  • the average thickness of the pressure-sensitive adhesive layer can be appropriately selected according to the purpose, but is preferably 5 ⁇ m to 500 ⁇ m, more preferably 10 ⁇ m to 300 ⁇ m, and further preferably 20 ⁇ m to 200 ⁇ m.
  • the pressure-sensitive adhesive layer may further contain other additives such as other drugs, softeners, antioxidants, absorption accelerators, inorganic fillers, ultraviolet absorbers and antioxidants.
  • the release sheet used for the patch in the patch product of the present invention is preferably a material that is difficult to absorb and adsorb the drug in the pressure-sensitive adhesive layer.
  • a polyester film having a silicone treatment on one or both sides silicone Examples include treated polyethylene laminate fine paper, silicone-treated glassine paper, and the like.
  • the method for producing the patch in the patch product of the present invention is not particularly limited and can be appropriately selected according to the purpose.
  • an adhesive containing an elastomer, a tackifier, a salt of nalfrafin, and a desalting agent examples thereof include a method of preparing an agent composition and coating it on a support, and a method of applying the support onto a release sheet and then bonding the support.
  • nalfurafine hydrochloride was used as all nalflaphine.
  • Example 1 As the elastomer, styrene-isoprene-styrene block copolymer (SIS; trade name “SIS5002”, manufactured by JSR Corporation) 7.97% by mass, styrene-isoprene-styrene block copolymer (SIS; trade name “Quintac”) 3520 ", manufactured by Nippon Zeon Co., Ltd.) 23.9% by mass, as the tackifier, terpene resin (trade name” YS Resin PX1150N “, Yashara Chemical Co., Ltd.) 19.1% by mass, and as the softener, liquid paraffin (Trade name “Hycol M352”, manufactured by Kaneda Co., Ltd.) 48.48% by mass, nalflaphine hydrochloride 0.25% by mass dissolved in an appropriate amount of methanol as the salt of nalfurafine, and monoethanol as the desalting agent 0.3% by weight of amine is present so that
  • the solvent (toluene) was added to prepare a pressure-sensitive adhesive composition was mixed until uniform.
  • the obtained pressure-sensitive adhesive composition was coated on a silicone-treated polyester film (average thickness 75 ⁇ m) as a cover material (release sheet) to an average thickness of 30 ⁇ m to form a pressure-sensitive adhesive layer.
  • a polyester film was laminated as a support on this pressure-sensitive adhesive layer, and cut into a size of 7.5 cm 2 to prepare patch 1.
  • the patch product 1 was produced as follows, and the stability test with time shown below was performed to evaluate the stability of the drug in the patch. The evaluation results are shown in Table 1.
  • patch products 1-6 were prepared using a packaging bag using a laminate in which PAN (polyacrylonitrile) was disposed as the innermost layer and AL was disposed as the air barrier layer. It was used for.
  • Patches 7-9 use packaging bags obtained using moist catch (manufactured by Kyodo Printing Co., Ltd., sealant layer / moisture absorbing layer / aluminum / PET), and patches 10-12 use oxycatch (Kyodo Printing Co., Ltd.)
  • Patch products 7 to 12 were produced using packaging bags obtained using PE (sealant layer) / oxygen absorbing layer / aluminum / PET (manufactured by the company) and subjected to the following tests.
  • the patch was housed in each packaging bag, the inside of the bag was purged with nitrogen, the packaging bag was sealed by heat sealing, and stored at 60 ° C.
  • the content of nalflaphine in the patch was quantified by high performance liquid chromatography.
  • the nalfuraffin content after 3 months with respect to the nalfurafine content at the start of storage was calculated as a percentage and used as the drug residual rate (%).
  • Example 2 In Example 1, 0.05% by mass of BHT was added as an antioxidant, and the same method as in Example 1 except that the amount of the softening agent was changed from 48.48% by mass to 48.43% by mass. A patch 2 and a patch product 2 were prepared and evaluated.
  • Example 3 In Example 1, instead of 19.1% by mass of “YS Resin PX1150N”, which is a terpene resin as the tackifier, “Pine Crystal KE-311 (ultra-light rosin ester)” (Arakawa Chemical) A patch 3 and a patch product 3 were prepared and evaluated in the same manner as in Example 1 except that 19.1% by mass (manufactured by Kogyo Co., Ltd.) was used.
  • Example 4 In Example 3, the desalting agent was 3.2% by mass of “Eudragit EPO” (manufactured by Evonik), which is a polymer compound containing an amino group instead of 0.3% by mass of monoethanolamine, and as an antioxidant.
  • the patch 4 and the patch product 4 were prepared in the same manner as in Example 3 except that 0.05% by mass of BHT was added and the amount of the softening agent was changed from 48.48% by mass to 45.53% by mass. Were made and evaluated.
  • Example 5 In Example 4, except that the antioxidant was not added and the amount of the softening agent was changed from 45.53 mass% to 45.58 mass%, the patch 5 and the patch were prepared in the same manner as in Example 4. Product 5 was made and evaluated.
  • Example 5 is the same as Example 5 except that nalfurafine hydrochloride is a free form of nalfurafine, no desalting agent is added, and the amount of the softening agent is changed from 45.58% by mass to 48.78% by mass.
  • a patch 6 and a patch product 6 were prepared and evaluated in the same manner.
  • Example 7 In Example 4, except that the packaging material was changed to a moist catch (made by Kyodo Printing Co., Ltd.) including a layer formed of a hygroscopic resin, the patch 7 and the patch product 7 were prepared in the same manner as in Example 4. Prepared and evaluated.
  • Example 8 In Example 5, except that the packaging material was changed to a moist catch (made by Kyodo Printing Co., Ltd.) including a layer formed from a hygroscopic resin, patch 8 and patch product 8 were produced in the same manner as in Example 5. And evaluated.
  • a moist catch made by Kyodo Printing Co., Ltd.
  • Example 9 In Example 2, instead of 19.1% by mass of “YS Resin PX1150N”, which is a terpene resin as the tackifier, “Pine Crystal KE-311 (ultra-light rosin ester)” (Arakawa Chemical) Kogyo Kogyo Co., Ltd. was used in the same manner as in Example 2 except that the product was changed to 19.1% by mass and the packaging material was changed to a moist catch (manufactured by Kyodo Printing Co., Ltd.). In addition, a patch product 9 was prepared and evaluated.
  • Example 10 In Example 4, the patch 10 and the patch product 10 were produced in the same manner as in Example 4 except that the packaging material was changed to Oxycatch (produced by Kyodo Printing Co., Ltd.) including a layer containing an oxygen absorbent. And evaluated.
  • Oxycatch produced by Kyodo Printing Co., Ltd.
  • Example 11 In Example 5, the patch 11 and the patch product 11 were produced in the same manner as in Example 5 except that the packaging material was changed to oxy catch (manufactured by Kyodo Printing Co., Ltd.) including a layer containing an oxygen absorbent. And evaluated.
  • oxy catch manufactured by Kyodo Printing Co., Ltd.
  • Example 12 In Example 2, instead of 19.1% by mass of “YS Resin PX1150N”, which is a terpene resin as the tackifier, “Pine Crystal KE-311 (ultra-light rosin ester)” (Arakawa Chemical) Kogyo Kogyo Co., Ltd., except that the packaging material was changed to 19.1% by mass and the packaging material was changed to Oxycatch (manufactured by Kyodo Printing Co., Ltd.). A patch product 12 was prepared and evaluated.
  • the water content of each patch was measured. Specifically, the patch 7 or the patch 13 was accommodated in each packaging bag, the inside of the bag was purged with nitrogen, the packaging bag was sealed by heat fusion, and stored at 60 ° C. At the start of storage and 1 month after the start of storage, the amount of water in the patch was quantified with an infrared moisture meter (AD-4715, A & D). The water content after one month with respect to the water content in the preparation at the start of storage was calculated as a percentage and used as the water content change rate (%). The infrared moisture meter was measured by assuming that the drying temperature was 100 ° C., the monitoring time was 300 seconds, and the amount of change in the measured value was 0.05% or less within the monitoring time as the final measured value.
  • AD-4715, A & D infrared moisture meter
  • the patches 1 to 12 (Examples 1 to 12) It was found that the configuration realized a patch product with good drug stability.
  • the patch products 10 to 12 using oxycatch as a packaging material showed a very good result that the drug residual amount in the patches 10 to 12 was 96% or more even when stored at 60 ° C. for 3 months. Met.
  • the adhesive layer of the patch from the patches 4, 5, 7, 8, 10-11, styrene-isoprene-styrene block copolymer (SIS), rosin resin as the tackifier, and desalting agent
  • SIS styrene-isoprene-styrene block copolymer
  • rosin resin as the tackifier
  • desalting agent As a result, it has been found that a composition containing an amino group-containing polymer compound is preferable.
  • the patch product 7 using the moist catch has a moisture decrease rate (%) of 37% when stored for one month at 60 ° C.
  • the moisture reduction rate of the agent 13 was 11%. This is because moisture in the packaging material is reliably absorbed by using a packaging bag formed of a laminate of at least two layers including a laminate including a layer formed of a hygroscopic resin. Was confirmed.

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Abstract

This adhesive patch product is provided with a packaging bag and a nalfurafine-containing adhesive patch housed in the interior of the packaging bag, and obtains excellent nalfurafine stability over time as a result of being provided with a means for reducing the oxygen concentration and/or moisture content within the packaging bag.

Description

貼付剤製品Patch products
　本発明は、経皮吸収型の貼付剤および包装袋からなる貼付剤製品に関する。 The present invention relates to a patch product comprising a transdermal patch and a packaging bag.
　血液透析患者におけるそう痒症の改善、及び慢性肝疾患患者におけるそう痒症の改善に使用される化合物として、κ型オピオイド受容体作動性化合物であるナルフラフィンが知られている。
　血液透析患者や慢性肝疾患患者におけるそう痒症は、生命を脅かす合併症ではないものの、睡眠時に多く発生し睡眠障害を起こすなど日常生活において支障をきたし、透析患者のＱＯＬを保つ上で軽視できない合併症となっている。
　薬剤の投与方法の中で、経口薬は最も一般的な方法であるが、ナルフラフィンの経口剤は、副作用として不眠、便秘、及び眠気などが認められており、用量依存的に副作用の発現率が増加していることから、血中での一過性のナルフラフィン濃度の上昇が副作用発現の原因である可能性が考えられている。このため、副作用の原因となる一過性の血中薬物濃度の上昇を抑制し、血中薬物濃度を長時間一定に維持するための、ナルフラフィンの剤形として、貼付剤が提案されている（特許文献１）。 As a compound used to improve pruritus in hemodialysis patients and pruritus in patients with chronic liver disease, nalfraphine, which is a κ-type opioid receptor agonist compound, is known.
Pruritus in hemodialysis patients and chronic liver disease patients is not a life-threatening complication, but it occurs frequently during sleep and causes problems in daily life such as causing sleep disorders, and cannot be neglected in maintaining QOL of dialysis patients It is a complication.
Among the drug administration methods, oral drugs are the most common method, but oral drugs of nalfrafin have insomnia, constipation, and sleepiness as side effects, and the incidence of side effects is dose-dependent. From the increase, it is considered that a transient increase in the concentration of nalflaphine in the blood may cause side effects. Therefore, a patch has been proposed as a dosage form of nalfrafin to suppress a transient increase in blood drug concentration causing side effects and to maintain the blood drug concentration constant for a long time ( Patent Document 1).
　また、ナルフラフィン含有貼付剤の改良として、貼付剤中でのナルフラフィンの経時安定性を向上させた貼付剤が報告されている（特許文献２～４）。これらの貼付剤におけるナルフラフィンの経時安定性を向上させる手段として、粘着層に特定の粘着付与樹脂を用いる方法（特許文献２）、フリー体のナルフラフィンを用いる方法（特許文献３）、及びナルフラフィンのフリー体又はその塩と特定の粘着剤とを用いる方法（特許文献４）が提案されている。 In addition, as an improvement of a patch containing nalflaphine, a patch having improved aging stability of nalflaphine in the patch has been reported (Patent Documents 2 to 4). As means for improving the temporal stability of nalfurafine in these patches, a method using a specific tackifying resin in the adhesive layer (Patent Document 2), a method using a free form of nalfurafine (Patent Document 3), and a free narfrafin A method using a body or a salt thereof and a specific pressure-sensitive adhesive (Patent Document 4) has been proposed.
