WO2015025766A1 - Transdermal patch - Google Patents

Transdermal patch Download PDF

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Publication number
WO2015025766A1
WO2015025766A1 PCT/JP2014/071216 JP2014071216W WO2015025766A1 WO 2015025766 A1 WO2015025766 A1 WO 2015025766A1 JP 2014071216 W JP2014071216 W JP 2014071216W WO 2015025766 A1 WO2015025766 A1 WO 2015025766A1
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WO
WIPO (PCT)
Prior art keywords
adhesive
patch
pressure
sensitive adhesive
mass
Prior art date
Application number
PCT/JP2014/071216
Other languages
French (fr)
Japanese (ja)
Inventor
藤田　直子
知宏 篠田
Original Assignee
久光製薬株式会社
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=52483542&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2015025766(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by 久光製薬株式会社 filed Critical 久光製薬株式会社
Priority to JP2015532824A priority Critical patent/JP6306594B2/en
Publication of WO2015025766A1 publication Critical patent/WO2015025766A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics

Definitions

  • the present invention relates to a patch.
  • Pruritus in hemodialysis patients is a disease in which the patient's QOL is greatly impaired due to the fact that it induces strong generalized itching without inflammation and is unable to get enough sleep at night.
  • nalfrafin hydrochloride which is a ⁇ -type opioid receptor agonist compound is known (see, for example, Patent Document 1).
  • Nalfurafine hydrochloride is prescribed as an oral agent for intractable pruritus associated with hemodialysis.
  • drugs are generally distributed in the form of acid addition salts such as hydrochlorides from the viewpoint of handling and stability, and narfraphine is no exception.
  • the present inventors have found that when preparations such as liquids and ointments containing nalfurafine hydrochloride are prepared, the preparation stability of nalfurafine is poor. In addition, the present inventors have found that the preparation stability is poor even when the preparation is prepared using the free base (free form) of nalflaphine.
  • an object of the present invention is to provide a nalflaphine-containing preparation that exhibits excellent preparation stability.
  • the inventors of the present invention prepared a patch containing a free form of nalflaphine and compared it with a patch containing a hydrochloride of nalflaphine. It has been found that it exhibits superior formulation stability.
  • the present invention is a patch comprising a support and an adhesive layer containing a drug and an adhesive disposed on at least one side of the support, wherein at least a part of the drug is free
  • a patch that is nalflavine, which is the body is provided.
  • the pressure-sensitive adhesive layer may be obtained by mixing a free body of nalfurafine with a pressure-sensitive adhesive, or may be obtained by mixing a salt of nalfrafin with a pressure-sensitive adhesive together with a desalting agent. .
  • the salt of narfrafin with an adhesive together with a desalting agent it exists in the form of a salt that is excellent in handleability until formulation, and it is converted into a free form by a desalting agent in the formulation, so it is more efficient.
  • the formulation can be prepared.
  • the desalting agent is preferably at least one selected from sodium acetate and sodium hydroxide, and more preferably sodium acetate.
  • the content of the desalting agent is preferably 0.3 to 5 mol per 1 mol of the salt of narfrafin.
  • the pressure-sensitive adhesive preferably contains at least one selected from an acrylic pressure-sensitive adhesive, a styrene block copolymer pressure-sensitive adhesive, a polyisobutylene pressure-sensitive adhesive, and a silicone pressure-sensitive adhesive.
  • nalflaphine-containing preparation that exhibits excellent preparation stability.
  • the patch according to the present embodiment is a patch comprising a support and a pressure-sensitive adhesive layer containing a drug and a pressure-sensitive adhesive (drug-containing pressure-sensitive adhesive layer) disposed on at least one side of the support.
  • a pressure-sensitive adhesive drug-containing pressure-sensitive adhesive layer
  • at least a part of the drug is nalflaphine, which is a free form.
  • a stretchable or non-stretchable material that can be usually used for a patch is used.
  • a film or sheet formed of a synthetic resin such as polyethylene terephthalate, polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate polymer, polyvinyl chloride, polyester, nylon, polyurethane, or a laminate thereof, or a porous film A foam, a woven fabric and a non-woven fabric, or a paper material can be suitably used.
  • the adhesive examples include those containing at least one selected from an acrylic adhesive, a styrene block copolymer adhesive, a polyisobutylene adhesive, and a silicone adhesive.
  • an adhesive 1 type may be used independently and 2 or more types may be used in combination.
  • Examples of the pressure-sensitive adhesive used in combination of two or more include an embodiment in which a styrene block copolymer pressure-sensitive adhesive and a polyisobutylene pressure-sensitive adhesive are combined.
  • acrylic pressure-sensitive adhesive a homopolymer or copolymer of (meth) acrylic acid ester or a copolymer of (meth) acrylic acid alkyl ester and other monomers is preferably used.
  • (meth) acryl means acryl or methacryl.
  • alkyl alcohol or alkyl diol (meth) acrylic acid ester is preferably used.
  • alkyl alcohol and the alkyl diol those having 4 to 16 carbon atoms are preferable.
  • examples of other monomers include styrene, methylstyrene, N-vinylpyrrolidone, (meth) acrylamide, and the like.
  • acrylic pressure-sensitive adhesives examples include DURO-TAK 87-2510, DURO-TAK 87-235A, and DURO-TAK 87-4098 (both manufactured by Henkel Corporation).
  • the styrene block copolymer-based pressure-sensitive adhesive is obtained by adding a tackifier or the like to a styrene block copolymer.
  • the styrene block copolymer adhesive include styrene-isoprene-styrene (SIS) adhesive, styrene-butadiene-styrene (SBS) adhesive, styrene-ethylenebutylene-styrene (SEBS) adhesive, and styrene- And ethylene propylene-styrene (SEPS) pressure sensitive adhesive.
  • SIS styrene-isoprene-styrene
  • SBS styrene-butadiene-styrene
  • SEBS styrene-ethylenebutylene-styrene
  • SEPS styrene- And ethylene propylene-styrene
  • tackifier examples include ester gum (trade name, manufactured by Arakawa Chemical Co., Ltd.), Harrier Star (trade name, manufactured by Harima Kasei Co., Ltd.), pentalin (trade name, manufactured by Eastman Chemical Company), and formal (Eastman Chemical). Rosin resins such as YS resin (Yasuhara Chemical Co., trade name), terpene resins such as picolite (Loose and Dilworth Co., trade name), Alcon (Arakawa Chemical Co., Ltd.
  • tackifiers may be used alone or in combination of two or more.
  • the content of the tackifier can be appropriately set by those skilled in the art in consideration of sufficient adhesive strength of the adhesive and local irritation at the time of peeling.
  • the upper limit of the content of the tackifier is preferably, for example, 10% by mass or more, more preferably 15% by mass or more, based on the total mass of the adhesive layer, and 20% by mass. % Or more is particularly preferable.
  • the lower limit of the content of the tackifier is preferably, for example, 90% by mass or less, more preferably 70% by mass or less, based on the total mass of the adhesive layer, and 60% by mass or less. It is particularly preferred.
  • the content of the tackifier is preferably 10 to 90% by mass, more preferably 15 to 70% by mass, and particularly preferably 20 to 60% by mass based on the total mass of the adhesive layer. preferable.
  • the polyisobutylene-based pressure-sensitive adhesive is one obtained by adding a plasticizer or the like to polyisobutylene (PIB) to impart adhesiveness.
  • plasticizer examples include petroleum oils such as paraffinic process oil, naphthenic process oil and aromatic process oil, vegetable oils such as olive oil, camellia oil, castor oil, tall oil and peanut oil, dibutyl phthalate and dioctyl.
  • examples thereof include dibasic acid esters such as phthalate, liquid rubbers such as polybutene and liquid isoprene rubber, squalane, squalene, diethylene glycol, polyethylene glycol, propylene glycol and dipropylene glycol. These can be used individually by 1 type or in combination of 2 or more types.
  • liquid paraffin and polybutene are particularly preferable.
  • the content of the plasticizer in the drug-containing pressure-sensitive adhesive layer can be appropriately adjusted by those skilled in the art in consideration of maintaining sufficient adhesive strength as a pressure-sensitive adhesive.
  • the upper limit of the content of the plasticizer is, for example, preferably 1% by mass or more, more preferably 2% by mass or more, based on the total mass of the drug-containing pressure-sensitive adhesive layer. It is particularly preferable that the content is at least mass%.
  • the lower limit of the content of the plasticizer is, for example, preferably 60% by mass or less, more preferably 50% by mass or less, further preferably 40% by mass or less, and 20% by mass or less. It is particularly preferred.
  • the plasticizer content is preferably 1 to 60% by mass, more preferably 2 to 50% by mass, and more preferably 3 to 40% by mass based on the total mass of the drug-containing pressure-sensitive adhesive layer. Further preferred is 3 to 20% by mass.
  • the silicone-based adhesive is an adhesive made of a condensation reaction product of dimethylpolysiloxane and a three-dimensional silicate resin, and examples thereof include Bio-PSA 7-4102 (trade name, manufactured by Dow Corning). Can do.
  • these various adhesives may be used individually by 1 type, and may be used in combination of 2 or more type. Further, the content of the pressure-sensitive adhesive can be appropriately set by those skilled in the art in consideration of the formation and adhesion of the drug-containing pressure-sensitive adhesive layer and the tissue permeability of the active ingredient.
  • using a combination of a styrene block copolymer adhesive and a polyisobutylene adhesive not only further improves the formulation stability of narfrafin, but also improves the cohesive strength of the patch. Also, the adhesive strength and the adhesion to the skin tend to be further improved.
  • the ratio of the styrene block copolymer pressure-sensitive adhesive and the polyisobutylene pressure-sensitive adhesive is preferably in the range of 1:10 to 10: 1 with respect to the styrene block copolymer, preferably 1: 1 to 9: 1. More preferably, it is in the range of 6: 4 to 8: 1.
