WO2016052522A1 - Preparation for percutaneous administration and package - Google Patents

Preparation for percutaneous administration and package Download PDF

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Publication number
WO2016052522A1
WO2016052522A1 PCT/JP2015/077547 JP2015077547W WO2016052522A1 WO 2016052522 A1 WO2016052522 A1 WO 2016052522A1 JP 2015077547 W JP2015077547 W JP 2015077547W WO 2016052522 A1 WO2016052522 A1 WO 2016052522A1
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WIPO (PCT)
Prior art keywords
ropinirole
mass
preparation
transdermal administration
mercaptobenzimidazole
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PCT/JP2015/077547
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French (fr)
Japanese (ja)
Inventor
川村　尚久
規弘 新開
弘晃 白石
曜 津田
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ニプロ株式会社
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Priority to JP2016552073A priority Critical patent/JPWO2016052522A1/en
Publication of WO2016052522A1 publication Critical patent/WO2016052522A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone

Definitions

  • the present invention relates to a preparation for transdermal administration and a package.
  • Ropinirole is known as a remedy for symptoms of Parkinson's disease.
  • the preparation containing ropinirole is prepared as a dosage form such as a preparation for transdermal administration containing ropinirole. Since ropinirole contained in a ropinirole-containing transdermal preparation may be denatured by oxygen, light, etc. during storage of the formulation, a method for storing the formulation to prevent denaturation of ropinirole is being investigated. .
  • a storage method for example, there is a method (Patent Document 1) in which a ropinirole-containing transdermal preparation is enclosed in a packaging bag maintained at a specific relative humidity.
  • the present invention has been made to solve the above-described problems, and an object of the present invention is to provide a method for preventing the degeneration of ropinirole in a ropinirole-containing transdermal preparation.
  • transdermal preparation comprising an adhesive layer containing a specific antioxidant together with ropinirole, and have completed the present invention.
  • the present invention provides the following.
  • a transdermal administration preparation comprising a support and an adhesive layer positioned on the support,
  • the pressure-sensitive adhesive layer is a transdermal preparation containing ropinirole or a pharmacologically acceptable salt thereof and mercaptobenzimidazole.
  • transdermal administration preparation according to (1) or (2), further comprising dibutylhydroxytoluene.
  • a method for preventing the degeneration of ropinirole in a ropinirole-containing transdermal preparation there is provided a method for preventing the degeneration of ropinirole in a ropinirole-containing transdermal preparation.
  • the preparation for transdermal administration of the present invention comprises a support and a pressure-sensitive adhesive layer located on the support and containing ropinirole or a pharmacologically acceptable salt thereof, mercaptobenzimidazole, and a pressure-sensitive adhesive.
  • the preparation for transdermal administration may be one obtained by laminating a known skin adhesive layer (such as polyisobutylene), a release controlling film, or a release liner (such as an oxygen-impermeable liner) on the adhesive layer.
  • the preparation for transdermal administration of the present invention contains ropinirole in the adhesive layer.
  • ropinirole a free form of ropinirole acting as a dopamine agonist or a pharmaceutically acceptable salt thereof can be used.
  • ropinirole salts include ropinirole hydrochloride.
  • ropinirole free form is preferable in terms of good skin permeability.
  • the content of ropinirole in the pressure-sensitive adhesive layer can be appropriately adjusted according to the therapeutic effect to be obtained, and is not particularly limited.
  • ropinirole may be contained in the pressure-sensitive adhesive layer in an amount of 1.0% by mass or more, preferably 5.0% by mass or more, more preferably 10% by mass or more, and still more preferably 15% by mass or more.
  • ropinirole is prevented from being modified, so that an excessive amount of ropinirole may not be blended, and ropinirole is 35% by mass or less, preferably 30% by mass or less, more preferably in the pressure-sensitive adhesive layer. It may be contained in an amount of 25% by mass or less, more preferably 20% by mass or less.
  • the content of ropinirole in the pressure-sensitive adhesive layer is specified by HPLC.
  • a drug other than ropinirole may be used instead of part or all of ropinirole.
  • the drug that can be used in the present invention is not particularly limited.
  • the free form or a pharmaceutically acceptable salt thereof may be mentioned.