特開２０１３－１４７４５９号公報JP 2013-147459 A 特開２０１４－１９６２７９号公報JP 2014-196279 A 国際公開第２０１５／０２５７６６号パンフレットInternational Publication No. 2015/025766 Pamphlet 国際公開第２０１５／０２５７６７号パンフレットInternational Publication No. 2015/025767 Pamphlet
　上述したように、従来より、貼付剤中でのナルフラフィンの経時安定性を向上させる手段としては、ナルフラフィン含有貼付剤中の成分に着目した手段が一般的であり、貼付剤に含ませる成分や成分同士の組み合わせが検討されている。
　その一方で、上記の手段以外の手段により、貼付剤中でのナルフラフィンの経時安定性を向上させることができれば、余計な成分を用いる必要がないので、ナルフラフィン含有貼付剤の製造の観点から、有利である。
　しかし、本発明者らが知る限り、貼付剤中でのナルフラフィンの経時安定性を向上させるために、ナルフラフィン含有貼付剤を収容する包装容器に着目した手段は提案されていない。
　そこで、本発明は、ナルフラフィン含有貼付剤を収容する包装容器によって、貼付剤中でのナルフラフィンの経時安定性を向上させ、これにより、ナルフラフィン含有貼付剤と包装袋とを備える貼付剤製品であって、貼付剤中でのナルフラフィンの経時安定性に優れる貼付剤製品を提供するものである。 As described above, conventionally, as a means for improving the temporal stability of nalfurafine in a patch, a means focusing on the components in the nalfurafine-containing patch is generally used, and the components and components to be included in the patch Combinations are being considered.
On the other hand, if it is possible to improve the temporal stability of nalfurafine in the patch by means other than the above-mentioned means, it is not necessary to use an extra component, which is advantageous from the viewpoint of producing a nalfurafine-containing patch. It is.
However, as far as the present inventors know, no means has been proposed that focuses on a packaging container that contains a nalfurafine-containing patch in order to improve the temporal stability of nalfurafine in the patch.
Therefore, the present invention is a patch product comprising a nalfurafine-containing patch and a packaging bag, thereby improving the aging stability of nalfurafine in the patch by a packaging container containing the nalfurafine-containing patch. The present invention provides a patch product having excellent temporal stability of nalflaphine in a patch.
　本発明者らは、前記課題を解決するために鋭意研究を行い、ナルフラフィンを含有する貼付剤の経時安定性に優れる包装袋の構成を検討した。そしてその結果、本発明者らは、包装袋内の酸素濃度及び／又は水分量を減少させる手段を用いることにより、上記課題を解決できることを見出し、本発明を完成した。 In order to solve the above-mentioned problems, the present inventors have conducted intensive research and studied the configuration of a packaging bag having excellent temporal stability of a patch containing nalfraphine. As a result, the present inventors have found that the above problems can be solved by using means for reducing the oxygen concentration and / or the amount of water in the packaging bag, and have completed the present invention.
　すなわち、本発明は、
　包装袋と、該包装袋の内部に収容されたナルフラフィン含有貼付剤とを備える貼付剤製品であって、
　前記包装袋内の酸素濃度及び／又は水分量を減少させる手段を備えてなる貼付剤製品
に関する。 That is, the present invention
A patch product comprising a packaging bag and a nalflaphine-containing patch housed in the packaging bag,
The present invention relates to a patch product comprising means for reducing the oxygen concentration and / or the amount of water in the packaging bag.
　本発明によれば、さらに以下の実施態様の貼付剤製品が提供される。
［１］前記包装袋内の酸素濃度及び／又は水分量を減少させる手段として、前記包装袋が、吸湿性樹脂から形成された層及び酸素吸収剤を含有した層からなる群から選ばれる１種以上を含む、少なくとも２層以上の積層体から形成されてなる、前記貼付剤製品。
［２］前記包装袋内の酸素濃度及び／又は水分量を減少させる手段として、前記包装袋内に、吸湿剤及び／又は酸素吸収剤を含有したパウチを同封した、前記貼付剤製品。
［３］前記包装袋内の酸素濃度及び／又は水分量を減少させる手段として、前記包装袋内が窒素置換されている、前記貼付剤製品。
［４］前記包装袋が吸湿性樹脂から形成された層及び酸素吸収剤を含有した層からなる群から選ばれる１種以上をを含む、少なくとも２層以上の積層体同士の間に熱融着層を配してなる、前記貼付剤製品。
［５］前記貼付剤が支持体と、該支持体の少なくとも一方の面上に設けられたナルフラフィン含有粘着剤層と、該ナルフラフィン含有粘着剤層上に設けられた剥離シートとからなる貼付剤である、前記貼付剤製品。
［６］前記粘着剤層がゴム系粘着剤およびロジン樹脂を含む、前記貼付剤製品。
［７］前記粘着剤層がナルフラフィンの塩及び脱塩剤を含む、前記貼付剤製品。
　また、本発明は、吸湿性樹脂から形成された層及び酸素吸収剤を含有した層からなる群から選ばれる１種以上を含む、少なくとも２層以上の積層体から形成されてなるナルフラフィン含有貼付剤用包装袋に関する。 According to this invention, the patch product of the following embodiments is further provided.
[1] As a means for reducing the oxygen concentration and / or moisture content in the packaging bag, the packaging bag is selected from the group consisting of a layer formed of a hygroscopic resin and a layer containing an oxygen absorbent. The above-mentioned patch product comprising the above and comprising a laminate of at least two layers.
[2] The patch product, wherein a pouch containing a hygroscopic agent and / or an oxygen absorbent is enclosed in the packaging bag as means for reducing the oxygen concentration and / or the amount of water in the packaging bag.
[3] The patch product, wherein the inside of the packaging bag is replaced with nitrogen as means for reducing the oxygen concentration and / or the amount of water in the packaging bag.
[4] Heat-sealing between at least two layers of laminates, wherein the packaging bag includes one or more selected from the group consisting of a layer formed of a hygroscopic resin and a layer containing an oxygen absorbent. The patch product, comprising a layer.
[5] A patch in which the patch comprises a support, a nalfurafine-containing pressure-sensitive adhesive layer provided on at least one surface of the support, and a release sheet provided on the nalfurafine-containing pressure-sensitive adhesive layer. Said patch product.
[6] The patch product, wherein the pressure-sensitive adhesive layer contains a rubber-based pressure-sensitive adhesive and a rosin resin.
[7] The patch product, wherein the pressure-sensitive adhesive layer contains a salt of narfrafin and a desalting agent.
The present invention also relates to a nalflaphine-containing patch formed from a laminate of at least two layers containing at least one selected from the group consisting of a layer formed from a hygroscopic resin and a layer containing an oxygen absorbent. Related to packaging bags.
　本発明は、ナルフラフィン含有貼付剤を収容する包装袋内の酸素濃度及び／又は水分量を減少させる手段を用いることにより、ナルフラフィンの分解を抑制して、経時における薬物含量の低下を抑えることができるという効果を奏する。よって、本発明によれば、貼付剤中でのナルフラフィンの経時安定性に優れる貼付剤製品を提供することができるという効果を奏する。 The present invention can suppress degradation of drug content over time by suppressing the decomposition of nalfrafin by using means for reducing the oxygen concentration and / or the amount of water in the packaging bag containing the nalfurafine-containing patch. There is an effect. Therefore, according to this invention, there exists an effect that the patch product which is excellent in the temporal stability of the narfrafin in a patch can be provided.
　本発明の包装袋は、化学的に不安定な化合物の分解を抑制することができるという効果を奏する。よって、本発明の包装袋は、化学的に不安定な化合物又は該化合物を含有する薬剤、例えば、ナルフラフィン含有貼付剤を保存する包装袋に適している。 The packaging bag of the present invention has an effect that the decomposition of chemically unstable compounds can be suppressed. Therefore, the packaging bag of this invention is suitable for the packaging bag which preserve | saves the chemical unstable compound or the chemical | medical agent containing this compound, for example, a patch containing nalfraphine.
図１は、吸湿性樹脂から形成された層を含む積層体の断面図を示す図である。FIG. 1 is a cross-sectional view of a laminate including a layer formed from a hygroscopic resin. 図２は、酸素吸収剤を含有した層を含む積層体の断面図を示す図である。FIG. 2 is a cross-sectional view of a laminate including a layer containing an oxygen absorbent. 図３は、包装袋と、該包装袋の内部にナルフラフィン含有貼付剤と吸湿剤を含有するパウチとを備える貼付剤製品の一実施態様（ｉ）と、該包装袋を構成する積層体の断面図（ｉｉ）を示す図である。FIG. 3 shows one embodiment (i) of a patch product comprising a packaging bag, a pouch containing a nalfurafine-containing patch and a hygroscopic agent inside the packaging bag, and a cross section of a laminate constituting the packaging bag. It is a figure which shows figure (ii). 図４は、包装袋と、該包装袋の内部に貼付剤と酸素吸収剤を含有するパウチとを備える貼付剤製品の別の実施態様（ｉ）と、該包装袋を構成する積層体の断面図（ｉｉ）を示す図である。FIG. 4 shows another embodiment (i) of a patch product comprising a packaging bag, and a pouch containing a patch and an oxygen absorbent inside the packaging bag, and a cross section of the laminate constituting the packaging bag. It is a figure which shows figure (ii).
＜貼付剤製品＞
　本発明は、包装袋と、該包装袋の内部に収容されたナルフラフィン含有貼付剤とを備える貼付剤製品に関する。 <Patch product>
The present invention relates to a patch product comprising a packaging bag and a nalfurafine-containing patch housed in the packaging bag.
＜包装袋＞
　本発明で使用される包装袋は、該包装袋内の酸素濃度を減少させる手段、水分量を減少させる手段、又はその双方の手段を備えており、これにより、ナルフラフィン及びその塩の分解を抑制することができる。
　上記の包装袋内の酸素濃度及び／又は水分量を減少させる手段としては、包装袋内の酸素濃度及び／又は水分量を減少させることができれば特に限定されないが、吸湿性樹脂から形成された層及び酸素吸収剤を含有した層からなる群から選ばれる１種以上を含む、少なくとも２層以上の積層体から形成されてなる包装袋を使用する方法、包装袋内に吸湿剤及び／又は酸素吸収剤を含有したパウチを同封する方法、並びに包装袋内を窒素置換する方法が好ましい。その中でも、包装袋内の酸素濃度及び／又は水分量をより減少させる観点から、吸湿性樹脂から形成された層及び酸素吸収剤を含有した層からなる群から選ばれる１種以上を含む、少なくとも２層以上の積層体から形成されてなる包装袋を使用する方法、並びに包装袋内を窒素置換する方法がより好ましい。
　また本発明では、上記の包装袋内の酸素濃度及び／又は水分量を減少させる手段として、上記の方法を複数組み合わせて使用することができる。 <Packaging bag>
The packaging bag used in the present invention includes means for reducing the oxygen concentration in the packaging bag, means for reducing the amount of water, or both means, thereby suppressing the decomposition of nalfrafin and its salts. can do.
The means for reducing the oxygen concentration and / or moisture content in the packaging bag is not particularly limited as long as the oxygen concentration and / or moisture content in the packaging bag can be reduced, but the layer formed from a hygroscopic resin. And a method of using a packaging bag formed of a laminate of at least two layers including at least one selected from the group consisting of layers containing oxygen absorbent, a hygroscopic agent and / or oxygen absorption in the packaging bag A method of enclosing a pouch containing an agent and a method of replacing the inside of the packaging bag with nitrogen are preferred. Among them, from the viewpoint of further reducing the oxygen concentration and / or moisture content in the packaging bag, at least one selected from the group consisting of a layer formed from a hygroscopic resin and a layer containing an oxygen absorbent is included, at least A method of using a packaging bag formed from a laminate of two or more layers and a method of replacing the inside of the packaging bag with nitrogen are more preferable.