  • the content of the tackifier is not particularly limited, but may be, for example, 0.4 times or more based on the content of the plasticizer, It may be 0.5 times or more, 1 time or more, 1.5 times or more, 2 times or more, or 2.5 times or more It may be 3 times or more, or 3.5 times or more.
  • the upper limit of the content of the tackifier is not particularly limited. For example, it may be 100 times or less, 50 times or less, or 10 times or less based on the content of the plasticizer. It may be 5 times or less, or 4 times or less.
  • the upper limit of the content of the adhesive is, for example, preferably 10% by mass or more, more preferably 15% by mass or more, and more preferably 20% by mass or more based on the total mass of the drug-containing adhesive layer. More preferably.
  • the lower limit of the content of the pressure-sensitive adhesive is, for example, preferably 99% by mass or less, more preferably 90% by mass or less, and further preferably 85% by mass or less.
  • the content of the pressure-sensitive adhesive may be 10 to 99% by mass or 15 to 90% by mass based on the total mass of the drug-containing pressure-sensitive adhesive layer.
  • the content is preferably 20 to 85% by mass.
  • narfraphine a free form of narfraphine. That is, it is only necessary that a free form of nalflaphine exists in the drug-containing pressure-sensitive adhesive layer, and a salt of nalfurafine may coexist. Furthermore, other drugs may be included as necessary.
  • a free form of nalfurafine may be used as a raw material, or a salt of nalfurafine may be used as a raw material together with a desalting agent.
  • a salt of narfrafin is used as a raw material together with a desalting agent, at least a part of the salt is converted into a free form during or after the manufacture of the patch.
  • the salt of nalfurafine is not particularly limited as long as it is a pharmaceutically acceptable salt, but is preferably an acid addition salt of nalfurafine from the viewpoint of storage stability before producing the patch.
  • acid addition salts include hydrochloride, acetate, maleate, oxalate, citrate, hydroiodide, hydrobromide, mesylate, tartrate, succinate, etc. be able to.
  • the desalting agent used together with the salt of nalfurafine a basic substance is preferable when the acid addition salt of nalfurafine is converted into a free form.
  • a desalting agent include sodium acetate and sodium hydroxide, among which sodium acetate is preferable.
  • the desalting agent is used to convert at least a part of the salt of nalfurafine into a free form in the preparation. It may be converted into a free body as long as stability can be improved. From such a viewpoint, the upper limit of the content of the desalting agent is preferably 0.3 mol or more, more preferably 0.5 mol or more, and more preferably 1 mol or more with respect to 1 mol of the salt of nalfurafine.
  • the lower limit of the content of the desalting agent is preferably 5 mol or less, more preferably 3 mol or less, and even more preferably 2 mol or less.
  • the content of the desalting agent is preferably in the range of 0.3 to 5 mol, more preferably in the range of 0.5 to 3 mol, with respect to 1 mol of the salt of narfrafin. An amount in the range of 0.5 to 2 mol is particularly preferable.
  • the desalting agent may be blended once during the production process, or may be divided into several times.
  • Two or more drug-containing pressure-sensitive adhesive layers may be laminated on the support, and may be laminated not only on one side of the support but also on both sides.
  • the drug-containing pressure-sensitive adhesive layer may contain an absorption accelerator, a filler, an ultraviolet absorber, an antioxidant, a crosslinking agent, a preservative, etc., as necessary. Moreover, you may further contain the tackifier and plasticizer which were mentioned above.
  • aliphatic alcohols such as isostearyl alcohol, fatty acids such as capric acid, fatty acid derivatives such as propylene glycol monolaurate and isopropyl myristate, propylene glycol, polyethylene glycol, diethanolamine laurate and the like can be suitably used.
  • fatty acids such as capric acid
  • fatty acid derivatives such as propylene glycol monolaurate and isopropyl myristate
  • propylene glycol polyethylene glycol, diethanolamine laurate and the like
  • the content of the absorption enhancer can be appropriately set by those skilled in the art in consideration of sufficient permeability of the active ingredient to the tissue as a preparation, local irritation, and the like.
  • the upper limit of the content of the absorption accelerator is, for example, preferably 1% by mass or more, more preferably 3% by mass or more, based on the total mass of the patch.
  • the above is particularly preferable.
  • the lower limit of the content of the absorption accelerator is, for example, preferably 30% by mass or less, more preferably 20% by mass or less, and particularly preferably 15% by mass or less.
  • the content of the absorption accelerator is preferably 1 to 30% by mass, more preferably 3 to 20% by mass, and more preferably 3 to 15% by mass based on the total mass of the patch. It is particularly preferably 5 to 15% by mass.
  • filler examples include silicates such as aluminum silicate and magnesium silicate, aluminum hydroxide, aluminum carbonate, magnesium carbonate, silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide and the like. .
  • silicates such as aluminum silicate and magnesium silicate, aluminum hydroxide, aluminum carbonate, magnesium carbonate, silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide and the like.
  • ultraviolet absorbers examples include p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, amino acid derivatives, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives and the like.
  • the above fillers, ultraviolet absorbers, antioxidants, crosslinking agents, preservatives are in total, preferably 5% by mass or less, more preferably 3% by mass or less, based on the total mass of the drug-containing pressure-sensitive adhesive layer. Particularly preferably, it is blended in an amount of 1% by mass or less.
  • the method for producing a patch according to the present embodiment includes, for example, a step of obtaining a mixture by dissolving or dispersing a drug and an adhesive in a solvent, and a step of arranging the mixture on at least one side of a support.
  • the pressure-sensitive adhesive, the free form of nalfurafine, or the salt and desalting agent of nalfurafine, and if necessary, other components are dissolved or dispersed in a solvent, thereby the pressure-sensitive adhesive.
  • a solution that is, a mixture for forming a drug-containing pressure-sensitive adhesive layer is obtained.
  • the solvent toluene, hexane, ethyl acetate, cyclohexane, heptane, butyl acetate, ethanol, methanol, xylene, isopropanol and the like can be used. These are appropriately selected according to the components to be dissolved or dispersed, and can be used alone or in combination of two or more.
  • Specific embodiments of the step of obtaining the above mixture include an embodiment in which a free body of nalfurafine is mixed with an adhesive, and an embodiment in which a salt of nalfurafine is mixed with an adhesive together with a desalting agent.
  • Examples of the pressure-sensitive adhesive and desalting agent include the same as those described above, and the content of these is preferably as described above.
  • the obtained mixture for forming a drug-containing pressure-sensitive adhesive layer is directly spread on a support to form a drug-containing pressure-sensitive adhesive layer, or is spread on a release-treated paper or film to form a drug.
  • a containing pressure-sensitive adhesive layer is formed, a support is placed thereon, and the drug-containing pressure-sensitive adhesive layer is pressure-transferred onto the support.
  • the patch according to this embodiment obtained as described above exhibits excellent formulation stability.
  • each patch was packaged with an aluminum wrapping material and sealed. After the sealed patch was stored at 60 ° C. and 75% RH for 2 weeks, the drug content in the preparation was measured by a high performance liquid chromatograph (HPLC) method. The ratio of the drug content after storage to the drug content immediately after sealing was calculated, and the stability was evaluated.
  • HPLC high performance liquid chromatograph
  • Example 1 Using a mixer, a mixture prepared by previously mixing the free form of nalfurafine with methanol was added to and mixed with an ethyl acetate solution of the acrylic adhesive DURO-TAK 87-2510 to obtain an adhesive solution. This adhesive solution is coated on a release paper, the solvent is removed by drying, and a drug-containing adhesive layer is formed. Then, a PET film support is placed thereon, and the drug-containing adhesive layer is pressure-transferred. As a result, a patch was obtained. Table 2 shows the blending amount of the patch according to this example and the results of the stability evaluation.
  • Example 2 A patch was obtained in the same manner as in Example 1 except that as the mixture, a mixture obtained by mixing nalflaphine hydrochloride and sodium acetate as a desalting agent in methanol was used. The content of sodium acetate as a desalting agent was 1.9 mol with respect to 1 mol of nalfurafine hydrochloride. Table 2 shows the blending amount of the patch according to this example and the results of the stability evaluation.
  • Example 3 A patch was obtained in the same manner as in Example 2 except that DURO-TAK 87-235A was used instead of DURO-TAK 87-2510 as the acrylic adhesive. Table 2 shows the blending amount of the patch according to this example and the results of the stability evaluation.
  • Example 4 A patch was obtained in the same manner as in Example 2, except that DURO-TAK 87-4098 was used instead of DURO-TAK 87-2510 as the acrylic adhesive. Table 2 shows the results of the stability evaluation of the blending amount of the patch according to this example.
  • Example 1 A patch was obtained in the same manner as in Example 1 except that a mixture of nalflavine hydrochloride mixed with methanol was used as the mixture.
  • Table 2 shows the blending amount of the patch according to this comparative example and the results of the stability evaluation.
  • Comparative Example 2 A patch was obtained in the same manner as in Comparative Example 1 except that DURO-TAK 87-235A was used instead of DURO-TAK 87-2510 as the acrylic adhesive. Table 2 shows the blending amount of the patch according to this comparative example and the results of the stability evaluation.
  • Comparative Example 3 A patch was obtained in the same manner as in Comparative Example 1 except that DURO-TAK 87-4098 was used instead of DURO-TAK 87-2510 as the acrylic adhesive.
  • Table 2 shows the blending amount of the patch according to this comparative example and the results of the stability evaluation.
  • Example 5 A mixture obtained by mixing methanol with a free form of narfrafin in advance was added to SIS, an alicyclic saturated hydrocarbon resin (Arcon P100; manufactured by Arakawa Chemical Industries, Ltd., trade name) and a liquid paraffin toluene solution, and mixed. A system adhesive solution was obtained. This adhesive solution is coated on a release paper, the solvent is removed by drying, and a drug-containing adhesive layer is formed. Then, a PET film support is placed thereon, and the drug-containing adhesive layer is pressure-transferred. As a result, a patch was obtained. Table 3 shows the blending amount of the patch according to this example and the results of stability evaluation.