  • the preparation for transdermal administration of the present invention contains mercaptobenzimidazole in the adhesive layer.
  • Mercaptobenzimidazole can increase the stability of ropinirole.
  • denaturation of ropinirole in a transdermal administration formulation can be suppressed by mix
  • the content of mercaptobenzimidazole in the pressure-sensitive adhesive layer can be appropriately adjusted according to the stability of ropinirole to be obtained, and is not particularly limited.
  • mercaptobenzimidazole may be contained in the pressure-sensitive adhesive layer by 0.10% by mass or more, preferably 0.15% by mass or more, and more preferably 0.20% by mass or more.
  • mercaptobenzimidazole is contained in the pressure-sensitive adhesive layer at 5.00% by mass or less, preferably 3.00% by mass or less, more preferably 2.00% by mass or less, and most preferably 1.00% by mass or less. May be.
  • the transdermal administration preparation of the present invention may contain dibutylhydroxytoluene in the adhesive layer.
  • dibutylhydroxytoluene is blended with mercaptobenzimidazole in the pressure-sensitive adhesive layer, the antioxidant action by mercaptobenzimidazole can be enhanced.
  • dibutylhydroxytoluene in the pressure-sensitive adhesive layer can be appropriately adjusted according to the stability of ropinirole to be obtained, and is not particularly limited.
  • dibutylhydroxytoluene may be contained in the pressure-sensitive adhesive layer by 0.10% by mass or more, preferably 0.15% by mass or more, and more preferably 0.20% by mass or more.
  • dibutylhydroxytoluene is contained in the pressure-sensitive adhesive layer in an amount of 10.0% by mass or less, preferably 8.00% by mass or less, more preferably 6.00% by mass or less, and most preferably 5.00% by mass or less. May be.
  • the content of mercaptobenzimidazole or dibutylhydroxytoluene in the pressure-sensitive adhesive layer is specified by HPLC or GC (gas chromatography).
  • the pressure-sensitive adhesive contained in the pressure-sensitive adhesive layer is not particularly limited as long as it is generally used in a preparation for transdermal administration applied to the skin, and is an acrylic pressure-sensitive adhesive, rubber-based pressure-sensitive adhesive, or silicon-based pressure-sensitive adhesive. 1 or more types may be sufficient.
  • an acrylic pressure-sensitive adhesive when used as a pressure-sensitive adhesive in a ropinirole-containing transdermal preparation, the stability of ropinirole may be impaired.
  • an acrylic pressure-sensitive adhesive can be preferably used.
  • an acrylic that does not substantially contain a carboxyl group (carboxy group) in that it has a low reactivity with ropinirole can suppress a decrease in transdermal absorbability of ropinirole, and is hardly affected by oxygen.
  • System adhesives are preferred.
  • “Substantially free of carboxyl groups” means not only those that do not contain any carboxyl groups, but also those in which all carboxyl groups are converted into substituents such as ester bonds by design. For example, the case where a very small part of ester bond or the like is converted to a free carboxyl group by hydrolysis or the case where a free carboxyl group is contained as an impurity derived from the raw material is included.
  • the acrylic pressure-sensitive adhesive which does not substantially contain a carboxyl group is not particularly limited, but for example, pressure-sensitive adhesives described in JP-A-2005-325101, Patent 3809462 and the like can be used. Of these, the acrylic pressure-sensitive adhesive described in JP-A-2005-325101 can be used particularly preferably.
  • the acrylic pressure-sensitive adhesive in the present invention the reactivity with ropinirole is lower, the decrease in the transdermal absorbability of ropinirole can be further suppressed, and the carboxyl group and hydroxy group are substantially reduced in that they are less susceptible to oxygen.
  • An acrylic pressure-sensitive adhesive containing no group is particularly preferable.
  • components other than the above may be contained as necessary.
  • Such components include tackifiers, plasticizers (such as isopropyl myristate), preservatives, pH adjusters, chelating agents, transdermal absorption promoters, excipients, fragrances, colorants, fatty acids, fats and oils, etc. Can be mentioned.