In the present invention, a plurality of the above methods can be used in combination as means for reducing the oxygen concentration and / or the amount of water in the packaging bag.
［特定の積層体から形成されてなる包装袋を使用する方法］
　上記の包装袋内の酸素濃度及び／又は水分量を減少させる手段として、吸湿性樹脂から形成された層及び酸素吸収剤を含有した層からなる群から選ばれる１種以上を含む、少なくとも２層以上の積層体から形成されてなる包装袋を使用する方法を用いた場合、これにより、ナルフラフィン及びその塩の分解を抑制することができる。
　なお本発明では、包装袋を構成する層として、吸湿性樹脂から形成された層及び酸素吸収剤を含有した層以外に、ポリエチレンから形成された層を使用してもよい。 [Method of using a packaging bag formed from a specific laminate]
As means for reducing the oxygen concentration and / or moisture content in the packaging bag, at least two layers comprising at least one selected from the group consisting of a layer formed from a hygroscopic resin and a layer containing an oxygen absorbent When using the method of using the packaging bag formed from the above laminated body, by this, decomposition | disassembly of nalfurafine and its salt can be suppressed.
In addition, in this invention, you may use the layer formed from polyethylene other than the layer formed from the hygroscopic resin and the layer containing the oxygen absorber as a layer which comprises a packaging bag.
　本発明で使用する包装袋は、吸湿性樹脂から形成された層及び酸素吸収剤を含有した層からなる群から選ばれる１種以上を含む、少なくとも２層以上の積層体から形成されていれば、その構成は特に限定されず、例えば、下記（１）及び（２）の実施形態をとることができる。 If the packaging bag used by this invention is formed from the laminated body of an at least 2 layer or more including 1 or more types chosen from the group which consists of the layer formed from the hygroscopic resin, and the layer containing an oxygen absorber. The configuration is not particularly limited, and for example, the following embodiments (1) and (2) can be taken.
（１）包装袋が吸湿性樹脂から形成された層構成からなる場合。
　本発明で使用する包装袋は、吸湿性樹脂から形成された層を含む、少なくとも２層以上の積層体を熱融着で貼り合わせて形成することができる。
　そして、上記積層体としては、例えば、包装袋の最内層としてシーラント層、該シーラント層より外側の層として吸湿性樹脂から形成されたフィルム又はシート層、及び吸湿性樹脂から形成されたフィルム又はシート層より外側の層として空気遮断層、及び必要により、該空気遮断層より外側の層として任意の樹脂フィルム等を夫々配した積層体を挙げることができる（図１参照）。 (1) The packaging bag has a layer structure formed from a hygroscopic resin.
The packaging bag used in the present invention can be formed by laminating at least two layers including a layer formed from a hygroscopic resin by heat-sealing.
And as said laminated body, for example, a sealant layer as an innermost layer of a packaging bag, a film or sheet layer formed from a hygroscopic resin as a layer outside the sealant layer, and a film or sheet formed from a hygroscopic resin Examples of the outer layer may include a laminate in which an air blocking layer is provided, and if necessary, an arbitrary resin film or the like is provided as an outer layer from the air blocking layer (see FIG. 1).
　包装袋の最内層はヒートシール可能な層、すなわちシーラント層が好ましい。
　前記シーラント層は、従来から知られているシーラント樹脂フィルムより形成され得るが、その中でも、ヒートシールのし易さの他、薬物非吸着能が高いものが好ましい。
　シーラント層としては、例えば、低密度ポリエチレン（ＬＤＰＥ）、直鎖状低密度ポリエチレン（Ｌ－ＬＤＰＥ）や高密度ポリエチレン（ＨＤＰＥ）などのポリエチレン樹脂フィルム；酸変性ポリエチレン、ポリプロピレン、酸変性ポリプロピレン、共重合ポリプロピレン、エチレン－ビニルアセテート共重合体（ＥＶＡ）、エチレン－（メタ）アクリル酸エステル共重合体、エチレン－（メタ）アクリル酸共重合体などのポリオレフィン系樹脂フィルム；ポリエチレンテレフタレート（ＰＥＴ）などのポリエステル系樹脂フィルム等が挙げられるが、ヒートシール性を考慮すると、特に、無延伸のポリプロピレン樹脂（以下ＰＰと表記することがある）フィルム、または、無延伸のポリエチレン樹脂（以下ＰＥと表記することがある）フィルムが好ましい。
　なお、本明細書において、（メタ）アクリル酸とは、アクリル酸とメタクリル酸の両方を表す。 The innermost layer of the packaging bag is preferably a heat-sealable layer, that is, a sealant layer.
The sealant layer may be formed from a conventionally known sealant resin film. Among them, a layer having a high drug non-adsorption ability in addition to easy heat sealing is preferable.
Examples of the sealant layer include polyethylene resin films such as low density polyethylene (LDPE), linear low density polyethylene (L-LDPE), and high density polyethylene (HDPE); acid-modified polyethylene, polypropylene, acid-modified polypropylene, copolymerization Polyolefin resin films such as polypropylene, ethylene-vinyl acetate copolymer (EVA), ethylene- (meth) acrylic acid ester copolymer, ethylene- (meth) acrylic acid copolymer; polyester such as polyethylene terephthalate (PET) In view of heat sealing properties, in particular, an unstretched polypropylene resin (hereinafter sometimes referred to as PP) film or an unstretched polyethylene resin (hereinafter referred to as PE). Yes) Beam is preferable.
In addition, in this specification, (meth) acrylic acid represents both acrylic acid and methacrylic acid.
　シーラント層は、ヒートシールして密閉包装袋を作製できる最低限の厚さを有し、１０μｍ～５０μｍ、例えば３０μｍが好ましい。 The sealant layer has a minimum thickness that can be heat sealed to produce a hermetic packaging bag, and is preferably 10 μm to 50 μm, for example, 30 μm.
　吸湿性樹脂から形成されたフィルム又はシート層とは、吸湿剤を樹脂に分散又は含有させて吸湿性を発現させた樹脂から形成されたフィルム又はシート層である。
　吸湿剤は、特に限定されないが、酸化バリウム、塩化カルシウム、硫酸マグネシウム、酸化カルシウム、硫酸カルシウム、塩化リチウム、過塩素酸リチウム、アルミナ、シリカゲル、ゼオライト等が用いられ、１つ以上を選択することができる。
　また、樹脂は、特に限定されないが、ポリオレフィン、特に低密度ポリエチレン（ＬＤＰＥ）が吸湿剤の分散性に優れているので好ましい。
　吸湿性樹脂から形成されたフィルム又はシートの形態としては、モイストキャッチ（登録商標）（共同印刷（株）製）が挙げられる。 The film or sheet layer formed from a hygroscopic resin is a film or sheet layer formed from a resin in which a hygroscopic agent is dispersed or contained in the resin to express hygroscopicity.
The hygroscopic agent is not particularly limited, and barium oxide, calcium chloride, magnesium sulfate, calcium oxide, calcium sulfate, lithium chloride, lithium perchlorate, alumina, silica gel, zeolite, etc. are used, and one or more may be selected. it can.
Further, the resin is not particularly limited, but polyolefin, particularly low density polyethylene (LDPE) is preferable because it is excellent in dispersibility of the hygroscopic agent.
Examples of the form of the film or sheet formed from the hygroscopic resin include Moist Catch (registered trademark) (manufactured by Kyodo Printing Co., Ltd.).
　吸湿性樹脂から形成されたフィルム又はシート層の外側に配する層は、空気中の水分がナルフラフィン及びその塩に影響するのを妨げる観点から、空気遮断層が好ましい。
　空気遮断層は、包装袋の外部からの空気の混入を遮断できる材料であればよく、例えばアルミニウム箔（以下、ＡＬとも称する）などの軟質金属箔の他、アルミ蒸着、シリカ蒸着、アルミナ蒸着、シリカアルミナ２元蒸着などの蒸着層などが採用できる。 The layer disposed on the outside of the film or sheet layer formed from the hygroscopic resin is preferably an air blocking layer from the viewpoint of preventing moisture in the air from affecting nalfrafin and its salt.
The air barrier layer only needs to be a material that can block the entry of air from the outside of the packaging bag. For example, in addition to a soft metal foil such as an aluminum foil (hereinafter also referred to as AL), aluminum deposition, silica deposition, alumina deposition, A vapor deposition layer such as silica alumina binary vapor deposition can be employed.
（２）包装袋が酸素吸収剤を含有した層構成からなる場合。
　本発明で使用する包装袋は、酸素吸収剤を含有した層を含む、少なくとも２層以上の積層体を熱融着で貼り合わせて形成することができる。
　そして、上記積層体としては、例えば、包装袋の最内層としてシーラント層、該シーラント層より外側の層として酸素吸収剤を含有したフィルム又はシート層、及び酸素吸収剤を含有したフィルム又はシート層より外側の層として空気遮断層、及び必要により、該空気遮断層より外側の層として任意の樹脂フィルム等を夫々配した積層体を挙げることができる（図２参照）。 (2) The packaging bag has a layer structure containing an oxygen absorbent.
The packaging bag used in the present invention can be formed by laminating at least two laminated bodies including a layer containing an oxygen absorbent by heat fusion.
And as said laminated body, for example, from a sealant layer as an innermost layer of a packaging bag, a film or sheet layer containing an oxygen absorbent as a layer outside the sealant layer, and a film or sheet layer containing an oxygen absorbent Examples of the outer layer include an air barrier layer, and if necessary, a laminate in which an arbitrary resin film or the like is disposed as an outer layer from the air barrier layer (see FIG. 2).
　包装袋の最内層はヒートシール可能な層、すなわちシーラント層が好ましい。前記シーラント層は、前述の（１）で示したシーラント層を用いることができる。 The innermost layer of the packaging bag is preferably a heat-sealable layer, that is, a sealant layer. As the sealant layer, the sealant layer shown in the above (1) can be used.
　酸素吸収剤としては、特に制限を受けるものではないが、無機酸化物のほか、電解質からなる混合物、還元性の無機塩、ポリフェノール類、還元性糖類、還元剤、不飽和脂肪酸化合物、不飽和有機化合物、熱可塑性重合物、酸素吸収促進物質を含む組成物、又はそれらの混合系が挙げられる。
　酸素吸収剤を含有する包装材料としては、例えばフィルム又はシートの形態として、オキシガード（登録商標）（東洋製罐（株）製）、オキシキャッチ（登録商標）（共同印刷（株）製）、エージレスオーマック（三菱ガス化学（株）製）が挙げられる。 The oxygen absorbent is not particularly limited, but in addition to inorganic oxides, mixtures made of electrolytes, reducing inorganic salts, polyphenols, reducing sugars, reducing agents, unsaturated fatty acid compounds, unsaturated organic compounds Examples thereof include a compound, a thermoplastic polymer, a composition containing an oxygen absorption promoting substance, or a mixed system thereof.
As a packaging material containing an oxygen absorbent, for example, in the form of a film or sheet, Oxygard (registered trademark) (manufactured by Toyo Seikan Co., Ltd.), Oxycatch (registered trademark) (manufactured by Kyodo Printing Co., Ltd.), AGELESS OMAC (Mitsubishi Gas Chemical Co., Ltd.) is mentioned.
　酸素吸収剤を含有したフィルム又はシート層の外側に配する層は、空気中の水分がナルフラフィン及びその塩に影響するのを妨げる観点から、空気遮断層が好ましい。前記空気遮断層は、前述の（１）で示した空気遮断層を用いることができる。 The layer disposed on the outside of the film or sheet layer containing the oxygen absorbent is preferably an air blocking layer from the viewpoint of preventing moisture in the air from affecting nalfrafin and salts thereof. As the air blocking layer, the air blocking layer shown in the above (1) can be used.