  • Example 6 A patch was obtained in the same manner as in Example 5 except that as the mixture, a mixture obtained by mixing nalflaphine hydrochloride and sodium acetate as a desalting agent in methanol was used. The content of sodium acetate as a desalting agent was 1.9 mol with respect to 1 mol of nalfurafine hydrochloride. Table 3 shows the blending amount of the patch according to this example and the results of stability evaluation.
  • Example 7 A patch was obtained in the same manner as in Example 6 except that an adhesive solution was obtained using SIS and PIB.
  • Table 3 shows the blending amount of the patch according to this example and the results of stability evaluation.
  • Example 8 A patch was obtained in the same manner as in Example 6 except that an adhesive solution was obtained using a toluene solution of PIB and liquid paraffin in place of the SIS, alicyclic saturated hydrocarbon resin Alcon P100 and liquid toluene solution of liquid paraffin. Got. Table 3 shows the blending amount of the patch according to this example and the results of stability evaluation.
  • Example 9 A patch was obtained in the same manner as in Example 7 except that sodium hydroxide was used instead of sodium acetate as the desalting agent.
  • the content of sodium hydroxide as a desalting agent was 1.0 mol with respect to 1 mol of nalfurafine hydrochloride.
  • Table 3 shows the blending amount of the patch according to this example and the results of stability evaluation.
  • Example 4 A patch was obtained in the same manner as in Example 5 except that a mixture obtained by mixing nalflaphine hydrochloride with methanol was used as the mixture.
  • Table 3 shows the blending amount of the patch according to this comparative example and the results of the stability evaluation.
  • Comparative Example 5 A patch was obtained in the same manner as in Comparative Example 4 except that an adhesive solution was obtained using SIS and PIB.
  • Table 3 shows the blending amount of the patch according to this comparative example and the results of the stability evaluation.
  • Comparative Example 6 A patch was obtained in the same manner as in Comparative Example 4 except that a pressure-sensitive adhesive solution was obtained using PIB and liquid paraffin instead of SIS, alicyclic saturated hydrocarbon resin Alcon P100 and liquid paraffin in toluene. .
  • Table 3 shows the blending amount of the patch according to this comparative example and the results of the stability evaluation.
  • Example 10 A mixture prepared by previously mixing methanol with a free form of narfrafin was added to and mixed with the silicone-based adhesive Bio-PSA 7-4102 to obtain an adhesive solution.
  • This adhesive solution is coated on a release paper, the solvent is removed by drying, and a drug-containing adhesive layer is formed. Then, a PET film support is placed thereon, and the drug-containing adhesive layer is pressure-transferred. As a result, a patch was obtained.
  • Table 4 shows the blending amount of the patch according to this example and the results of stability evaluation.
  • Example 11 A patch was obtained in the same manner as in Example 10 except that a mixture in which methanol was mixed with nalflaphine hydrochloride and sodium acetate as a desalting agent as the mixture was used.
  • the content of sodium acetate as a desalting agent was 1.9 mol with respect to 1 mol of nalfurafine hydrochloride.
  • Table 4 shows the results of evaluating the blending amount stability of the patch according to the present example.
  • Example 7 A patch was obtained in the same manner as in Example 10, except that a mixture obtained by mixing nalflaphine hydrochloride with methanol was used as the mixture.
  • Table 4 shows the blending amount of the patch according to this comparative example and the results of the stability evaluation.
  • nalflaphine-containing preparation that exhibits excellent preparation stability.

Abstract

This transdermal patch has a support body and an adhesive layer disposed on at least one surface of the support body and containing a drug and an adhesive, wherein at least a portion of the drug is nalfurafine in free-body form.

Description

貼付剤Patch
　本発明は、貼付剤に関する。 The present invention relates to a patch.
　血液透析患者における掻痒症は、炎症を伴わない全身性の強い痒みを誘発し、夜間の睡眠が十分に取れないなどの理由で患者のＱＯＬが大きく損なわれる疾患である。掻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塩酸塩が知られている（例えば、特許文献１等を参照。）。ナルフラフィン塩酸塩は、経口剤として、血液透析に伴う難治性の掻痒症に対して処方される。 Pruritus in hemodialysis patients is a disease in which the patient's QOL is greatly impaired due to the fact that it induces strong generalized itching without inflammation and is unable to get enough sleep at night. As a compound used for the improvement of pruritus, nalfrafin hydrochloride which is a κ-type opioid receptor agonist compound is known (see, for example, Patent Document 1). Nalfurafine hydrochloride is prescribed as an oral agent for intractable pruritus associated with hemodialysis.
特許第２５２５５５２号Japanese Patent No. 2525552
　一方で、重度の透析患者においては飲水制限が設けられる場合があり、服薬に際し水分摂取を必要としない製剤の開発が急務である。このような透析患者に対する服薬コンプライアンスを向上させるために、軟膏剤が検討されている。 On the other hand, in severe dialysis patients, there may be restrictions on drinking water, and there is an urgent need to develop a formulation that does not require water intake when taking the medicine. Ointments are being studied to improve compliance with such dialysis patients.
　他方、薬物はその取り扱い性や安定性の面から塩酸塩等の酸付加塩の形で流通させるのが一般的であり、ナルフラフィンも例外ではない。 On the other hand, drugs are generally distributed in the form of acid addition salts such as hydrochlorides from the viewpoint of handling and stability, and narfraphine is no exception.
　しかしながら、ナルフラフィン塩酸塩を含有する液剤や軟膏剤等の製剤を調製したところ、ナルフラフィンの製剤安定性が悪いことを本発明者らは見出した。また、ナルフラフィンの遊離塩基（フリー体）を用いて上記製剤を調製した場合においても、製剤安定性が悪いことを本発明者らは見出した。 However, the present inventors have found that when preparations such as liquids and ointments containing nalfurafine hydrochloride are prepared, the preparation stability of nalfurafine is poor. In addition, the present inventors have found that the preparation stability is poor even when the preparation is prepared using the free base (free form) of nalflaphine.
　そこで、本発明は、優れた製剤安定性を発揮するナルフラフィン含有製剤を提供することを目的とする。 Therefore, an object of the present invention is to provide a nalflaphine-containing preparation that exhibits excellent preparation stability.
　本発明者らは、ナルフラフィンのフリー体を含有する貼付剤を調製し、ナルフラフィンの塩酸塩を含有する貼付剤と比較したところ、上記一般的な予想に反して、フリー体を含有する貼付剤の方が優れた製剤安定性を発揮することを見出した。 The inventors of the present invention prepared a patch containing a free form of nalflaphine and compared it with a patch containing a hydrochloride of nalflaphine. It has been found that it exhibits superior formulation stability.
　すなわち、本発明は、支持体と、該支持体の少なくとも片面上に配置された、薬物及び粘着剤を含有する粘着剤層と、を備える貼付剤であって、薬物の少なくとも一部は、フリー体であるナルフラフィンである、貼付剤を提供する。 That is, the present invention is a patch comprising a support and an adhesive layer containing a drug and an adhesive disposed on at least one side of the support, wherein at least a part of the drug is free Provided is a patch that is nalflavine, which is the body.
　このような貼付剤とすることにより、優れた製剤安定性が発揮されるばかりでなく、透析患者に対する服薬コンプライアンスを向上させることができる。さらに、血中濃度を一定に保つことができることからＱＯＬを向上させるメリットもある。 By using such a patch, not only excellent formulation stability is exhibited, but also compliance with dialysis patients can be improved. Furthermore, since the blood concentration can be kept constant, there is a merit of improving QOL.
　粘着剤層は、ナルフラフィンのフリー体を粘着剤と混合させて得られたものであってもよいし、ナルフラフィンの塩を脱塩剤とともに粘着剤と混合させて得られたものであってもよい。 The pressure-sensitive adhesive layer may be obtained by mixing a free body of nalfurafine with a pressure-sensitive adhesive, or may be obtained by mixing a salt of nalfrafin with a pressure-sensitive adhesive together with a desalting agent. .
　ナルフラフィンの塩を脱塩剤とともに粘着剤と混合させる場合は、製剤化までは取り扱い性において優れる塩の形で存在させ、製剤中で脱塩剤によってフリー体に変換させることから、より効率的に製剤の調製が可能となる。 When mixing the salt of narfrafin with an adhesive together with a desalting agent, it exists in the form of a salt that is excellent in handleability until formulation, and it is converted into a free form by a desalting agent in the formulation, so it is more efficient. The formulation can be prepared.
　脱塩剤は、酢酸ナトリウム及び水酸化ナトリウムから選ばれる少なくとも１種であることが好ましく、特に酢酸ナトリウムであることがより好ましい。また、脱塩剤の含有量は、ナルフラフィンの塩１モルに対し、０．３～５モルであることが好ましい。このような貼付剤とすることにより、ナルフラフィンの塩のうちの少なくとも一部が製剤中でフリー体に変換され、より製剤安定性が向上し得る。 The desalting agent is preferably at least one selected from sodium acetate and sodium hydroxide, and more preferably sodium acetate. The content of the desalting agent is preferably 0.3 to 5 mol per 1 mol of the salt of narfrafin. By setting it as such a patch, at least one part of the salt of narfrafin is converted into a free body in a formulation, and formulation stability can be improved more.
　粘着剤は、アクリル系粘着剤、スチレンブロックコポリマー系粘着剤、ポリイソブチレン系粘着剤及びシリコーン系粘着剤から選ばれる少なくとも１種を含むことが好ましい。これらの粘着剤が粘着剤層に含まれることによって、ナルフラフィンの分解等が一層抑制され、製剤安定性をより一層向上させることができる。 The pressure-sensitive adhesive preferably contains at least one selected from an acrylic pressure-sensitive adhesive, a styrene block copolymer pressure-sensitive adhesive, a polyisobutylene pressure-sensitive adhesive, and a silicone pressure-sensitive adhesive. By including these pressure-sensitive adhesives in the pressure-sensitive adhesive layer, the decomposition of nalflaphine and the like can be further suppressed, and the formulation stability can be further improved.