  • the support in the present invention is not particularly limited, and is manufactured from stretchable or non-stretchable woven or non-woven fabrics made from polyethylene, polypropylene, etc., polyethylene, polypropylene, ethylene vinyl acetate copolymer, vinyl chloride, etc. Film, or a foamable support produced from urethane, polyurethane, or the like, and these may be used alone or in a laminate of plural kinds.
  • the preparation for transdermal administration of the present invention comprises a support and a pressure-sensitive adhesive layer laminated on one side of the support, but usually on the surface opposite to the contact surface of the pressure-sensitive adhesive layer with the support, You may provide with the form further provided with the peelable liner (peeling liner).
  • the peelable liner there can be used a film made of polyethylene, polypropylene, ethylene vinyl acetate copolymer, vinyl chloride or the like, an aluminum-deposited metallic film, or the like.
  • a liner surface that has been subjected to a peeling treatment such as a silicon treatment may be used.
  • the liner may be provided with a straight or curved cut, or may have two or more liners partially overlapped or may have a folded portion.
  • the preparation method of a transdermal administration formulation is not specifically limited, It can prepare by the known preparation method of a transdermal administration formulation.
  • the component which comprises an adhesive layer is stirred uniformly, The method of obtaining a transdermal administration formulation after coating and drying the obtained composition on the support surface using a coating machine etc. is mentioned.
  • the preparation for transdermal administration of the present invention may be packaged in a packaging material.
  • the “packaging material” encapsulates a preparation for transdermal administration, and can also be called a packaging bag or the like.
  • the packaging material is not particularly limited as long as it can seal a gas, and may be a packaging material for a preparation for transdermal administration such as a tape or a poultice.
  • the transdermal administration preparation may be enclosed in a packaging material substituted with an inert gas (such as nitrogen), or in a packaging material that is not replaced.
  • a preparation for transdermal administration may be enclosed.
  • the sealing can be performed by sealing or the like.
  • a packaging material in which a preparation for transdermal administration is enclosed is also referred to as a “packaging body”.
  • the oxygen concentration in the packaging material is 5.0 mass% or less, preferably 3.0 mass% or less (more preferably 1.0 mass% or less). It is preferable to adjust to.
  • Replacement with an inert gas (such as nitrogen) can be performed by enclosing the packaging material in an inert gas environment.
  • the transdermal administration preparation of the present invention comprises oxygen scavengers (iron powder, zinc powder, hydrosulfite, ascorbic acid-based agent, polyhydric alcohol-based agent, activated carbon-based agent, etc., which are separate or integrated with the transdermally administered formulation.
  • oxygen scavengers iron powder, zinc powder, hydrosulfite, ascorbic acid-based agent, polyhydric alcohol-based agent, activated carbon-based agent, etc.
  • the denaturation of ropinirole in the preparation for transdermal administration can be suppressed without enclosing an agent generally used for reducing the amount of oxygen in the packaging material in the packaging material.
  • encapsulating the oxygen scavenger in the packaging material is not excluded from the scope of the present invention, and the denaturation of ropinirole can be more effectively suppressed by encapsulating the oxygen scavenger in the packaging material.
  • the oxygen scavenger may be one having an action as a desiccant
  • the replacement of the inside of the packaging material with an inert gas (nitrogen or the like) and the encapsulation of the oxygen scavenger in the packaging material may be performed either alone or in combination.
  • the preparation for transdermal administration of the present invention can be packaged in a packaging material having a reduced oxygen concentration.
  • the oxygen concentration in the packaging material is maintained at 5.0% by mass or less, preferably 3.0% by mass or less (more preferably 1.0% by mass or less).
  • the percutaneous preparation of the present invention is not easily affected by oxygen and the stability of ropinirole is not easily impaired, it is not excluded that the oxygen concentration in the packaging material is 5.0% by mass or more.
  • the oxygen concentration in the packaging material is specified by an oxygen concentration meter (for example, Oxygen Meter Model RO-102 (manufactured by Iijima Electronics Co., Ltd.)).
  • the degeneration of ropinirole in the transdermal preparation is suppressed, and the drug stability is good.