　上述した包装袋の中でも、本発明で使用する包装袋としては、ナルフラフィン及びその塩の分解をより抑制する観点から、吸湿性樹脂から形成された層及び／又は酸素吸収剤を含有した層を含む、少なくとも２層以上の積層体同士の間に熱融着層を配してなるものが特に好ましい。
　熱融着層は、加熱により溶融して熱融着する熱融着性樹脂よりなり、吸湿性樹脂から形成された層及び／又は酸素吸収剤を含有した層を含む積層体同士の間を熱融着するものである。
　熱融着性樹脂としては、熱融着可能な樹脂であれば特に限定されないが、例えば、ポリエチレン、ポリプロピレン、エチレン－酢酸ビニル共重合体、エチレン－メタクリル酸共重合体、エチレン－メタクリル酸エステル共重合体、エチレン－アクリル酸共重合体、及びエチレン－アクリル酸エステル共重合体などが挙げられる。 Among the packaging bags described above, the packaging bag used in the present invention includes a layer formed from a hygroscopic resin and / or a layer containing an oxygen absorbent from the viewpoint of further suppressing the decomposition of nalfurafine and its salt. Particularly preferred are those in which a heat-sealing layer is disposed between at least two laminates.
The heat-fusible layer is made of a heat-fusible resin that melts and heat-fuses by heating, and heats between laminates including a layer formed from a hygroscopic resin and / or a layer containing an oxygen absorbent. To be fused.
The heat-sealable resin is not particularly limited as long as it is a heat-sealable resin. For example, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, ethylene-methacrylic acid copolymer, ethylene-methacrylic acid ester copolymer Examples thereof include a polymer, an ethylene-acrylic acid copolymer, and an ethylene-acrylic acid ester copolymer.
　本発明で使用する包装袋は、吸湿性樹脂から形成された層及び酸素吸収剤を含有した層からなる群から選ばれる１種以上を含む、少なくとも２層以上の積層体からなるものであって、該積層体は、例えば、前述の積層構成を有していればよく、必要に応じて任意の樹脂フィルム等を含む積層構成としてもよい。
　上記の任意の樹脂フィルム等としては、例えば包装袋の層構成として用いることのできる密封性や遮光性の高いものとして、ポリエチレンフィルム、ポリプロピレンフィルム、ポリメチルペンテンフィルム等のポリオレフィン系樹脂フィルム；ポリ塩化ビニルフィルム、ポリ塩化ビニリデンフィルム、ポリビニルアルコールフィルム、ポリスチレンフィルム、ポリアクリロニトリルフィルム、アイオノマーフィルム等のビニル系樹脂フィルム；ポリエチレンテレフタレートフィルム等のポリエステル系樹脂フィルム；ナイロンフィルム等のポリアミド系樹脂フィルム；セロファン等のセルロース系樹脂フィルム；ポリカーボネート樹脂フィルム；及びこれらの積層フィルム等が挙げられる。また、上記の任意の樹脂フィルム等としては、密封性に加えて、遮光性を高めるものとして、上述の樹脂フィルム及びそれらの積層フィルム等と軟質アルミ箔（以下ＡＬと略す場合がある）の積層フィルムや、上述の樹脂フィルムにおいて黒色顔料等を添加した顔料添加樹脂フィルム等が挙げられる。上記の任意の樹脂フィルム等において、これら樹脂フィルム、積層フィルム等は種々組み合わせて積層体として用いることができる。
　その他、包装袋の構成としてエチレン－ビニルアルコール共重合体（以下、ＥＶＯＨとも称する）、または環状ポリオレフィンフィルム（以下、ＣＯＣとも称する）を含む積層体から形成されることが考えられる。 The packaging bag used in the present invention is composed of a laminate of at least two layers including at least one selected from the group consisting of a layer formed from a hygroscopic resin and a layer containing an oxygen absorbent. For example, the laminated body only needs to have the above-described laminated structure, and may have a laminated structure including an arbitrary resin film or the like as necessary.
As said arbitrary resin film etc., polyolefin-type resin films, such as a polyethylene film, a polypropylene film, a polymethylpentene film, etc. as a thing with high sealing property and light-shielding property which can be used, for example as a layer structure of a packaging bag; Vinyl resin film such as vinyl film, polyvinylidene chloride film, polyvinyl alcohol film, polystyrene film, polyacrylonitrile film, ionomer film; polyester resin film such as polyethylene terephthalate film; polyamide resin film such as nylon film; cellophane, etc. Cellulosic resin films; polycarbonate resin films; and laminated films thereof. Moreover, as said arbitrary resin film etc., in order to improve light-shielding property in addition to sealing properties, the above-mentioned resin films and their laminated films are laminated with soft aluminum foil (hereinafter sometimes abbreviated as AL). Examples thereof include a film and a pigment-added resin film obtained by adding a black pigment or the like to the above-described resin film. In the above arbitrary resin films, etc., these resin films, laminated films, etc. can be used in various combinations as a laminate.
In addition, the packaging bag may be formed from a laminate including an ethylene-vinyl alcohol copolymer (hereinafter also referred to as EVOH) or a cyclic polyolefin film (hereinafter also referred to as COC).
　本発明で使用する包装袋に用いる好ましい積層体の具体的な積層構成の一例として、ナルフラフィン及びその塩をより安定にする観点から、包装袋の最内層からポリエチレン（ＰＥ）／吸湿性樹脂から形成された層又は酸素吸着剤を含有した層／ＡＬ／ポリエステルなどの構成が挙げられる。
　上記積層体は、ドライラミネート、押出ラミネート又は共押し出しラミネートにより製造でき、積層体の厚さは１０μｍ～１００μｍ程度とすることができる。それぞれの層は直接積層されるか、接着剤などを介して積層される。層間を接着剤で接着する場合は、薬物吸着の少ない接着剤を使用することが望ましい。例えば、トルエンジイソシアネート（ＴＤＩ）やジフェニルメタンジイソシアネート（ＭＤＩ）等のイソシアネートを接着剤として用いるか、或いはポリオール等を配合したポリウレタン接着剤を用いることができる。
　包装体は、ナルフラフィン含有貼付剤よりも一回り大きく形成する。貼付剤の面積は適宜決定することができるが、薬剤が包材内で揮散して支持体に付着する量をできるだけ少なくし、かつ貼付しやすさを考慮すると、好ましくは１ｃｍ２～２５ｃｍ２である。 As an example of a specific laminated structure of a preferable laminate used in the packaging bag used in the present invention, from the viewpoint of making nalfrafin and its salt more stable, it is formed from the innermost layer of the packaging bag from polyethylene (PE) / hygroscopic resin. Or a layer containing an oxygen adsorbent / AL / polyester.
The laminate can be produced by dry lamination, extrusion lamination, or coextrusion lamination, and the thickness of the laminate can be about 10 μm to 100 μm. Each layer is laminated directly or via an adhesive or the like. When the layers are bonded with an adhesive, it is desirable to use an adhesive with little drug adsorption. For example, an isocyanate such as toluene diisocyanate (TDI) or diphenylmethane diisocyanate (MDI) can be used as an adhesive, or a polyurethane adhesive containing a polyol or the like can be used.
The package is formed to be slightly larger than the patch containing nalflavine. The area of the patch can be determined as appropriate, but it is preferably 1 cm 2 to 25 cm 2 in view of minimizing the amount of the drug volatilized in the packaging material and adhering to the support as much as possible and considering the ease of application. is there.
　なお、本発明で使用する包装袋を構成する積層体において、アルミニウムを含むプラスチックラミネートフィルム素材を採用した場合、プラスチックラミネートフィルムの具有する引裂き強度が高く、手で開封することが難しいため、Ｖ形ノッチやＩ形ノッチを複数設けることが好ましい。 In addition, in the laminated body which comprises the packaging bag used by this invention, when the plastic laminate film raw material containing aluminum is employ | adopted, since the tear strength which the plastic laminate film has is high and it is difficult to open by hand, it is V shape. It is preferable to provide a plurality of notches and I-shaped notches.
［包装袋内にパウチを同封する方法］
　上記の包装袋内の酸素濃度及び／又は水分量を減少させる手段として、包装袋内に吸湿剤を含有したパウチ、酸素吸収剤を含有したパウチ、又はその双方を含有したパウチを同封する方法を用いた場合、包装袋内に同封した、吸湿剤及び／又は酸素吸収剤を含有したパウチにより、ナルフラフィン及びその塩の分解を抑制することができる。 [Method of enclosing a pouch in a packaging bag]
As a means for reducing the oxygen concentration and / or the amount of water in the packaging bag, a method of enclosing a pouch containing a hygroscopic agent, a pouch containing an oxygen absorbent, or both in the packaging bag. When used, the pouch containing the hygroscopic agent and / or the oxygen absorbent enclosed in the packaging bag can suppress the decomposition of nalfurafine and its salt.
　本発明において、包装袋内に吸湿剤及び／又は酸素吸収剤を含有したパウチを同封する形態としては、例えば、下記（３）及び（４）の実施形態をとることができる。 In the present invention, for example, the following embodiments (3) and (4) can be taken as a form in which a pouch containing a hygroscopic agent and / or an oxygen absorbent is enclosed in the packaging bag.
（３）貼付剤製品１が、包装袋２と、該包装袋の内部にナルフラフィン含有貼付剤（以下、単に貼付剤とも称する）３と吸湿剤を含有したパウチ４とを備える場合［図３（ｉ）参照。なお図３では包装袋内部の雰囲気について略す。］。
　上記包装袋としては、例えば、包装袋の最内層としてシーラント層、該シーラント層より外側の層として空気遮断層、及び必要により、該空気遮断層より外側の層として任意の樹脂フィルム等を夫々配した積層体を挙げることができる［図３（ｉｉ）参照］。 (3) When the patch product 1 is provided with a packaging bag 2, a nalfrafin-containing patch (hereinafter also simply referred to as a patch) 3 and a pouch 4 containing a hygroscopic agent inside the packaging bag [FIG. i) See. In FIG. 3, the atmosphere inside the packaging bag is omitted. ].
Examples of the packaging bag include a sealant layer as the innermost layer of the packaging bag, an air barrier layer as an outer layer from the sealant layer, and an optional resin film as a layer outside the air barrier layer as necessary. Can be mentioned [see FIG. 3 (ii)].
　包装袋の最内層はヒートシール可能な層、すなわちシーラント層が好ましい。前記シーラント層は、前述の（１）で示したシーラント層を用いることができる。
　シーラント層の外側に配する層は、空気中の水分がナルフラフィン及びその塩に影響するのを妨げる観点から、空気遮断層が好ましい。前記空気遮断層は、前述の（１）で示した空気遮断層を用いることができる。
　また、任意の樹脂フィルム等は前述した任意の樹脂フィルム等を用いることができる。
　さらに、前記吸湿剤を含有したパウチとしては、吸湿剤が包装袋内部の湿気を吸湿することができる形態であれば、特に制限されないが、例えば、上記（１）で挙げた吸湿剤を不織布等で覆って袋状とするか、吸湿剤を不織布等に含ませてシート状とすることが好ましい。 The innermost layer of the packaging bag is preferably a heat-sealable layer, that is, a sealant layer. As the sealant layer, the sealant layer shown in the above (1) can be used.
The layer disposed on the outer side of the sealant layer is preferably an air barrier layer from the viewpoint of preventing moisture in the air from affecting nalflavine and its salt. As the air blocking layer, the air blocking layer shown in the above (1) can be used.
Moreover, the arbitrary resin films etc. which were mentioned above can be used for arbitrary resin films.
Further, the pouch containing the hygroscopic agent is not particularly limited as long as the hygroscopic agent can absorb moisture inside the packaging bag. For example, the hygroscopic agent mentioned in the above (1) may be a nonwoven fabric or the like. It is preferable to cover it with a bag or to add a hygroscopic agent to a nonwoven fabric or the like to form a sheet.