　本発明によれば、優れた製剤安定性を発揮するナルフラフィン含有製剤を提供することができる。 According to the present invention, it is possible to provide a nalflaphine-containing preparation that exhibits excellent preparation stability.
　以下、本発明の好適な実施形態について詳細に説明するが、本発明はこれら実施形態に何ら限定されるものではない。 Hereinafter, preferred embodiments of the present invention will be described in detail, but the present invention is not limited to these embodiments.
　本実施形態に係る貼付剤は、支持体と、該支持体の少なくとも片面上に配置された、薬物及び粘着剤を含有する粘着剤層（薬物含有粘着剤層）と、を備える貼付剤であって、薬物の少なくとも一部は、フリー体であるナルフラフィンである。 The patch according to the present embodiment is a patch comprising a support and a pressure-sensitive adhesive layer containing a drug and a pressure-sensitive adhesive (drug-containing pressure-sensitive adhesive layer) disposed on at least one side of the support. Thus, at least a part of the drug is nalflaphine, which is a free form.
　支持体としては、通常貼付剤に使用できる伸縮性又は非伸縮性のものが用いられる。具体的には、ポリエチレンテレフタレート、ポリエチレン、ポリプロピレン、ポリブタジエン、エチレン酢酸ビニル重合体、ポリ塩化ビニル、ポリエステル、ナイロン、ポリウレタン等の合成樹脂で形成された、フィルム若しくはシート又はこれらの積層体、多孔質膜、発泡体、織布及び不織布、或いは紙材等を好適に用いることができる。 As the support, a stretchable or non-stretchable material that can be usually used for a patch is used. Specifically, a film or sheet formed of a synthetic resin such as polyethylene terephthalate, polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate polymer, polyvinyl chloride, polyester, nylon, polyurethane, or a laminate thereof, or a porous film A foam, a woven fabric and a non-woven fabric, or a paper material can be suitably used.
　粘着剤としては、例えば、アクリル系粘着剤、スチレンブロックコポリマー系粘着剤、ポリイソブチレン系粘着剤及びシリコーン系粘着剤から選ばれる少なくとも１種を含むものが挙げられる。粘着剤としては、１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。２種以上を併用して用いる粘着剤としては、スチレンブロックコポリマー系粘着剤及びポリイソブチレン系粘着剤を組み合わせる態様等が挙げられる。 Examples of the adhesive include those containing at least one selected from an acrylic adhesive, a styrene block copolymer adhesive, a polyisobutylene adhesive, and a silicone adhesive. As an adhesive, 1 type may be used independently and 2 or more types may be used in combination. Examples of the pressure-sensitive adhesive used in combination of two or more include an embodiment in which a styrene block copolymer pressure-sensitive adhesive and a polyisobutylene pressure-sensitive adhesive are combined.
　アクリル系粘着剤としては、（メタ）アクリル酸エステルの単独重合体若しくは共重合体又は（メタ）アクリル酸アルキルエステルとその他の単量体との共重合体が好適に用いられる。なお、（メタ）アクリルとは、アクリル又はメタクリルを意味する。 As the acrylic pressure-sensitive adhesive, a homopolymer or copolymer of (meth) acrylic acid ester or a copolymer of (meth) acrylic acid alkyl ester and other monomers is preferably used. In addition, (meth) acryl means acryl or methacryl.
　上記（メタ）アクリル酸エステル及び上記（メタ）アクリル酸アルキルエステルとしては、アルキルアルコール又はアルキルジオールの（メタ）アクリル酸エステルが好適に用いられる。アルキルアルコール及び上記アルキルジオールとしては、炭素数４～１６のものが好ましい。また、その他の単量体としては、例えば、スチレン、メチルスチレン、Ｎ－ビニルピロリドン、（メタ）アクリルアミド等が挙げられる。 As the (meth) acrylic acid ester and the (meth) acrylic acid alkyl ester, alkyl alcohol or alkyl diol (meth) acrylic acid ester is preferably used. As the alkyl alcohol and the alkyl diol, those having 4 to 16 carbon atoms are preferable. Examples of other monomers include styrene, methylstyrene, N-vinylpyrrolidone, (meth) acrylamide, and the like.
　このようなアクリル系粘着剤としては、例えば、ＤＵＲＯ－ＴＡＫ　８７－２５１０、ＤＵＲＯ－ＴＡＫ　８７－２３５Ａ、ＤＵＲＯ－ＴＡＫ　８７－４０９８（いずれもヘンケル社製、商品名）が挙げられる。 Examples of such acrylic pressure-sensitive adhesives include DURO-TAK 87-2510, DURO-TAK 87-235A, and DURO-TAK 87-4098 (both manufactured by Henkel Corporation).
　スチレンブロックコポリマー系粘着剤とは、スチレンブロックコポリマーに粘着付与剤等を添加し粘着性を付与したものである。スチレンブロックコポリマー系粘着剤としては、例えば、スチレン－イソプレン－スチレン（ＳＩＳ）系粘着剤、スチレン－ブタジエン－スチレン（ＳＢＳ）系粘着剤、スチレン－エチレンブチレン－スチレン（ＳＥＢＳ）系粘着剤又はスチレン－エチレンプロピレン－スチレン（ＳＥＰＳ）系粘着剤等が挙げられる。 The styrene block copolymer-based pressure-sensitive adhesive is obtained by adding a tackifier or the like to a styrene block copolymer. Examples of the styrene block copolymer adhesive include styrene-isoprene-styrene (SIS) adhesive, styrene-butadiene-styrene (SBS) adhesive, styrene-ethylenebutylene-styrene (SEBS) adhesive, and styrene- And ethylene propylene-styrene (SEPS) pressure sensitive adhesive.
　粘着付与剤としては、例えば、エステルガム（荒川化学工業社製、商品名）、ハリエスター（ハリマ化成社製、商品名）、ペンタリン（イーストマンケミカル社製、商品名）、フォーラル（イーストマンケミカル社製、商品名）等のロジン系樹脂、ＹＳレジン（ヤスハラケミカル社製、商品名）、ピコライト（ルースアンドディルワース社製、商品名）等のテルペン系樹脂、アルコン（荒川化学工業社製、商品名）、リガレッツ（イーストマンケミカル社製、商品名）、ピコラスチック（イーストマンケミカル社製、商品名）、エスコレッツ（エクソン社製、商品名）、ウイングタック（グッドイヤー社製、商品名）、クイントン（日本ゼオン社製、商品名）等の石油樹脂、フェノール系樹脂、キシレン系樹脂等が使用可能である。 Examples of the tackifier include ester gum (trade name, manufactured by Arakawa Chemical Co., Ltd.), Harrier Star (trade name, manufactured by Harima Kasei Co., Ltd.), pentalin (trade name, manufactured by Eastman Chemical Company), and formal (Eastman Chemical). Rosin resins such as YS resin (Yasuhara Chemical Co., trade name), terpene resins such as picolite (Loose and Dilworth Co., trade name), Alcon (Arakawa Chemical Co., Ltd. product) Name), Rigaletz (Eastman Chemical, trade name), Picolastic (Eastman Chemical, trade name), Escorez (Exxon, trade name), Wingtack (Goodyear, trade name), Quinton Petroleum resins such as (manufactured by Zeon Corporation, trade name), phenolic resins, xylene resins, and the like can be used.
　これらの粘着付与剤は、１種を単独で用いても、２種以上を組み合わせて用いてもよい。また、粘着付与剤の含有量は、粘着剤の十分な粘着力及び剥離時の局所刺激性を考慮し、当業者が適宜設定することが可能である。このような観点から、粘着付与剤の含有量の上限は、粘着剤層の全質量を基準として、例えば１０質量％以上であることが好ましく、１５質量％以上であることがさらに好ましく、２０質量％以上であることが特に好ましい。一方、粘着付与剤の含有量の下限は、粘着剤層の全質量を基準として、例えば９０質量％以下であることが好ましく、７０質量％以下であることがさらに好ましく、６０質量％以下であることが特に好ましい。粘着付与剤の含有量は、粘着剤層の全質量を基準として１０～９０質量％であることが好ましく、１５～７０質量％であることがさらに好ましく、２０～６０質量％であることが特に好ましい。 These tackifiers may be used alone or in combination of two or more. The content of the tackifier can be appropriately set by those skilled in the art in consideration of sufficient adhesive strength of the adhesive and local irritation at the time of peeling. From such a viewpoint, the upper limit of the content of the tackifier is preferably, for example, 10% by mass or more, more preferably 15% by mass or more, based on the total mass of the adhesive layer, and 20% by mass. % Or more is particularly preferable. On the other hand, the lower limit of the content of the tackifier is preferably, for example, 90% by mass or less, more preferably 70% by mass or less, based on the total mass of the adhesive layer, and 60% by mass or less. It is particularly preferred. The content of the tackifier is preferably 10 to 90% by mass, more preferably 15 to 70% by mass, and particularly preferably 20 to 60% by mass based on the total mass of the adhesive layer. preferable.
　ポリイソブチレン系粘着剤とは、ポリイソブチレン（ＰＩＢ）に可塑剤等を添加し粘着性を付与したものである。 The polyisobutylene-based pressure-sensitive adhesive is one obtained by adding a plasticizer or the like to polyisobutylene (PIB) to impart adhesiveness.