  • “modification of ropinirole” means that ropinirole is decomposed or the like, thereby reducing the amount of ropinirole or increasing the decomposition product or related substances of ropinirole. Whether or not the degeneration of ropinirole in the preparation for transdermal administration is suppressed is specified by detecting ropinirole or a related substance of ropinirole in the preparation for transdermal administration by HPLC or the like.
  • a related substance of ropinirole is a substance that is produced by denaturation of ropinirole by oxygen or light, and is a substance that has reduced the original medicinal effect of ropinirole or a substance that does not have the original medicinal effect of ropinirole. Therefore, it shows that the drug stability of ropinirole is so high that the amount of the related substance detected from a transdermal administration formulation is low.
  • Examples of the related substances of ropinirole include 4E-indolelone, Monopropyl ropirile, propylidene ropirirole, Unknown 1, and Unknown 2. The amount of these substances is determined by HPLC.
  • Example 1 Ropinirole (15 mass%)-containing transdermal administration formulation packaged in a packaging material-Ropinirole stability evaluation-I>
  • a composition in which mercaptobenzimidazole, ropinirole, isopropyl myristate and an acrylic pressure-sensitive adhesive were blended in the following proportions and coating and drying (80 ° C., 15 minutes) on a PET (polyethylene terephthalate) film
  • An adhesive layer was formed, and a support was laminated on the adhesive layer to obtain a preparation for transdermal administration.
  • stacked PET nonwoven fabric and PET film was used as a support body.
  • the acrylic pressure-sensitive adhesive used in this example was prepared as follows. That is, the copolymer (A) solution obtained by the synthesis method shown below and the copolymer (B) solution were mixed at a mass ratio of 100: 5 (copolymer (A): copolymer (B )) To obtain an acrylic pressure-sensitive adhesive.
  • Each of the obtained preparations for transdermal administration is a packaging material having a configuration of polyacrylonitrile (hereinafter also referred to as “PAN”) / aluminum (hereinafter also referred to as “AL”) / polyethylene terephthalate (hereinafter also referred to as “PET”).
  • PAN polyacrylonitrile
  • AL aluminum
  • PET polyethylene terephthalate
  • Each formulation for transdermal administration packaged in a packaging material was stored at 60 ° C.
  • the content of ropinirole analogue (4E-indolene) in the transdermal administration preparation at the time of storage start (initial) and at each time point 1 week, 2 weeks, or 1 month after the start of storage was measured by HPLC (UV 250 nm). It was measured. The result is shown in FIG. The lower the amount of ropinirole analog detected, the higher the drug stability of ropinirole in the transdermal formulation.
  • MBI mercaptobenzimidazole
  • % In FIG. 1 refers to mass%.
  • a transdermal preparation containing mercaptobenzimidazole contains mercaptobenzimidazole.
  • the production of ropinirole-related substances in the preparation for transdermal administration was suppressed as compared with the preparation for percutaneous administration (see “MBI 0%”).
  • the higher the concentration of mercaptobenzimidazole in the preparation for transdermal administration the more the production of ropinirole analogues tended to be suppressed.
  • Example 2 Evaluation of stability of ropinirole in a transdermal preparation containing ropinirole (15% by mass) packaged in a packaging material-II>
  • a composition in which mercaptobenzimidazole, ropinirole, isopropyl myristate and an acrylic pressure-sensitive adhesive are blended in the following proportions is prepared, and this is coated on a PET (polyethylene terephthalate) film and dried (80 ° C., 15 minutes).
  • a support was laminated on the pressure-sensitive adhesive layer to obtain a preparation for transdermal administration.
  • stacked PET nonwoven fabric and PET film was used as a support body.
  • the acrylic pressure-sensitive adhesive used in this example was prepared in the same manner as in Example 1.
  • Mercaptobenzimidazole 0.0 mass%, 0.1 mass%, 0.3 mass%, or 0.6 mass%
  • Ropinirole 15% by mass
  • Isopropyl myristate 20% by mass
  • Acrylic adhesive 100- (Mixed amount of mercaptobenzimidazole, ropinirole and isopropyl myristate) (unit: mass%)
  • Each obtained transdermal preparation was individually put into a packaging material having a configuration of PAN / AL / PET, and the inside of the packaging material was sealed in a nitrogen environment.
  • Each formulation for transdermal administration packaged in a packaging material was stored at 60 ° C.