（４）貼付剤製品１０が、包装袋２と、該包装袋の内部に貼付剤３と酸素吸収剤を含有したパウチ５とを備える場合［図４（ｉ）参照。なお図４では包装袋内部の雰囲気について略す。］。
　上記包装袋としては、例えば、包装袋の最内層としてシーラント層、該シーラント層より外側の層として空気遮断層、及び必要により、該空気遮断層より外側の層として任意の樹脂フィルム等を夫々配した積層体を挙げることができる［図４（ｉｉ）参照］。 (4) When the patch product 10 includes the packaging bag 2 and the pouch 5 containing the patch 3 and the oxygen absorbent inside the packaging bag [see FIG. 4 (i). In FIG. 4, the atmosphere inside the packaging bag is omitted. ].
Examples of the packaging bag include a sealant layer as the innermost layer of the packaging bag, an air barrier layer as an outer layer from the sealant layer, and an optional resin film as a layer outside the air barrier layer as necessary. Can be mentioned [see FIG. 4 (ii)].
　包装袋の最内層はヒートシール可能な層、すなわちシーラント層が好ましい。前記シーラント層は、前述の（１）で示したシーラント層を用いることができる。
　シーラント層の外側に配する層は、空気中の水分がナルフラフィン及びその塩に影響するのを妨げる観点から、空気遮断層が好ましい。前記空気遮断層は、前述の（１）で示した空気遮断層を用いることができる。
　また、任意の樹脂フィルム等は前述した任意の樹脂フィルム等を用いることができる。
　さらに、前記酸素吸収剤を含有したパウチとしては、酸素吸収剤が包装袋中の酸素濃度を低下することができる形態であれば、特に制限されないが、例えば、上記（２）で挙げた酸素吸収剤を不織布等で覆って袋状とすることが好ましい。 The innermost layer of the packaging bag is preferably a heat-sealable layer, that is, a sealant layer. As the sealant layer, the sealant layer shown in the above (1) can be used.
The layer disposed on the outer side of the sealant layer is preferably an air barrier layer from the viewpoint of preventing moisture in the air from affecting nalflavine and its salt. As the air blocking layer, the air blocking layer shown in the above (1) can be used.
Moreover, the arbitrary resin films etc. which were mentioned above can be used for arbitrary resin films.
Further, the pouch containing the oxygen absorbent is not particularly limited as long as the oxygen absorbent can reduce the oxygen concentration in the packaging bag. For example, the oxygen absorbent mentioned in (2) above. The agent is preferably covered with a non-woven fabric to form a bag.
［包装袋内を窒素置換する方法］
　上記の包装袋内の酸素濃度及び／又は水分量を減少させる手段として、包装袋内を窒素置換する方法を採用する場合、包装袋内を窒素で充満させることにより、空気中の酸素及び水分によるナルフラフィン及びその塩の分解を抑制することができる。 [Method of replacing the inside of the packaging bag with nitrogen]
As a means for reducing the oxygen concentration and / or the amount of water in the packaging bag, when the method of replacing the inside of the packaging bag with nitrogen is adopted, the packaging bag is filled with nitrogen, thereby causing oxygen and moisture in the air. Decomposition of nalfurafine and its salt can be suppressed.
　包装袋内を窒素置換する方法としては、公知の方法を用いることができ、例えば、包装袋内を真空にした後、窒素を注入する方法等が挙げられる。 As a method for replacing the inside of the packaging bag with nitrogen, a known method can be used, for example, a method of injecting nitrogen after evacuating the inside of the packaging bag.
＜貼付剤製品の製造方法＞
　本発明の貼付剤製品の製造方法としては、特に制限はないが、例えば、本発明で使用する包装袋に用いる吸湿性樹脂から形成された層及び酸素吸収剤を含有した層からなる群から選ばれる１種以上を含む、少なくとも２層以上の積層体同士を貼付剤の大きさよりも大きい枠として、３辺を熱融着により貼り合わせて袋状として、貼付剤を封入後、残りの１辺を熱融着して、封入することにより、本発明の貼付剤製品を得ることができる。
　また、本発明の貼付剤製品の製造方法としては、包装袋に用いる好ましい積層体同士を貼付剤の大きさよりも大きい枠として、３辺を熱融着により貼り合わせて袋状として、貼付剤並びに吸湿剤及び／又は酸素吸収剤を含有したパウチを封入後、残りの１辺を熱融着して、封入することにより、本発明の貼付剤製品を得ることができる。 <Manufacturing method of patch products>
The method for producing the patch product of the present invention is not particularly limited. For example, the patch product is selected from the group consisting of a layer formed from a hygroscopic resin used in the packaging bag used in the present invention and a layer containing an oxygen absorbent. One or more of the laminates containing at least two layers are framed larger than the size of the patch, and three sides are bonded together by heat fusion to form a bag, and after the patch is sealed, the remaining one side The patch product of the present invention can be obtained by heat-sealing and encapsulating.
In addition, as a method for producing the patch product of the present invention, preferable laminates used for packaging bags are frames larger than the size of the patch, and three sides are bonded together by heat fusion to form a bag, After enclosing a pouch containing a hygroscopic agent and / or an oxygen absorbent, the remaining one side is heat-sealed and encapsulated, whereby the patch product of the present invention can be obtained.
　また、ナルフラフィンが一層安定する観点から、包装袋内の水分含量又は酸素含量は低いことが好ましく、公知の方法で包装袋内の水分濃度又は酸素濃度を低下させることができる。
　例えば、包装袋内の雰囲気を真空ガス包装機等で窒素置換及び充満させることにより、包装袋内部の水分含量や残存酸素濃度を減じることができる。本工程における雰囲気の状態は、窒素置換を行う工程に設置した測定装置で、水分含量や酸素含量を測定するか、直接包装袋内に封入できる測定装置を用いることによって、測定できる。直接包装袋内に封入できる測定装置では、貼付剤製品について、経時的に包装袋内の水分含量や酸素濃度について測定することができる。
　貼付剤製品中の包装袋内の、好ましい水分含量（濃度）は、２５℃で相対湿度２５％に相当する水分量以下、残存酸素濃度は１０体積％以下である。
　また、貼付剤の水分量は、赤外水分計で測定することができ、初期値を１００％としたとき、６０℃、１ヶ月間恒温室で保存後の変化率（水分減少率）は、２０～７０％が好ましく、特に２５～５０％が好ましい。 In addition, from the viewpoint of further stabilizing narfrafin, the moisture content or oxygen content in the packaging bag is preferably low, and the moisture concentration or oxygen concentration in the packaging bag can be lowered by a known method.
For example, the moisture content and residual oxygen concentration inside the packaging bag can be reduced by substituting and filling the atmosphere inside the packaging bag with a vacuum gas packaging machine or the like. The state of the atmosphere in this step can be measured by measuring the moisture content or oxygen content with a measuring device installed in the step of performing nitrogen substitution, or by using a measuring device that can be directly enclosed in a packaging bag. With the measuring device that can be directly enclosed in the packaging bag, the moisture content and oxygen concentration in the packaging bag can be measured over time for the patch product.
The preferable moisture content (concentration) in the packaging bag in the patch product is not more than the amount of moisture corresponding to a relative humidity of 25% at 25 ° C., and the residual oxygen concentration is not more than 10% by volume.
The moisture content of the patch can be measured with an infrared moisture meter. When the initial value is 100%, the rate of change after storage in a constant temperature room at 60 ° C. for 1 month (water reduction rate) is: It is preferably 20 to 70%, particularly preferably 25 to 50%.
　また、上記の包装袋、すなわち、吸湿性樹脂から形成された層及び酸素吸収剤を含有した層からなる群から選ばれる１種以上を含む、少なくとも２層以上の積層体から形成されてなるナルフラフィン含有貼付剤用の包装袋も本発明の対象である。 Further, the above-mentioned packaging bag, that is, a narfrafin formed from a laminate of at least two layers including at least one selected from the group consisting of a layer formed from a hygroscopic resin and a layer containing an oxygen absorbent. Packaging bags for containing patches are also the subject of the present invention.
＜ナルフラフィン含有貼付剤＞
　以下に本発明の貼付剤製品におけるナルフラフィン含有貼付剤（以下、単に貼付剤とも称する）について詳述する。貼付剤は、支持体と、該支持体の少なくとも一方の面上に設けられたナルフラフィン含有粘着剤層と、該ナルフラフィン含有粘着剤層上に設けられた剥離シートを含む構成である。 <Nalflaphine-containing patch>
In the following, the nalfrafin-containing patch (hereinafter also simply referred to as patch) in the patch product of the present invention will be described in detail. The patch includes a support, a nalfurafine-containing pressure-sensitive adhesive layer provided on at least one surface of the support, and a release sheet provided on the nalfurafine-containing pressure-sensitive adhesive layer.
［支持体］
　本発明の貼付剤製品における貼付剤に用いる支持体としては、フィルム、不織布、和紙、綿布、編布、織布、不織布とフィルムのラミネート複合体等の柔軟性を有する支持体が挙げられる。
　これらの支持体は、皮膚に密着することができ、かつ、皮膚の動きに追随することができる程度の柔軟な材質、そして長時間貼付後において皮膚のかぶれ等の発生を抑制できる材質が好ましい。これらの支持体の材質としては、例えば、ポリエチレン、ポリプロピレン、ポリエチレンテレフタレート等が挙げられる。
　前記支持体の大きさとしては、特に制限はなく、目的に応じて適宜選択することができる。 [Support]
Examples of the support used for the patch in the patch product of the present invention include flexible supports such as films, nonwoven fabrics, Japanese paper, cotton cloth, knitted fabrics, woven fabrics, and laminate composites of nonwoven fabrics and films.
These supports are preferably made of a flexible material that can adhere to the skin and can follow the movement of the skin, and a material that can suppress the occurrence of skin irritation after being applied for a long time. Examples of the material of these supports include polyethylene, polypropylene, polyethylene terephthalate, and the like.
There is no restriction | limiting in particular as a magnitude | size of the said support body, According to the objective, it can select suitably.
［粘着剤層］
　本発明の貼付剤製品における貼付剤において、粘着剤層を構成する粘着剤は特に限定されるものではなく、ゴム系粘着剤、アクリル系粘着剤、シリコーン系粘着剤、ウレタン系粘着剤、ハイドロコロイド系粘着剤などが挙げられるが、特に好ましくはゴム系粘着剤である。
　前記粘着剤層の構造としては、１層構造でもよく、多層構造であってもよい。前記粘着剤層が多層構造である場合は、ナルフラフィンはそのうちの１層以上に含まれていればよい。
　特に好ましい形態としては、前記粘着剤層は、（ａ）エラストマー、（ｂ）テルペン樹脂とロジン樹脂から選択される粘着付与剤１種以上、（ｃ）ナルフラフィン及びその塩の少なくともいずれか、並びに（ｄ）脱塩剤を含有し、更に必要に応じてその他の成分を含有してなる。
　本発明の貼付剤製品における貼付剤中の粘着剤層は非水系で構成し、製造工程上、意図的に水を添加することは行わない。 [Adhesive layer]
In the patch of the patch product of the present invention, the pressure-sensitive adhesive constituting the pressure-sensitive adhesive layer is not particularly limited, and rubber-based pressure-sensitive adhesive, acrylic pressure-sensitive adhesive, silicone pressure-sensitive adhesive, urethane pressure-sensitive adhesive, hydrocolloid-based Although an adhesive etc. are mentioned, Especially preferably, it is a rubber-type adhesive.
The pressure-sensitive adhesive layer may have a single-layer structure or a multilayer structure. In the case where the pressure-sensitive adhesive layer has a multilayer structure, the narfrafin may be contained in one or more of them.
In a particularly preferred form, the pressure-sensitive adhesive layer comprises (a) an elastomer, (b) one or more tackifiers selected from terpene resins and rosin resins, (c) at least one of nalflavine and salts thereof, and ( d) It contains a desalting agent and further contains other components as required.