　可塑剤としては、例えば、パラフィン系プロセスオイル、ナフテン系プロセスオイル及び芳香族系プロセスオイル等の石油系オイル、オリーブ油、ツバキ油、ひまし油、トール油及びラッカセイ油等の植物系オイル、ジブチルフタレート及びジオクチルフタレート等の二塩基酸エステル、ポリブテン及び液状イソプレンゴム等の液状ゴム、スクワラン、スクワレン、ジエチレングリコール、ポリエチレングリコール、プロピレングリコール、ジプロピレングリコール等が挙げられる。これらは１種を単独で又は２種以上を組み合わせて用いることができる。可塑剤としては、特に流動パラフィン、ポリブテンが好ましい。 Examples of the plasticizer include petroleum oils such as paraffinic process oil, naphthenic process oil and aromatic process oil, vegetable oils such as olive oil, camellia oil, castor oil, tall oil and peanut oil, dibutyl phthalate and dioctyl. Examples thereof include dibasic acid esters such as phthalate, liquid rubbers such as polybutene and liquid isoprene rubber, squalane, squalene, diethylene glycol, polyethylene glycol, propylene glycol and dipropylene glycol. These can be used individually by 1 type or in combination of 2 or more types. As the plasticizer, liquid paraffin and polybutene are particularly preferable.
　薬物含有粘着剤層中の可塑剤の含有量は、粘着剤としての十分な粘着力の維持を考慮し、当業者が適宜調整することができる。このような観点から、可塑剤の含有量の上限は、薬物含有粘着剤層の全質量を基準として、例えば１質量％以上であることが好ましく、２質量％以上であることがより好ましく、３質量％以上であることが特に好ましい。一方、可塑剤の含有量の下限は、例えば６０質量％以下であることが好ましく、５０質量％以下であることがより好ましく、４０質量％以下であることがさらに好ましく、２０質量％以下であることが特に好ましい。可塑剤の含有量は、薬物含有粘着剤層の全質量を基準として１～６０質量％であることが好ましく、２～５０質量％であることがより好ましく、３～４０質量％であることがさらに好ましく、３～２０質量％であることが特に好ましい。 The content of the plasticizer in the drug-containing pressure-sensitive adhesive layer can be appropriately adjusted by those skilled in the art in consideration of maintaining sufficient adhesive strength as a pressure-sensitive adhesive. From such a viewpoint, the upper limit of the content of the plasticizer is, for example, preferably 1% by mass or more, more preferably 2% by mass or more, based on the total mass of the drug-containing pressure-sensitive adhesive layer. It is particularly preferable that the content is at least mass%. On the other hand, the lower limit of the content of the plasticizer is, for example, preferably 60% by mass or less, more preferably 50% by mass or less, further preferably 40% by mass or less, and 20% by mass or less. It is particularly preferred. The plasticizer content is preferably 1 to 60% by mass, more preferably 2 to 50% by mass, and more preferably 3 to 40% by mass based on the total mass of the drug-containing pressure-sensitive adhesive layer. Further preferred is 3 to 20% by mass.
　シリコーン系粘着剤とは、ジメチルポリシロキサンと、三次元構造のシリケートレジンとの縮合反応物からなる粘着剤であり、例えばＢｉｏ－ＰＳＡ　７－４１０２（ダウコーニング社製、商品名）等を挙げることができる。 The silicone-based adhesive is an adhesive made of a condensation reaction product of dimethylpolysiloxane and a three-dimensional silicate resin, and examples thereof include Bio-PSA 7-4102 (trade name, manufactured by Dow Corning). Can do.
　これらの各種粘着剤は、１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。また、粘着剤の含有量は、薬物含有粘着剤層の形成及び粘着性、有効成分の組織透過性を考慮し、当業者によって適宜設定され得る。
　なお、スチレンブロックコポリマー系粘着剤とポリイソブチレン系粘着剤とを組み合わせて用いると、それぞれを単独で用いる場合と比較して、ナルフラフィンの製剤安定性がさらに向上するばかりでなく、貼付剤の凝集力、粘着力、皮膚への付着性もさらに改善される傾向がある。スチレンブロックコポリマー系粘着剤とポリイソブチレン系粘着剤を組み合わせる比率としては、スチレンブロックコポリマーに対してポリイソブチレンが１：１０～１０：１の範囲であることが好ましく、１：１～９：１の範囲であることがより好ましく、６：４～８：１の範囲であることがさらに好ましい。
　また、スチレンブロックコポリマーを含有する粘着剤においては、上記粘着付与剤の含有量は特に制限はないが、上記可塑剤の含有量を基準として、例えば、０．４倍以上であってもよく、０．５倍以上であってもよく、１倍以上であってもよく、１．５倍以上であってもよく、２倍以上であってもよく、２．５倍以上であってもよく、３倍以上であってもよく、３．５倍以上であってもよい。他方、粘着付与剤の含有量の上限は特に制限はないが、例えば、可塑剤の含有量を基準として１００倍以下であってもよく、５０倍以下であってもよく、１０倍以下であってもよく、５倍以下であってもよく、４倍以下であってもよい。粘着付与剤の含有量を多くすることによって、貼付剤の皮膚への付着性をより効果的に向上させることができる。
　粘着剤の含有量の上限は、薬物含有粘着剤層の全体の質量を基準として、例えば１０質量％以上であることが好ましく、１５質量％以上であることがより好ましく、２０質量％以上であることがさらに好ましい。一方、粘着剤の含有量の下限は、例えば９９質量％以下であることが好ましく、９０質量％以下であることがより好ましく、８５質量％以下であることがさらに好ましい。例えば、粘着剤の含有量は、薬物含有粘着剤層の全体の質量を基準として１０～９９質量％であってよく、１５～９０質量％であってもよい。特に２０～８５質量％であることが好ましい。 These various adhesives may be used individually by 1 type, and may be used in combination of 2 or more type. Further, the content of the pressure-sensitive adhesive can be appropriately set by those skilled in the art in consideration of the formation and adhesion of the drug-containing pressure-sensitive adhesive layer and the tissue permeability of the active ingredient.
In addition, using a combination of a styrene block copolymer adhesive and a polyisobutylene adhesive not only further improves the formulation stability of narfrafin, but also improves the cohesive strength of the patch. Also, the adhesive strength and the adhesion to the skin tend to be further improved. The ratio of the styrene block copolymer pressure-sensitive adhesive and the polyisobutylene pressure-sensitive adhesive is preferably in the range of 1:10 to 10: 1 with respect to the styrene block copolymer, preferably 1: 1 to 9: 1. More preferably, it is in the range of 6: 4 to 8: 1.
Further, in the pressure-sensitive adhesive containing the styrene block copolymer, the content of the tackifier is not particularly limited, but may be, for example, 0.4 times or more based on the content of the plasticizer, It may be 0.5 times or more, 1 time or more, 1.5 times or more, 2 times or more, or 2.5 times or more It may be 3 times or more, or 3.5 times or more. On the other hand, the upper limit of the content of the tackifier is not particularly limited. For example, it may be 100 times or less, 50 times or less, or 10 times or less based on the content of the plasticizer. It may be 5 times or less, or 4 times or less. By increasing the content of the tackifier, the adhesiveness of the patch to the skin can be improved more effectively.
The upper limit of the content of the adhesive is, for example, preferably 10% by mass or more, more preferably 15% by mass or more, and more preferably 20% by mass or more based on the total mass of the drug-containing adhesive layer. More preferably. On the other hand, the lower limit of the content of the pressure-sensitive adhesive is, for example, preferably 99% by mass or less, more preferably 90% by mass or less, and further preferably 85% by mass or less. For example, the content of the pressure-sensitive adhesive may be 10 to 99% by mass or 15 to 90% by mass based on the total mass of the drug-containing pressure-sensitive adhesive layer. In particular, the content is preferably 20 to 85% by mass.
　薬物含有粘着剤層における薬物のうちの少なくとも一部は、フリー体であるナルフラフィンである。すなわち、薬物含有粘着剤層においてナルフラフィンのフリー体が存在していればよく、ナルフラフィンの塩が共存していてもよい。さらに、必要に応じて他の薬物を含んでいてもよい。薬物含有粘着剤層の製造に際しては、ナルフラフィンのフリー体が原材料として使用されていてもよいし、ナルフラフィンの塩が原材料として脱塩剤とともに使用されていてもよい。ナルフラフィンの塩が原材料として脱塩剤とともに使用された場合、貼付剤の製造中又は製造後に、該塩のうちの少なくとも一部がフリー体に変換される。 少 な く と も At least a part of the drug in the drug-containing pressure-sensitive adhesive layer is a free form of narfraphine. That is, it is only necessary that a free form of nalflaphine exists in the drug-containing pressure-sensitive adhesive layer, and a salt of nalfurafine may coexist. Furthermore, other drugs may be included as necessary. In the production of the drug-containing pressure-sensitive adhesive layer, a free form of nalfurafine may be used as a raw material, or a salt of nalfurafine may be used as a raw material together with a desalting agent. When a salt of narfrafin is used as a raw material together with a desalting agent, at least a part of the salt is converted into a free form during or after the manufacture of the patch.
　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限定されるものではないが、貼付剤製造前の保管安定性の観点から、ナルフラフィンの酸付加塩であることが好ましい。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、クエン酸塩、ヨウ化水素酸塩、臭化水素酸塩、メシル酸塩、酒石酸塩、コハク酸塩等を例示することができる。 The salt of nalfurafine is not particularly limited as long as it is a pharmaceutically acceptable salt, but is preferably an acid addition salt of nalfurafine from the viewpoint of storage stability before producing the patch. Examples of acid addition salts include hydrochloride, acetate, maleate, oxalate, citrate, hydroiodide, hydrobromide, mesylate, tartrate, succinate, etc. be able to.