The pressure-sensitive adhesive layer in the patch in the patch product of the present invention is composed of a non-aqueous system, and water is not intentionally added in the manufacturing process.
（ａ）エラストマー
　前記エラストマーとしては、特に制限はなく、目的に応じて適宜選択することができる。例えば、スチレン－イソプレン－スチレンブロック共重合体である、ＳＩＳ５００２（ＪＳＲ株式会社製）及びクインタック３５２０（日本ゼオン株式会社製）などが挙げられる。
　前記エラストマーは、１種単独で使用してもよいし、２種以上を併用してもよい。 (A) Elastomer There is no restriction | limiting in particular as said elastomer, According to the objective, it can select suitably. Examples thereof include SIS5002 (manufactured by JSR Corporation) and quinac 3520 (manufactured by Nippon Zeon Corporation), which are styrene-isoprene-styrene block copolymers.
The said elastomer may be used individually by 1 type, and may use 2 or more types together.
　前記エラストマーの前記粘着剤層における含有量としては、目的に応じて適宜選択することができるが、１５質量％以上が好ましく、２０質量％以上がより好ましく、３０質量％以上がさらに好ましい。また、６０質量％以下が好ましく、５０質量％以下がより好ましく、４０質量％以下がさらに好ましい。 The content of the elastomer in the pressure-sensitive adhesive layer can be appropriately selected according to the purpose, but is preferably 15% by mass or more, more preferably 20% by mass or more, and further preferably 30% by mass or more. Moreover, 60 mass% or less is preferable, 50 mass% or less is more preferable, and 40 mass% or less is further more preferable.
（ｂ）粘着付与剤
　前記粘着付与剤としては、粘着性を向上させるものであれば特に制限はないが、テルペン樹脂とロジン樹脂から選択される粘着付与剤１種以上を含有することが好ましい。
　前記テルペン樹脂としては、例えば、β－ピネン樹脂、α－ピネン樹脂、テルペン－フェノール樹脂、芳香族変性テルペン樹脂、水添テルペン樹脂などが挙げられる。
　前記ロジン樹脂としては、例えば、ガムロジン、トール油ロジン、ウッドロジン等のロジン；水添ロジン、不均化ロジン、重合ロジン、マレイン化ロジン等の変性ロジン；ロジングリセリンエステル、水添ロジンエステル、水添ロジングリセリンエステル等のロジンエステル；などが挙げられる。
　前記粘着付与剤としては、例えば、ＹＳレジンＰＸ１１５０Ｎ（ヤスハラケミカル株式会社製）、及びパインクリスタルＫＥ－３１１（荒川化学工業株式会社製）などが挙げられる。
　前記粘着付与剤は、１種単独で使用してもよいし、２種以上を併用してもよい。また、前記テルペン樹脂と前記ロジン樹脂から選択される粘着付与剤を組み合わせてもよい。特に、ナルフラフィンの安定性の点で、ロジン樹脂が好ましい。 (B) Tackifier There are no particular limitations on the tackifier as long as it improves tackiness, but it is preferable to contain one or more tackifiers selected from terpene resins and rosin resins.
Examples of the terpene resin include β-pinene resin, α-pinene resin, terpene-phenol resin, aromatic modified terpene resin, hydrogenated terpene resin and the like.
Examples of the rosin resin include rosins such as gum rosin, tall oil rosin, and wood rosin; hydrogenated rosin, disproportionated rosin, polymerized rosin, modified rosin such as maleated rosin; rosin glycerin ester, hydrogenated rosin ester, hydrogenated Rosin ester such as rosin glycerin ester; and the like.
Examples of the tackifier include YS resin PX1150N (manufactured by Yasuhara Chemical Co., Ltd.) and Pine Crystal KE-311 (manufactured by Arakawa Chemical Industries, Ltd.).
The said tackifier may be used individually by 1 type, and may use 2 or more types together. Moreover, you may combine the tackifier selected from the said terpene resin and the said rosin resin. In particular, rosin resin is preferable from the viewpoint of stability of narfrafin.
　前記粘着付与剤の前記粘着剤層における含有量としては、特に制限はなく、目的に応じて適宜選択することができるが、１０質量％以上が好ましく、１５質量％以上がより好ましい。また、５０質量％以下が好ましく、４０質量％以下がより好ましく、３０質量％以下がさらに好ましい。 There is no restriction | limiting in particular as content in the said adhesive layer of the said tackifier, Although it can select suitably according to the objective, 10 mass% or more is preferable and 15 mass% or more is more preferable. Moreover, 50 mass% or less is preferable, 40 mass% or less is more preferable, and 30 mass% or less is further more preferable.
（ｃ）ナルフラフィン及びその塩の少なくともいずれか
　前記のナルフラフィンは、ナルフラフィンのフリー体を使用することもできるが、ナルフラフィンの塩として、粘着剤層中に配合されることが好ましい。前記ナルフラフィンの塩は、後述する脱塩剤により、フリー体に変換される。
　前記ナルフラフィンの塩としては、薬学的に許容される塩であれば、特に制限はないが、皮膚透過性の点で、ナルフラフィンの酸付加塩が好ましい。酸付加塩としては、塩酸塩、酢酸塩、マレイン酸塩、シュウ酸塩などが挙げられる。これらの中でも、皮膚透過性の点で、ナルフラフィン塩酸塩が好ましい。
　前記ナルフラフィンの塩は、１種単独で使用してもよいし、２種以上を併用してもよい。 (C) At least one of Nalflaphine and its salt As the above-mentioned nalfurafine, a free form of nalfurafine can be used, but it is preferably blended in the pressure-sensitive adhesive layer as a salt of nalfurafine. The salt of narfrafin is converted into a free form by a desalting agent described later.
The salt of nalfurafine is not particularly limited as long as it is a pharmaceutically acceptable salt, but an acid addition salt of nalfurafine is preferable from the viewpoint of skin permeability. Examples of the acid addition salt include hydrochloride, acetate, maleate, and oxalate. Among these, nalfrafin hydrochloride is preferable from the viewpoint of skin permeability.
The nalflaphine salt may be used alone or in combination of two or more.
　前記ナルフラフィンの塩の前記粘着剤層における含有量としては、０．１質量％以上が好ましく、０．２質量％以上がより好ましい。また、皮膚透過性、及び皮膚刺激性の点で、５．０質量％以下が好ましく、４．０質量％以下がより好ましく、３．０質量％以下がさらに好ましい。
　前記ナルフラフィンの塩の代わりに、ナルフラフィンのフリー体を用いる場合も、前記ナルフラフィンの塩の含有量と同様の量を、粘着剤層に配合することができる。
　本発明において、ナルフラフィンと記載した場合、特に断りのない場合は、ナルフラフィンのフリー体及びこれらの薬学的に許容される塩の両方を指す。 As content in the said adhesive layer of the salt of the said nalfurafine, 0.1 mass% or more is preferable, and 0.2 mass% or more is more preferable. Moreover, 5.0 mass% or less is preferable at the point of skin permeability and skin irritation, 4.0 mass% or less is more preferable, and 3.0 mass% or less is further more preferable.
Even when a free form of nalfurafine is used in place of the nalflaphine salt, an amount similar to the content of the nalfurafine salt can be added to the pressure-sensitive adhesive layer.
In the present invention, when it is described as nalflavine, it refers to both a free form of nalflaphine and a pharmaceutically acceptable salt thereof unless otherwise specified.
（ｄ）脱塩剤
　前記脱塩剤としては、前記ナルフラフィンの塩をフリー体に変換するものであれば、特に制限はなく、目的に応じて適宜選択することができるが、例えば、モノエタノールアミン、炭酸水素ナトリウム、及びアミノ基を有するポリマー化合物の少なくともいずれかが好ましい。
　前記脱塩剤の含有量としては、目的に応じて適宜選択することができるが、皮膚刺激性、及び皮膚透過性の点で、前記ナルフラフィンの塩１モルに対し、５モル以上であることが好ましく、１０モル以上であることがより好ましい。また、３０モル以下であることが好ましく、２５モル以下であることがより好ましい。
　前記脱塩剤の配合方法としては、製造工程中１回で行ってもよく、数回に分けて行ってもよい。 (D) Desalting agent The desalting agent is not particularly limited as long as it converts the salt of nalflaphine into a free form, and can be appropriately selected according to the purpose. For example, monoethanolamine , Sodium bicarbonate, and a polymer compound having an amino group are preferred.
The content of the desalting agent can be appropriately selected according to the purpose, but in terms of skin irritation and skin permeability, the content is 5 mol or more with respect to 1 mol of the salt of narfrafin. Preferably, it is 10 mol or more. Moreover, it is preferable that it is 30 mol or less, and it is more preferable that it is 25 mol or less.
As a blending method of the desalting agent, it may be performed once during the production process or may be performed in several steps.
　前記脱塩剤がモノエタノールアミンや炭酸水素ナトリウムである場合、前記粘着剤層中、０．０１質量％以上が好ましく、０．１質量％以上がより好ましく、０．３質量％以上がさらに好ましい。また、１０質量％以下が好ましく、５．０質量％以下がより好ましく、１．０質量％以下がさらに好ましい。 When the desalting agent is monoethanolamine or sodium hydrogen carbonate, the content in the pressure-sensitive adhesive layer is preferably 0.01% by mass or more, more preferably 0.1% by mass or more, and further preferably 0.3% by mass or more. . Moreover, 10 mass% or less is preferable, 5.0 mass% or less is more preferable, and 1.0 mass% or less is further more preferable.
　前記アミノ基を有するポリマー化合物としては、皮膚透過性の点で、（メタ）アクリル酸ジアルキル（メチル、又はエチル）アミノアルキル（メチル、又はエチル）と、（メタ）アクリル酸アルキル（メチル、エチル、プロピル、又はブチル）、（メタ）アクリル酸モノヒドロキシアルキル（エチル、プロピル、又はブチル）及びこれらの組合せから選択されるモノマー単位とから構成されるコポリマーが好ましい。
　このようなアミノ基を有するポリマー化合物としては、例えば、メタクリル酸メチル－メタクリル酸ブチル－メタクリル酸ジメチルアミノエチルコポリマーである、オイドラギット（登録商標）ＥＰＯ（エボニック社製）などが挙げられる。 As the polymer compound having an amino group, in terms of skin permeability, dialkyl (meth) acrylate (methyl or ethyl) aminoalkyl (methyl or ethyl) and alkyl (meth) acrylate (methyl, ethyl, Propylene or butyl), copolymers composed of monomer units selected from monohydroxyalkyl (meth) acrylates (ethyl, propyl or butyl) and combinations thereof are preferred.
Examples of such a polymer compound having an amino group include Eudragit (registered trademark) EPO (manufactured by Evonik), which is a methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer.
　前記脱塩剤がアミノ基を有するポリマー化合物である場合、前記粘着剤層中、１．０質量％以上が好ましく、２．０質量％以上がより好ましい。また、皮膚透過性、及び皮膚刺激性の点で、前記粘着剤層中、４０質量％以下が好ましい。
　前記脱塩剤は、１種単独で使用してもよいし、２種以上を併用してもよい。 When the desalting agent is a polymer compound having an amino group, 1.0% by mass or more is preferable in the pressure-sensitive adhesive layer, and 2.0% by mass or more is more preferable. Moreover, 40 mass% or less is preferable in the said adhesive layer at the point of skin permeability and skin irritation.
The said desalting agent may be used individually by 1 type, and may use 2 or more types together.
　前記粘着剤層の平均厚みとしては、目的に応じて適宜選択することができるが、５μｍ～５００μｍが好ましく、１０μｍ～３００μｍがより好ましく、２０μｍ～２００μｍがさらに好ましい。 The average thickness of the pressure-sensitive adhesive layer can be appropriately selected according to the purpose, but is preferably 5 μm to 500 μm, more preferably 10 μm to 300 μm, and further preferably 20 μm to 200 μm.
　本発明において、上記粘着剤層は、他の薬物、軟化剤、酸化防止剤、吸収促進剤、無機充填剤、紫外線吸収剤、抗酸化剤等のその他添加剤を更に含有していてもよい。 In the present invention, the pressure-sensitive adhesive layer may further contain other additives such as other drugs, softeners, antioxidants, absorption accelerators, inorganic fillers, ultraviolet absorbers and antioxidants.
［剥離シート］
　また本発明の貼付剤製品における貼付剤に用いる剥離シートとしては、粘着剤層中の薬物等が吸収・吸着しにくい材質であることが好ましく、例えば、片面又は両面にシリコーン処理したポリエステルフィルム、シリコーン処理したポリエチレンラミネート上質紙、シリコーン処理したグラシン紙などが挙げられる。 [Peeling sheet]
Further, the release sheet used for the patch in the patch product of the present invention is preferably a material that is difficult to absorb and adsorb the drug in the pressure-sensitive adhesive layer. For example, a polyester film having a silicone treatment on one or both sides, silicone Examples include treated polyethylene laminate fine paper, silicone-treated glassine paper, and the like.
[貼付剤の製造方法]
　本発明の貼付剤製品における貼付剤の製造方法は、特に制限はなく、目的に応じて適宜選択することができ、例えば、エラストマー、粘着付与剤、ナルフラフィンの塩、及び脱塩剤を含有する粘着剤組成物を調製して、これを支持体上に塗工する方法、剥離シート上に塗工した後、支持体を貼り合わせる方法などが挙げられる。 [Manufacturing method of patch]
The method for producing the patch in the patch product of the present invention is not particularly limited and can be appropriately selected according to the purpose. For example, an adhesive containing an elastomer, a tackifier, a salt of nalfrafin, and a desalting agent. Examples thereof include a method of preparing an agent composition and coating it on a support, and a method of applying the support onto a release sheet and then bonding the support.
［投与方法］
　前記貼付剤の適用時間としては、特に制限はなく、目的に応じて適宜選択することができるが、２４時間以上、皮膚に適用されることが好ましい。 [Method of administration]
There is no restriction | limiting in particular as application time of the said patch, Although it can select suitably according to the objective, It is preferable to apply to skin for 24 hours or more.
　以下に実施例及び比較例を示して、本発明について具体的に説明するが、本発明は、これらの実施例に限定されるものではない。実施例において、ナルフラフィンはすべてナルフラフィン塩酸塩を用いた。 Hereinafter, the present invention will be described in detail with reference to examples and comparative examples, but the present invention is not limited to these examples. In the examples, nalfurafine hydrochloride was used as all nalflaphine.
（実施例１）
　前記エラストマーとして、スチレン－イソプレン－スチレンブロック共重合体（ＳＩＳ；商品名「ＳＩＳ５００２」、ＪＳＲ株式会社製）７．９７質量％、スチレン－イソプレン－スチレンブロック共重合体（ＳＩＳ；商品名「クインタック３５２０」、日本ゼオン株式会社製）２３．９質量％、前記粘着付与剤として、テルペン樹脂（商品名「ＹＳレジンＰＸ１１５０Ｎ」、ヤスハラケミカル株式会社製）１９．１質量％、前記軟化剤として、流動パラフィン（商品名「ハイコールＭ３５２」、カネダ株式会社製）４８．４８質量％、前記ナルフラフィンの塩として、適量のメタノールに溶解させたナルフラフィン塩酸塩０．２５質量％、及び前記脱塩剤として、モノエタノールアミン０．３質量％を、固形分が５０質量％となるように有機溶媒（トルエン）を添加し、均一になるまで混合して粘着剤組成物を調製した。次いで、得られた粘着剤組成物を、カバー材（剥離シート）であるシリコーン処理したポリエステルフィルム（平均厚み７５μｍ）上に、３０μｍの平均厚みに塗工して、粘着剤層を形成した。この粘着剤層の上に支持体としてポリエステルフィルムをラミネートし、７．５ｃｍ２の大きさに裁断して貼付剤１を作製した。
　得られた貼付剤１について、以下の通り貼付剤製品１を作製し、下記に示した経時安定性試験を行い、貼付剤中の薬物の安定性を評価した。評価結果を表１に示した。 Example 1
As the elastomer, styrene-isoprene-styrene block copolymer (SIS; trade name “SIS5002”, manufactured by JSR Corporation) 7.97% by mass, styrene-isoprene-styrene block copolymer (SIS; trade name “Quintac”) 3520 ", manufactured by Nippon Zeon Co., Ltd.) 23.9% by mass, as the tackifier, terpene resin (trade name" YS Resin PX1150N ", Yashara Chemical Co., Ltd.) 19.1% by mass, and as the softener, liquid paraffin (Trade name “Hycol M352”, manufactured by Kaneda Co., Ltd.) 48.48% by mass, nalflaphine hydrochloride 0.25% by mass dissolved in an appropriate amount of methanol as the salt of nalfurafine, and monoethanol as the desalting agent 0.3% by weight of amine is present so that the solid content is 50% by weight. It was added the solvent (toluene) to prepare a pressure-sensitive adhesive composition was mixed until uniform. Next, the obtained pressure-sensitive adhesive composition was coated on a silicone-treated polyester film (average thickness 75 μm) as a cover material (release sheet) to an average thickness of 30 μm to form a pressure-sensitive adhesive layer. A polyester film was laminated as a support on this pressure-sensitive adhesive layer, and cut into a size of 7.5 cm 2 to prepare patch 1.
About the obtained patch 1, the patch product 1 was produced as follows, and the stability test with time shown below was performed to evaluate the stability of the drug in the patch. The evaluation results are shown in Table 1.
＜安定性試験＞
　貼付剤１～６は、最内層としてＰＡＮ（ポリアクリロニトリル）を、空気遮断層としてＡＬを配置した積層体を用いた包装袋を使用して、貼付剤製品１～６を作製し、以下の試験に供した。
　貼付剤７～９は、モイストキャッチ（共同印刷株式会社製、シーラント層／吸湿層／アルミ／ＰＥＴ）を用いて得た包装袋を使用し、貼付剤１０～１２は、オキシキャッチ（共同印刷株式会社製、ＰＥ（シーラント層）／酸素吸収層／アルミ／ＰＥＴ）を用いて得た包装袋を使用して、貼付剤製品７～１２を作製し、以下の試験に供した。
　詳細には、それぞれの包装袋に貼付剤を収容し、袋内を窒素置換した後に熱融着により包装袋を密封した後、６０℃で保存した。保存開始時および保存開始３ヶ月後に、貼付剤中のナルフラフィン含有量を高速液体クロマトグラフィーによって定量した。保存開始時のナルフラフィン含有量に対する３ヶ月後のナルフラフィン含有量を百分率で算出し、薬物残存率（ ％ ）とした。 <Stability test>
For patches 1-6, patch products 1-6 were prepared using a packaging bag using a laminate in which PAN (polyacrylonitrile) was disposed as the innermost layer and AL was disposed as the air barrier layer. It was used for.
Patches 7-9 use packaging bags obtained using moist catch (manufactured by Kyodo Printing Co., Ltd., sealant layer / moisture absorbing layer / aluminum / PET), and patches 10-12 use oxycatch (Kyodo Printing Co., Ltd.) Patch products 7 to 12 were produced using packaging bags obtained using PE (sealant layer) / oxygen absorbing layer / aluminum / PET (manufactured by the company) and subjected to the following tests.
Specifically, the patch was housed in each packaging bag, the inside of the bag was purged with nitrogen, the packaging bag was sealed by heat sealing, and stored at 60 ° C. At the start of storage and 3 months after the start of storage, the content of nalflaphine in the patch was quantified by high performance liquid chromatography. The nalfuraffin content after 3 months with respect to the nalfurafine content at the start of storage was calculated as a percentage and used as the drug residual rate (%).
（実施例２）
　実施例１において、酸化防止剤として、ＢＨＴを０．０５質量％添加し、前記軟化剤の量を４８．４８質量％から４８．４３質量％に変更した以外は、実施例１と同様の方法で貼付剤２並びに貼付剤製品２を作製し、評価した。 (Example 2)
In Example 1, 0.05% by mass of BHT was added as an antioxidant, and the same method as in Example 1 except that the amount of the softening agent was changed from 48.48% by mass to 48.43% by mass. A patch 2 and a patch product 2 were prepared and evaluated.
（実施例３）
　実施例１において、前記粘着付与剤をテルペン樹脂である、「ＹＳレジンＰＸ１１５０Ｎ」１９．１質量％の代わりに、ロジン樹脂である、「パインクリスタルＫＥ－３１１（超淡色ロジンエステル）」（荒川化学工業社製）１９．１質量％とした以外は、実施例１と同様の方法で貼付剤３並びに貼付剤製品３を作製し、評価した。 (Example 3)
In Example 1, instead of 19.1% by mass of “YS Resin PX1150N”, which is a terpene resin as the tackifier, “Pine Crystal KE-311 (ultra-light rosin ester)” (Arakawa Chemical) A patch 3 and a patch product 3 were prepared and evaluated in the same manner as in Example 1 except that 19.1% by mass (manufactured by Kogyo Co., Ltd.) was used.
（実施例４）
　実施例３において、脱塩剤をモノエタノールアミン０．３質量％の代わりにアミノ基を含有するポリマー化合物である、「オイドラギットＥＰＯ」（エボニック社製）３．２質量％とし、酸化防止剤として、ＢＨＴを０．０５質量％添加し、前記軟化剤の量を４８．４８質量％から４５．５３質量％に変更した以外は、実施例３と同様の方法で貼付剤４並びに貼付剤製品４を作製し、評価した。 (Example 4)
In Example 3, the desalting agent was 3.2% by mass of “Eudragit EPO” (manufactured by Evonik), which is a polymer compound containing an amino group instead of 0.3% by mass of monoethanolamine, and as an antioxidant. The patch 4 and the patch product 4 were prepared in the same manner as in Example 3 except that 0.05% by mass of BHT was added and the amount of the softening agent was changed from 48.48% by mass to 45.53% by mass. Were made and evaluated.
（実施例５）
　実施例４において、酸化防止剤を添加せず、前記軟化剤の量を４５．５３質量％から４５．５８質量％に変更した以外は、実施例４と同様の方法で貼付剤５並びに貼付剤製品５を作製し、評価した。 (Example 5)
In Example 4, except that the antioxidant was not added and the amount of the softening agent was changed from 45.53 mass% to 45.58 mass%, the patch 5 and the patch were prepared in the same manner as in Example 4. Product 5 was made and evaluated.
（実施例６）
　実施例５において、ナルフラフィン塩酸塩をナルフラフィンのフリー体とし、脱塩剤を添加せず、前記軟化剤の量を４５．５８質量％から４８．７８質量％に変更した以外は、実施例５と同様の方法で貼付剤６並びに貼付剤製品６を作製し、評価した。 (Example 6)
Example 5 is the same as Example 5 except that nalfurafine hydrochloride is a free form of nalfurafine, no desalting agent is added, and the amount of the softening agent is changed from 45.58% by mass to 48.78% by mass. A patch 6 and a patch product 6 were prepared and evaluated in the same manner.
（実施例７）
　実施例４において、包装材を吸湿性樹脂から形成された層を含むモイストキャッチ（共同印刷株式会社製）に変更した以外は、実施例４と同様の方法で貼付剤７並びに貼付剤製品７を作製し、評価した。 (Example 7)
In Example 4, except that the packaging material was changed to a moist catch (made by Kyodo Printing Co., Ltd.) including a layer formed of a hygroscopic resin, the patch 7 and the patch product 7 were prepared in the same manner as in Example 4. Prepared and evaluated.
（実施例８）
　実施例５において、包装材を吸湿性樹脂から形成された層を含むモイストキャッチ（共同印刷株式会社製）に変更した以外は、実施例５と同様の方法で貼付剤８並びに貼付剤製品８作製し、評価した。 (Example 8)
In Example 5, except that the packaging material was changed to a moist catch (made by Kyodo Printing Co., Ltd.) including a layer formed from a hygroscopic resin, patch 8 and patch product 8 were produced in the same manner as in Example 5. And evaluated.