　ナルフラフィンの塩とともに使用される脱塩剤としては、ナルフラフィンの酸付加塩をフリー体に変換させる場合は塩基性物質が好適である。このような脱塩剤の具体例としては、特に酢酸ナトリウム、水酸化ナトリウム等が挙げられ、この中でも酢酸ナトリウムが好ましい。脱塩剤は、ナルフラフィンの塩のうちの少なくとも一部を製剤中でフリー体に変換させるために使用されるが、必ずしもナルフラフィンの塩の全量がフリー体に変換されなくともよく、実質的に製剤安定性が向上し得る範囲でフリー体に変換されていればよい。このような観点から、脱塩剤の含有量の上限は、ナルフラフィンの塩１モルに対し、０．３モル以上であることが好ましく、０．５モル以上であることがより好ましく、１モル以上であることがさらに好ましく、１．５モル以上であることが特に好ましく、１．８モル以上であることが最も好ましい。一方、脱塩剤の含有量の下限は、５モル以下であることが好ましく、３モル以下であることがより好ましく、２モル以下であることがさらに好ましい。脱塩剤の含有量は、ナルフラフィンの塩１モルに対し、０．３～５モルの範囲内の量であることが好ましく、０．５～３モルの範囲内の量であることがより好ましく、０．５～２モルの範囲内の量であることが特に好ましい。脱塩剤の配合は、製造工程中１回で行ってもよいし、数回に分けて行ってもよい。 As the desalting agent used together with the salt of nalfurafine, a basic substance is preferable when the acid addition salt of nalfurafine is converted into a free form. Specific examples of such a desalting agent include sodium acetate and sodium hydroxide, among which sodium acetate is preferable. The desalting agent is used to convert at least a part of the salt of nalfurafine into a free form in the preparation. It may be converted into a free body as long as stability can be improved. From such a viewpoint, the upper limit of the content of the desalting agent is preferably 0.3 mol or more, more preferably 0.5 mol or more, and more preferably 1 mol or more with respect to 1 mol of the salt of nalfurafine. Is more preferably 1.5 mol or more, and most preferably 1.8 mol or more. On the other hand, the lower limit of the content of the desalting agent is preferably 5 mol or less, more preferably 3 mol or less, and even more preferably 2 mol or less. The content of the desalting agent is preferably in the range of 0.3 to 5 mol, more preferably in the range of 0.5 to 3 mol, with respect to 1 mol of the salt of narfrafin. An amount in the range of 0.5 to 2 mol is particularly preferable. The desalting agent may be blended once during the production process, or may be divided into several times.
　薬物含有粘着剤層は、支持体に２層以上積層されていてもよく、支持体の一方の面だけでなく両方の面に積層されていてもよい。 Two or more drug-containing pressure-sensitive adhesive layers may be laminated on the support, and may be laminated not only on one side of the support but also on both sides.
　薬物含有粘着剤層は、必要に応じて、吸収促進剤、充填剤、紫外線吸収剤、抗酸化剤、架橋剤、保存剤等を含有してもよい。また、上述した粘着付与剤や可塑剤をさらに含有していてもよい。 The drug-containing pressure-sensitive adhesive layer may contain an absorption accelerator, a filler, an ultraviolet absorber, an antioxidant, a crosslinking agent, a preservative, etc., as necessary. Moreover, you may further contain the tackifier and plasticizer which were mentioned above.
　吸収促進剤としては、イソステアリルアルコール等の脂肪族アルコール、カプリン酸等の脂肪酸、プロピレングリコールモノラウレートやミリスチン酸イソプロピル等の脂肪酸誘導体、プロピレングリコール、ポリエチレングリコール、ラウリン酸ジエタノールアミン等が好適に使用できる。これらの吸収促進剤は１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。また、吸収促進剤の含有量は、製剤としての組織への有効成分の十分な透過性及び局所刺激性等を考慮し、当業者によって適宜設定され得る。このような観点から、吸収促進剤の含有量の上限は、貼付剤の全質量を基準として、例えば１質量％以上であることが好ましく、３質量％以上であることがさらに好ましく、５質量％以上であることが特に好ましい。一方、吸収促進剤の含有量の下限は、例えば３０質量％以下であることが好ましく、２０質量％以下であることがさらに好ましく、１５質量％以下であることが特に好ましい。吸収促進剤の含有量は、貼付剤の全質量を基準として１～３０質量％であることが好ましく、３～２０質量％であることがさらに好ましく、３～１５質量％であることがより好ましく、５～１５質量％であることが特に好ましい。 As the absorption accelerator, aliphatic alcohols such as isostearyl alcohol, fatty acids such as capric acid, fatty acid derivatives such as propylene glycol monolaurate and isopropyl myristate, propylene glycol, polyethylene glycol, diethanolamine laurate and the like can be suitably used. . One of these absorption promoters may be used alone, or two or more thereof may be used in combination. The content of the absorption enhancer can be appropriately set by those skilled in the art in consideration of sufficient permeability of the active ingredient to the tissue as a preparation, local irritation, and the like. From such a viewpoint, the upper limit of the content of the absorption accelerator is, for example, preferably 1% by mass or more, more preferably 3% by mass or more, based on the total mass of the patch. The above is particularly preferable. On the other hand, the lower limit of the content of the absorption accelerator is, for example, preferably 30% by mass or less, more preferably 20% by mass or less, and particularly preferably 15% by mass or less. The content of the absorption accelerator is preferably 1 to 30% by mass, more preferably 3 to 20% by mass, and more preferably 3 to 15% by mass based on the total mass of the patch. It is particularly preferably 5 to 15% by mass.
　充填剤としては、ケイ酸アルミニウムやケイ酸マグネシウム等のケイ酸塩、水酸化アルミニウム、炭酸アルミニウム、炭酸マグネシウム、ケイ酸、硫酸バリウム、硫酸カルシウム、亜鉛酸カルシウム、酸化亜鉛、酸化チタン等が例示できる。 Examples of the filler include silicates such as aluminum silicate and magnesium silicate, aluminum hydroxide, aluminum carbonate, magnesium carbonate, silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide and the like. .
　紫外線吸収剤としては、ｐ－アミノ安息香酸誘導体、アントラニル酸誘導体、サリチル酸誘導体、クマリン誘導体、アミノ酸誘導体、イミダゾリン誘導体、ピリミジン誘導体、ジオキサン誘導体等が例示できる。 Examples of ultraviolet absorbers include p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, amino acid derivatives, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives and the like.
　上記の充填剤、紫外線吸収剤、抗酸化剤、架橋剤、保存剤は、合計で、薬物含有粘着剤層の全質量に基づいて、好ましくは５質量％以下、さらに好ましくは３質量％以下、特に好ましくは１質量％以下の量で配合される。 The above fillers, ultraviolet absorbers, antioxidants, crosslinking agents, preservatives are in total, preferably 5% by mass or less, more preferably 3% by mass or less, based on the total mass of the drug-containing pressure-sensitive adhesive layer. Particularly preferably, it is blended in an amount of 1% by mass or less.
　以下、本実施形態に係る貼付剤の製造方法の一例を示す。 Hereinafter, an example of a method for producing the patch according to the present embodiment will be shown.
　本実施形態に係る貼付剤の製造方法は、例えば、薬物及び粘着剤を溶媒に溶解又は分散させて混合物を得る工程と、当該混合物を支持体の少なくとも片面上に配置させる工程と、を備える。 The method for producing a patch according to the present embodiment includes, for example, a step of obtaining a mixture by dissolving or dispersing a drug and an adhesive in a solvent, and a step of arranging the mixture on at least one side of a support.
　より具体的には、混合機を用いて、粘着剤、ナルフラフィンのフリー体、又はナルフラフィンの塩並びに脱塩剤、及び必要に応じてその他の成分を、溶媒に溶解又は分散させることにより、粘着剤溶液、すなわち薬物含有粘着剤層形成用の混合物が得られる。上記溶媒としては、トルエン、ヘキサン、酢酸エチル、シクロヘキサン、ヘプタン、酢酸ブチル、エタノール、メタノール、キシレン、イソプロパノール等が使用できる。これらは、溶解又は分散させる成分に応じて適宜選択し、１種を単独で又は２種以上を混合して組み合わせて用いることができる。 More specifically, by using a mixer, the pressure-sensitive adhesive, the free form of nalfurafine, or the salt and desalting agent of nalfurafine, and if necessary, other components are dissolved or dispersed in a solvent, thereby the pressure-sensitive adhesive. A solution, that is, a mixture for forming a drug-containing pressure-sensitive adhesive layer is obtained. As the solvent, toluene, hexane, ethyl acetate, cyclohexane, heptane, butyl acetate, ethanol, methanol, xylene, isopropanol and the like can be used. These are appropriately selected according to the components to be dissolved or dispersed, and can be used alone or in combination of two or more.
　上記混合物を得る工程の具体的な態様としては、ナルフラフィンのフリー体を粘着剤と混合させる態様、及びナルフラフィンの塩を脱塩剤とともに粘着剤と混合させる態様等が挙げられる。 Specific embodiments of the step of obtaining the above mixture include an embodiment in which a free body of nalfurafine is mixed with an adhesive, and an embodiment in which a salt of nalfurafine is mixed with an adhesive together with a desalting agent.
　上記粘着剤及び脱塩剤としては、例えば上記で述べたものと同様のものが挙げられ、これらの含有量は、それぞれ上述したとおりであることが好ましい。 Examples of the pressure-sensitive adhesive and desalting agent include the same as those described above, and the content of these is preferably as described above.
　得られた薬物含有粘着剤層形成用の混合物を、支持体の上に直接展延して薬物含有粘着剤層を形成するか、或いは離型処理された紙又はフィルム上に展延して薬物含有粘着剤層を形成し、その上に支持体を載せて、薬物含有粘着剤層を支持体上に圧着転写させる。 The obtained mixture for forming a drug-containing pressure-sensitive adhesive layer is directly spread on a support to form a drug-containing pressure-sensitive adhesive layer, or is spread on a release-treated paper or film to form a drug. A containing pressure-sensitive adhesive layer is formed, a support is placed thereon, and the drug-containing pressure-sensitive adhesive layer is pressure-transferred onto the support.