（実施例９）
　実施例２において、前記粘着付与剤をテルペン樹脂である、「ＹＳレジンＰＸ１１５０Ｎ」１９．１質量％の代わりに、ロジン樹脂である、「パインクリスタルＫＥ－３１１（超淡色ロジンエステル）」（荒川化学工業社製）１９．１質量％とし、包装材を吸湿性樹脂から形成された層を含むモイストキャッチ（共同印刷株式会社製）に変更した以外は、実施例２と同様の方法で貼付剤９並びに貼付剤製品９を作製し、評価した。 Example 9
In Example 2, instead of 19.1% by mass of “YS Resin PX1150N”, which is a terpene resin as the tackifier, “Pine Crystal KE-311 (ultra-light rosin ester)” (Arakawa Chemical) Kogyo Kogyo Co., Ltd. was used in the same manner as in Example 2 except that the product was changed to 19.1% by mass and the packaging material was changed to a moist catch (manufactured by Kyodo Printing Co., Ltd.). In addition, a patch product 9 was prepared and evaluated.
（実施例１０）
　実施例４において、包装材を酸素吸収剤を含有した層を含むオキシキャッチ（共同印刷株式会社製）に変更した以外は、実施例４と同様の方法で貼付剤１０並びに貼付剤製品１０を作製し、評価した。 (Example 10)
In Example 4, the patch 10 and the patch product 10 were produced in the same manner as in Example 4 except that the packaging material was changed to Oxycatch (produced by Kyodo Printing Co., Ltd.) including a layer containing an oxygen absorbent. And evaluated.
（実施例１１）
　実施例５において、包装材を酸素吸収剤を含有した層を含むオキシキャッチ（共同印刷株式会社製）に変更した以外は、実施例５と同様の方法で貼付剤１１並びに貼付剤製品１１を作製し、評価した。 (Example 11)
In Example 5, the patch 11 and the patch product 11 were produced in the same manner as in Example 5 except that the packaging material was changed to oxy catch (manufactured by Kyodo Printing Co., Ltd.) including a layer containing an oxygen absorbent. And evaluated.
（実施例１２）
　実施例２において、前記粘着付与剤をテルペン樹脂である、「ＹＳレジンＰＸ１１５０Ｎ」１９．１質量％の代わりに、ロジン樹脂である、「パインクリスタルＫＥ－３１１（超淡色ロジンエステル）」（荒川化学工業社製）１９．１質量％とし、包装材を酸素吸収剤を含有した層を含むオキシキャッチ（共同印刷株式会社製）に変更した以外は、実施例２と同様の方法で貼付剤１２並びに貼付剤製品１２を作製し、評価した。 (Example 12)
In Example 2, instead of 19.1% by mass of “YS Resin PX1150N”, which is a terpene resin as the tackifier, “Pine Crystal KE-311 (ultra-light rosin ester)” (Arakawa Chemical) Kogyo Kogyo Co., Ltd., except that the packaging material was changed to 19.1% by mass and the packaging material was changed to Oxycatch (manufactured by Kyodo Printing Co., Ltd.). A patch product 12 was prepared and evaluated.
（参考例１）
　実施例４において、最内層がポリエチレンを主成分とするアルミ包装袋に変更した以外は、実施例４と同様の方法で貼付剤１３並びに貼付剤製品１３を作製した。 (Reference Example 1)
A patch 13 and a patch product 13 were produced in the same manner as in Example 4 except that in Example 4, the innermost layer was changed to an aluminum packaging bag mainly composed of polyethylene.
＜貼付剤の水分量＞
　上記参考例１で調製した貼付剤製品１３と、前記実施例７において調製した貼付剤製品７について、それぞれの貼付剤の水分量を測定した。
　詳細には、それぞれの包装袋に貼付剤７または貼付剤１３をそれぞれ収容し、袋内を窒素置換した後に熱融着により包装袋を密封した後、６０℃で保存した。保存開始時および保存開始１ヶ月後に、貼付剤中の水分量を赤外水分計（ＡＤ－４７１５、（株）エー・アンド・ディー）によって定量した。保存開始時の製剤中の水分含有量に対する１ヶ月後の水分含有量を百分率で算出し、水分量変化率（％）とした。
　なお、赤外線水分計は、乾燥温度を１００℃、監視時間を３００秒とし、測定値の変化量が監視時間内で０．０５％以下になったときを最終測定値とみなして測定した。 <Moisture content of the patch>
For the patch product 13 prepared in Reference Example 1 and the patch product 7 prepared in Example 7, the water content of each patch was measured.
Specifically, the patch 7 or the patch 13 was accommodated in each packaging bag, the inside of the bag was purged with nitrogen, the packaging bag was sealed by heat fusion, and stored at 60 ° C. At the start of storage and 1 month after the start of storage, the amount of water in the patch was quantified with an infrared moisture meter (AD-4715, A & D). The water content after one month with respect to the water content in the preparation at the start of storage was calculated as a percentage and used as the water content change rate (%).
The infrared moisture meter was measured by assuming that the drying temperature was 100 ° C., the monitoring time was 300 seconds, and the amount of change in the measured value was 0.05% or less within the monitoring time as the final measured value.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　表１の結果から、実施例で使用した酸素濃度及び／又は水素濃度を減少させる手段を用いると、６０℃という高温における苛酷試験においても、貼付剤１～１２（実施例１～１２）の、薬物の安定性が良い貼付剤製品を実現させた構成であることがわかった。中でも、包装材としてオキシキャッチを用いた貼付剤製品１０～１２は、特に６０℃で３ヶ月の保存を行っても、貼付剤１０～１２における薬物残存量が９６％以上と非常に良好な結果であった。また、貼付剤の粘着剤層として、貼付剤４，５，７，８，１０－１１より、スチレン－イソプレン－スチレンブロック共重合体（ＳＩＳ）、粘着付与剤としてロジン樹脂、及び、脱塩剤としてアミノ基を含有するポリマー化合物を含む構成とすることが良いことがわかった。
　また、モイストキャッチを用いた貼付剤製品７は、６０℃で１ヶ月の保存を行ったときに、貼付剤７の水分減少変化率（％）が３７％であり、一方貼付剤製品１３における貼付剤１３の水分減少変化率は１１％であった。これは、吸湿性樹脂から形成された層を含む積層体を含む、少なくとも２層以上の積層体から形成されてなる包装袋を用いることにより、確実に包装材内の水分が吸収されていることが確認できた。 From the results of Table 1, using the means for reducing the oxygen concentration and / or hydrogen concentration used in the examples, even in severe tests at a high temperature of 60 ° C., the patches 1 to 12 (Examples 1 to 12) It was found that the configuration realized a patch product with good drug stability. In particular, the patch products 10 to 12 using oxycatch as a packaging material showed a very good result that the drug residual amount in the patches 10 to 12 was 96% or more even when stored at 60 ° C. for 3 months. Met. Further, as the adhesive layer of the patch, from the patches 4, 5, 7, 8, 10-11, styrene-isoprene-styrene block copolymer (SIS), rosin resin as the tackifier, and desalting agent As a result, it has been found that a composition containing an amino group-containing polymer compound is preferable.
In addition, the patch product 7 using the moist catch has a moisture decrease rate (%) of 37% when stored for one month at 60 ° C. The moisture reduction rate of the agent 13 was 11%. This is because moisture in the packaging material is reliably absorbed by using a packaging bag formed of a laminate of at least two layers including a laminate including a layer formed of a hygroscopic resin. Was confirmed.
１・・・・貼付剤製品
２・・・・包装袋
３・・・・ナルフラフィン含有貼付剤
４・・・・吸湿剤を含有したパウチ
５・・・・酸素吸収剤を含有したパウチ
１０・・・貼付剤製品 DESCRIPTION OF SYMBOLS 1 ... Patch product 2 ... Packaging bag 3 ... Nalfrafin containing patch 4 ... Pouch 5 containing hygroscopic agent ... Pouch 10 containing oxygen absorbent ...・ Patch products

Claims (9)

  1. 　包装袋と、該包装袋の内部に収容されたナルフラフィン含有貼付剤とを備える貼付剤製品であって、
    　前記包装袋内の酸素濃度及び／又は水分量を減少させる手段を備えてなる貼付剤製品。     A patch product comprising a packaging bag and a nalflaphine-containing patch housed in the packaging bag,
    A patch product comprising means for reducing the oxygen concentration and / or the amount of water in the packaging bag.
  2. 　前記包装袋内の酸素濃度及び／又は水分量を減少させる手段として、
    　前記包装袋が、吸湿性樹脂から形成された層及び酸素吸収剤を含有した層からなる群から選ばれる１種以上を含む、少なくとも２層以上の積層体から形成されてなる、
    請求項１に記載の貼付剤製品。     As means for reducing the oxygen concentration and / or the amount of water in the packaging bag,
    The packaging bag is formed from a laminate of at least two layers including one or more selected from the group consisting of a layer formed from a hygroscopic resin and a layer containing an oxygen absorbent,
    The patch product according to claim 1.
  3. 　前記包装袋内の酸素濃度及び／又は水分量を減少させる手段として、
    　前記包装袋内に、吸湿剤及び／又は酸素吸収剤を含有したパウチを同封した、
    請求項１に記載の貼付剤製品。     As means for reducing the oxygen concentration and / or the amount of water in the packaging bag,
    In the packaging bag, a pouch containing a hygroscopic agent and / or an oxygen absorbent was enclosed.
    The patch product according to claim 1.
  4. 　前記包装袋内の酸素濃度及び／又は水分量を減少させる手段として、
    　前記包装袋内が窒素置換されている、
    請求項１に記載の貼付剤製品。     As means for reducing the oxygen concentration and / or the amount of water in the packaging bag,
    The inside of the packaging bag is replaced with nitrogen,
    The patch product according to claim 1.
  5. 　前記包装袋が吸湿性樹脂から形成された層及び酸素吸収剤を含有した層からなる群から選ばれる１種以上を含む、少なくとも２層以上の積層体同士の間に、熱融着層を配してなる請求項１または請求項２に記載の貼付剤製品。 A thermal fusion layer is disposed between at least two laminates including one or more selected from the group consisting of a layer formed of a hygroscopic resin and a layer containing an oxygen absorbent. The patch product according to claim 1 or claim 2 formed as described above.
  6. 　前記貼付剤が支持体と、該支持体の少なくとも一方の面上に設けられたナルフラフィン含有粘着剤層と、該ナルフラフィン含有粘着剤層上に設けられた剥離シートとからなる貼付剤である、請求項１から請求項５のいずれか１項に記載の貼付剤製品。 The patch is a patch comprising a support, a nalfurafine-containing pressure-sensitive adhesive layer provided on at least one surface of the support, and a release sheet provided on the nalfurafine-containing pressure-sensitive adhesive layer. The patch product according to any one of claims 1 to 5.
  7. 　前記粘着剤層がゴム系粘着剤およびロジン樹脂を含む、請求項６に記載の貼付剤製品。 The patch product according to claim 6, wherein the pressure-sensitive adhesive layer contains a rubber-based pressure-sensitive adhesive and a rosin resin.
  8. 　前記粘着剤層がナルフラフィンの塩及び脱塩剤を含む、請求項６または請求項７に記載の貼付剤製品。 The patch product according to claim 6 or 7, wherein the pressure-sensitive adhesive layer contains a salt of nalfrafin and a desalting agent.
  9. 　吸湿性樹脂から形成された層及び酸素吸収剤を含有した層からなる群から選ばれる１種以上を含む、少なくとも２層以上の積層体から形成されてなるナルフラフィン含有貼付剤用包装袋。 A packaging bag for a narfrafin-containing patch comprising at least two layers comprising at least one selected from the group consisting of a layer formed from a hygroscopic resin and a layer containing an oxygen absorbent.
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