　上記のようにして得られた本実施形態に係る貼付剤は、優れた製剤安定性を発揮する。 The patch according to this embodiment obtained as described above exhibits excellent formulation stability.
　以下、実施例に基づいて本発明を具体的に説明するが、本発明はこれらに何ら限定されるものではなく、本発明の趣旨を逸脱しない範囲での種々の変更が可能である。なお、各実施例及び比較例並びに各表における配合量に関する「％」は、質量％を意味する。 Hereinafter, the present invention will be specifically described based on examples, but the present invention is not limited thereto, and various modifications can be made without departing from the gist of the present invention. In addition, "%" regarding the compounding quantity in each Example, Comparative Example, and each table | surface means the mass%.
　以下の各実施例及び比較例で製造された貼付剤の安定性評価は以下のようにして行った。まず、貼付剤をそれぞれアルミ包材にて包装し密閉した。密閉した貼付剤を６０℃、７５％ＲＨで２週間保存した後、製剤中の薬物含量を高速液体クロマトグラフ（ＨＰＬＣ）法により測定した。密閉直後の薬物含量に対する保存後の薬物含量の割合を算出し、安定性を評価した。 The stability evaluation of the patches produced in the following Examples and Comparative Examples was performed as follows. First, each patch was packaged with an aluminum wrapping material and sealed. After the sealed patch was stored at 60 ° C. and 75% RH for 2 weeks, the drug content in the preparation was measured by a high performance liquid chromatograph (HPLC) method. The ratio of the drug content after storage to the drug content immediately after sealing was calculated, and the stability was evaluated.
（参考例）
　ナルフラフィンフリー体及び塩酸塩の原末における安定性を確認するために、２０ｍｇのナルフラフィンフリー体及び塩酸塩をそれぞれ５０ｍＬのメタノールで溶解し、６０℃、７５％ＲＨで２週間保存した後、メタノールで１０００倍希釈したサンプルを高速液体クロマトグラフィー（ＨＰＬＣ）法により測定した。保存開始直後のナルフラフィン含量に対する、保存後の含量割合を表１に示す。 (Reference example)
In order to confirm the stability in the bulk powder of nalflaphine-free product and hydrochloride, 20 mg of nalflaphine-free product and hydrochloride were each dissolved in 50 mL of methanol and stored at 60 ° C. and 75% RH for 2 weeks. A sample diluted 1000 times with methanol was measured by a high performance liquid chromatography (HPLC) method. Table 1 shows the ratio of the content after storage to the content of nalflaphine immediately after the start of storage.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　表１に示されるように、ナルフラフィンの原末は、他の一般的な薬剤と同様にフリー体よりも塩酸塩の方が保存安定性がよいことが確認された。 As shown in Table 1, it was confirmed that the bulk powder of nalfrafin was better in storage stability in the hydrochloride than in the free form, as in other general drugs.
（実施例１）
　混合機を用いて予めナルフラフィンのフリー体をメタノールに混合させた混合物を、アクリル系粘着剤ＤＵＲＯ－ＴＡＫ　８７－２５１０の酢酸エチル溶液に添加、混合し、粘着剤溶液を得た。この粘着剤溶液を離型紙上に塗工し、溶媒を乾燥除去して、薬物含有粘着剤層を形成させた後、その上にＰＥＴフィルム支持体を載せ、薬物含有粘着剤層を圧着転写させることにより貼付剤を得た。本実施例に係る貼付剤の配合量及び安定性評価の結果を表２に示す。 Example 1
Using a mixer, a mixture prepared by previously mixing the free form of nalfurafine with methanol was added to and mixed with an ethyl acetate solution of the acrylic adhesive DURO-TAK 87-2510 to obtain an adhesive solution. This adhesive solution is coated on a release paper, the solvent is removed by drying, and a drug-containing adhesive layer is formed. Then, a PET film support is placed thereon, and the drug-containing adhesive layer is pressure-transferred. As a result, a patch was obtained. Table 2 shows the blending amount of the patch according to this example and the results of the stability evaluation.
（実施例２）
　混合物として、ナルフラフィン塩酸塩及び脱塩剤としての酢酸ナトリウムをメタノールに混合させた混合物を用いた以外は、実施例１と同様の方法によって貼付剤を得た。脱塩剤としての酢酸ナトリウムの含有量は、ナルフラフィン塩酸塩１モルに対し、１．９モルとした。本実施例に係る貼付剤の配合量及び安定性評価の結果を表２に示す。 (Example 2)
A patch was obtained in the same manner as in Example 1 except that as the mixture, a mixture obtained by mixing nalflaphine hydrochloride and sodium acetate as a desalting agent in methanol was used. The content of sodium acetate as a desalting agent was 1.9 mol with respect to 1 mol of nalfurafine hydrochloride. Table 2 shows the blending amount of the patch according to this example and the results of the stability evaluation.
（実施例３）
　アクリル系粘着剤として、ＤＵＲＯ－ＴＡＫ　８７－２５１０に替えてＤＵＲＯ－ＴＡＫ　８７－２３５Ａを用いた以外は、実施例２と同様の方法によって貼付剤を得た。本実施例に係る貼付剤の配合量及び安定性評価の結果を表２に示す。 Example 3
A patch was obtained in the same manner as in Example 2 except that DURO-TAK 87-235A was used instead of DURO-TAK 87-2510 as the acrylic adhesive. Table 2 shows the blending amount of the patch according to this example and the results of the stability evaluation.
（実施例４）
　アクリル系粘着剤として、ＤＵＲＯ－ＴＡＫ　８７－２５１０に替えてＤＵＲＯ－ＴＡＫ　８７－４０９８を用いた以外は、実施例２と同様の方法によって貼付剤を得た。本実施例に係る貼付剤の配合量安定性評価の結果を表２に示す。 Example 4
A patch was obtained in the same manner as in Example 2, except that DURO-TAK 87-4098 was used instead of DURO-TAK 87-2510 as the acrylic adhesive. Table 2 shows the results of the stability evaluation of the blending amount of the patch according to this example.
（比較例１）
　混合物として、ナルフラフィン塩酸塩をメタノールに混合させた混合物を用いた以外は、実施例１と同様の方法によって貼付剤を得た。本比較例に係る貼付剤の配合量及び安定性評価の結果を表２に示す。 (Comparative Example 1)
A patch was obtained in the same manner as in Example 1 except that a mixture of nalflavine hydrochloride mixed with methanol was used as the mixture. Table 2 shows the blending amount of the patch according to this comparative example and the results of the stability evaluation.
（比較例２）
　アクリル系粘着剤として、ＤＵＲＯ－ＴＡＫ　８７－２５１０に替えてＤＵＲＯ－ＴＡＫ　８７－２３５Ａを用いた以外は、比較例１と同様の方法によって貼付剤を得た。本比較例に係る貼付剤の配合量及び安定性評価の結果を表２に示す。 (Comparative Example 2)
A patch was obtained in the same manner as in Comparative Example 1 except that DURO-TAK 87-235A was used instead of DURO-TAK 87-2510 as the acrylic adhesive. Table 2 shows the blending amount of the patch according to this comparative example and the results of the stability evaluation.
（比較例３）
　アクリル系粘着剤として、ＤＵＲＯ－ＴＡＫ　８７－２５１０に替えてＤＵＲＯ－ＴＡＫ　８７－４０９８を用いた以外は、比較例１と同様の方法によって貼付剤を得た。本比較例に係る貼付剤の配合量及び安定性評価の結果を表２に示す。 (Comparative Example 3)
A patch was obtained in the same manner as in Comparative Example 1 except that DURO-TAK 87-4098 was used instead of DURO-TAK 87-2510 as the acrylic adhesive. Table 2 shows the blending amount of the patch according to this comparative example and the results of the stability evaluation.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
（実施例５）
　予め、ナルフラフィンのフリー体をメタノールに混合させた混合物を、ＳＩＳ、脂環族飽和炭化水素樹脂（アルコンＰ１００；荒川化学工業社製、商品名）及び流動パラフィンのトルエン溶液に添加、混合し、ＳＩＳ系粘着剤溶液を得た。この粘着剤溶液を離型紙上に塗工し、溶媒を乾燥除去して、薬物含有粘着剤層を形成させた後、その上にＰＥＴフィルム支持体を載せ、薬物含有粘着剤層を圧着転写させることにより貼付剤を得た。本実施例に係る貼付剤の配合量及び安定性評価の結果を表３に示す。 (Example 5)
A mixture obtained by mixing methanol with a free form of narfrafin in advance was added to SIS, an alicyclic saturated hydrocarbon resin (Arcon P100; manufactured by Arakawa Chemical Industries, Ltd., trade name) and a liquid paraffin toluene solution, and mixed. A system adhesive solution was obtained. This adhesive solution is coated on a release paper, the solvent is removed by drying, and a drug-containing adhesive layer is formed. Then, a PET film support is placed thereon, and the drug-containing adhesive layer is pressure-transferred. As a result, a patch was obtained. Table 3 shows the blending amount of the patch according to this example and the results of stability evaluation.
（実施例６）
　混合物として、ナルフラフィン塩酸塩及び脱塩剤としての酢酸ナトリウムをメタノールに混合させた混合物を用いた以外は、実施例５と同様の方法によって貼付剤を得た。脱塩剤としての酢酸ナトリウムの含有量は、ナルフラフィン塩酸塩１モルに対し、１．９モルとした。本実施例に係る貼付剤の配合量及び安定性評価の結果を表３に示す。 (Example 6)
A patch was obtained in the same manner as in Example 5 except that as the mixture, a mixture obtained by mixing nalflaphine hydrochloride and sodium acetate as a desalting agent in methanol was used. The content of sodium acetate as a desalting agent was 1.9 mol with respect to 1 mol of nalfurafine hydrochloride. Table 3 shows the blending amount of the patch according to this example and the results of stability evaluation.
（実施例７）
　ＳＩＳ及びＰＩＢを用いて粘着剤溶液を得た以外は、実施例６と同様の方法によって貼付剤を得た。本実施例に係る貼付剤の配合量及び安定性評価の結果を表３に示す。 (Example 7)
A patch was obtained in the same manner as in Example 6 except that an adhesive solution was obtained using SIS and PIB. Table 3 shows the blending amount of the patch according to this example and the results of stability evaluation.
（実施例８）
　ＳＩＳ、脂環族飽和炭化水素樹脂アルコンＰ１００及び流動パラフィンのトルエン溶液に替えて、ＰＩＢ及び流動パラフィンのトルエン溶液を用いて粘着剤溶液を得た以外は、実施例６と同様の方法によって貼付剤を得た。本実施例に係る貼付剤の配合量及び安定性評価の結果を表３に示す。 (Example 8)
A patch was obtained in the same manner as in Example 6 except that an adhesive solution was obtained using a toluene solution of PIB and liquid paraffin in place of the SIS, alicyclic saturated hydrocarbon resin Alcon P100 and liquid toluene solution of liquid paraffin. Got. Table 3 shows the blending amount of the patch according to this example and the results of stability evaluation.
（実施例９）
　脱塩剤としての酢酸ナトリウムに替えて水酸化ナトリウムを用いた以外は、実施例７と同様の方法によって貼付剤を得た。脱塩剤としての水酸化ナトリウムの含有量は、ナルフラフィン塩酸塩１モルに対し、１．０モルとした。本実施例に係る貼付剤の配合量及び安定性評価の結果を表３に示す。 Example 9
A patch was obtained in the same manner as in Example 7 except that sodium hydroxide was used instead of sodium acetate as the desalting agent. The content of sodium hydroxide as a desalting agent was 1.0 mol with respect to 1 mol of nalfurafine hydrochloride. Table 3 shows the blending amount of the patch according to this example and the results of stability evaluation.
（比較例４）
　混合物として、ナルフラフィン塩酸塩をメタノールに混合させた混合物を用いた以外は、実施例５と同様の方法によって貼付剤を得た。本比較例に係る貼付剤の配合量及び安定性評価の結果を表３に示す。 (Comparative Example 4)
A patch was obtained in the same manner as in Example 5 except that a mixture obtained by mixing nalflaphine hydrochloride with methanol was used as the mixture. Table 3 shows the blending amount of the patch according to this comparative example and the results of the stability evaluation.
（比較例５）
　ＳＩＳ及びＰＩＢを用いて粘着剤溶液を得た以外は、比較例４と同様の方法によって貼付剤を得た。本比較例に係る貼付剤の配合量及び安定性評価の結果を表３に示す。 (Comparative Example 5)
A patch was obtained in the same manner as in Comparative Example 4 except that an adhesive solution was obtained using SIS and PIB. Table 3 shows the blending amount of the patch according to this comparative example and the results of the stability evaluation.
（比較例６）
　ＳＩＳ、脂環族飽和炭化水素樹脂アルコンＰ１００及び流動パラフィンのトルエン溶液に替えて、ＰＩＢ及び流動パラフィンを用いて粘着剤溶液を得た以外は、比較例４と同様の方法によって貼付剤を得た。本比較例に係る貼付剤の配合量及び安定性評価の結果を表３に示す。 (Comparative Example 6)
A patch was obtained in the same manner as in Comparative Example 4 except that a pressure-sensitive adhesive solution was obtained using PIB and liquid paraffin instead of SIS, alicyclic saturated hydrocarbon resin Alcon P100 and liquid paraffin in toluene. . Table 3 shows the blending amount of the patch according to this comparative example and the results of the stability evaluation.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
（実施例１０）
　予め、ナルフラフィンのフリー体をメタノールに混合させた混合物を、シリコーン系粘着剤Ｂｉｏ－ＰＳＡ　７－４１０２に添加、混合し、粘着剤溶液を得た。この粘着剤溶液を離型紙上に塗工し、溶媒を乾燥除去して、薬物含有粘着剤層を形成させた後、その上にＰＥＴフィルム支持体を載せ、薬物含有粘着剤層を圧着転写させることにより貼付剤を得た。本実施例に係る貼付剤の配合量及び安定性評価の結果を表４に示す。 (Example 10)
A mixture prepared by previously mixing methanol with a free form of narfrafin was added to and mixed with the silicone-based adhesive Bio-PSA 7-4102 to obtain an adhesive solution. This adhesive solution is coated on a release paper, the solvent is removed by drying, and a drug-containing adhesive layer is formed. Then, a PET film support is placed thereon, and the drug-containing adhesive layer is pressure-transferred. As a result, a patch was obtained. Table 4 shows the blending amount of the patch according to this example and the results of stability evaluation.
（実施例１１）
　混合物として、ナルフラフィン塩酸塩及び脱塩剤としての酢酸ナトリウムをメタノールに混合させた混合物を用いた以外は、実施例１０と同様の方法によって貼付剤を得た。脱塩剤としての酢酸ナトリウムの含有量は、ナルフラフィン塩酸塩１モルに対し、１．９モルとした。本実施例に係る貼付剤の配合量安定性評価の結果を表４に示す。 (Example 11)
A patch was obtained in the same manner as in Example 10 except that a mixture in which methanol was mixed with nalflaphine hydrochloride and sodium acetate as a desalting agent as the mixture was used. The content of sodium acetate as a desalting agent was 1.9 mol with respect to 1 mol of nalfurafine hydrochloride. Table 4 shows the results of evaluating the blending amount stability of the patch according to the present example.
（比較例７）
　混合物として、ナルフラフィン塩酸塩をメタノールに混合させた混合物を用いた以外は、実施例１０と同様の方法によって貼付剤を得た。本比較例に係る貼付剤の配合量及び安定性評価の結果を表４に示す。 (Comparative Example 7)
A patch was obtained in the same manner as in Example 10, except that a mixture obtained by mixing nalflaphine hydrochloride with methanol was used as the mixture. Table 4 shows the blending amount of the patch according to this comparative example and the results of the stability evaluation.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　表２～４に示されるように、粘着剤として、アクリル系粘着剤、ＳＩＳ系粘着剤、ＰＩＢ系粘着剤、及びシリコーン系粘着剤のいずれを用いた場合にも、ナルフラフィンのフリー体が原材料として使用されるか、又はその塩酸塩が原材料として脱塩剤とともに使用されることによって、製剤安定性が向上することが分かった。 As shown in Tables 2 to 4, when any of an acrylic adhesive, a SIS adhesive, a PIB adhesive, and a silicone adhesive is used as the adhesive, a free form of narfrafin is used as a raw material. It has been found that formulation stability is improved when used or when its hydrochloride salt is used as a raw material with a desalting agent.
　この結果は、薬剤は塩の状態の方がフリー体の状態よりも保存安定性が高いという、一般的な予想に反し驚くべきものである。 This result is surprising, contrary to the general expectation that the drug is more storage stable in the salt form than in the free form.
　中でも、表３及び４に示すように、ＳＩＳ系粘着剤、ＰＩＢ系粘着剤、及びシリコーン系粘着剤を用いた場合に、特に良好な安定性を示した。 In particular, as shown in Tables 3 and 4, when SIS adhesive, PIB adhesive, and silicone adhesive were used, particularly good stability was exhibited.
　本発明によれば、優れた製剤安定性を発揮するナルフラフィン含有製剤を提供することができる。 According to the present invention, it is possible to provide a nalflaphine-containing preparation that exhibits excellent preparation stability.

Claims (6)

  1. 　支持体と、該支持体の少なくとも片面上に配置された、薬物及び粘着剤を含有する粘着剤層と、を備える貼付剤であって、
    　前記薬物の少なくとも一部は、フリー体であるナルフラフィンである、貼付剤。     A patch comprising: a support; and an adhesive layer containing a drug and an adhesive disposed on at least one side of the support,
    The patch, wherein at least a part of the drug is nalflaphine which is a free form.
  2. 　前記粘着剤層は、ナルフラフィンのフリー体を前記粘着剤と混合させて得られたものであるか、又はナルフラフィンの塩を脱塩剤とともに前記粘着剤と混合させて得られたものである、請求項１に記載の貼付剤。 The pressure-sensitive adhesive layer is obtained by mixing a free body of nalfurafine with the pressure-sensitive adhesive, or obtained by mixing a salt of nalfurafine with the pressure-sensitive adhesive together with a desalting agent. Item 4. The patch according to Item 1.
  3. 　前記脱塩剤は、酢酸ナトリウム及び水酸化ナトリウムから選ばれる少なくとも１種である、請求項２に記載の貼付剤。 The patch according to claim 2, wherein the desalting agent is at least one selected from sodium acetate and sodium hydroxide.
  4. 　前記脱塩剤は、酢酸ナトリウムである、請求項２又は３に記載の貼付剤。 The patch according to claim 2 or 3, wherein the desalting agent is sodium acetate.
  5. 　前記脱塩剤の含有量は、ナルフラフィンの塩１モルに対し、０．３～５モルである、請求項２～４のいずれか一項に記載の貼付剤。 The patch according to any one of claims 2 to 4, wherein the content of the desalting agent is 0.3 to 5 mol with respect to 1 mol of the salt of narfrafin.
  6. 　前記粘着剤は、アクリル系粘着剤、スチレンブロックコポリマー系粘着剤、ポリイソブチレン系粘着剤及びシリコーン系粘着剤から選ばれる少なくとも１種を含む、請求項１～５のいずれか一項に記載の貼付剤。 The adhesive according to any one of claims 1 to 5, wherein the adhesive comprises at least one selected from an acrylic adhesive, a styrene block copolymer adhesive, a polyisobutylene adhesive, and a silicone adhesive. Agent.
PCT/JP2014/071216 2013-08-21 2014-08-11 Transdermal patch WO2015025766A1 (en)

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