  • the content of ropinirole analogue (Propydine ropinirole) in the transdermal preparation at 0.5 months, 1 month, and 2 months after the start of storage was measured by HPLC (UV 250 nm). It was measured. The result is shown in FIG. The lower the amount of ropinirole analog detected, the higher the drug stability of ropinirole in the transdermal dosage formulation.
  • MBI mercaptobenzimidazole
  • % In FIG. 2 refers to mass%.
  • Example 3 Evaluation of stability of ropinirole in a transdermal preparation containing ropinirole (25% by mass) packaged in a packaging material-I>
  • the same test as in Example 1 was performed as follows by increasing the amount of ropinirole.
  • a composition in which mercaptobenzimidazole, ropinirole, isopropyl myristate and an acrylic pressure-sensitive adhesive are blended in the following proportions is prepared, and this is coated on a PET (polyethylene terephthalate) film and dried (80 ° C., 15 minutes).
  • a PET polyethylene terephthalate
  • Each obtained transdermal preparation was individually put into a packaging material having a configuration of PAN / AL / PET, and the inside of the packaging material was sealed in a nitrogen environment.
  • Each formulation for transdermal administration packaged in a packaging material was stored at 60 ° C.
  • the content of ropinirole-related substance (4E-indolene) in the preparation for transdermal administration at the time of the start of storage (initial) and 0.5 months, 1 month, and 2 months after the start of storage is HPLC (UV 250 nm) Measured with The result is shown in FIG.
  • MBI mercaptobenzimidazole
  • % In FIG. 3 refers to mass%.
  • Example 4 Evaluation of stability of ropinirole in a preparation for transdermal administration containing ropinirole (15% by mass) packaged in a packaging material-III>
  • PET polyethylene terephthalate
  • Each obtained transdermal preparation was individually put into a packaging material having a configuration of PAN / AL / PET, and the inside of the packaging material was sealed as it was without replacing the gas.
  • Each formulation for transdermal administration packaged in a packaging material was stored at 60 ° C.
  • the content of ropinirole analogue (4E-indolene) in the preparation for transdermal administration at the time of starting storage (initial) and at each time one week after the start of storage was measured by HPLC (UV 250 nm). The result is shown in FIG.
  • MBI mercaptobenzimidazole
  • BHT dibutylhydroxytoluene
  • % In FIG. 4 refers to mass%.
  • Example 5 Stability evaluation of ropinirole in a transdermal preparation containing ropinirole (15% by mass) packaged in a packaging material-IV>
  • the acrylic pressure-sensitive adhesive used in this example was prepared in the same manner as in Example 1.
  • Mercaptobenzimidazole 0.0 mass%, 0.1 mass%, or 0.3 mass%
  • Dibutylhydroxytoluene 0.0 mass%, 0.5 mass%, 1.0 mass%, or 2.0 mass%
  • Ropinirole 15% by mass
  • Isopropyl myristate 20% by mass
  • Acrylic adhesive 100- (Mixed amount of mercaptobenzimidazole, dibutylhydroxytoluene, ropinirole and isopropyl myristate) (unit: mass%)
  • Each obtained transdermal preparation was individually put into a packaging material having a configuration of PAN / AL / PET, and the inside of the packaging material was sealed in a nitrogen environment.
  • Each formulation for transdermal administration packaged in a packaging material was stored at 60 ° C.
  • the content of ropinirole analogue (Propylidene ropinirole) in the preparation for transdermal administration at the time of the start of storage (initial) and at each time point 2 months after the start of storage was measured by HPLC (UV 250 nm). The result is shown in FIG. The lower the amount of ropinirole analog detected, the higher the drug stability of ropinirole in the transdermal formulation.
  • MBI mercaptobenzimidazole
  • BHT dibutylhydroxytoluene
  • % In FIG. 5 refers to mass%.
  • Example 6 Stability evaluation of ropinirole in a preparation for transdermal administration containing ropinirole (25% by mass) packaged in a packaging material-II>
  • PET polyethylene terephthalate
  • Each obtained transdermal preparation was individually put into a packaging material having a configuration of PAN / AL / PET, and the inside of the packaging material was sealed in a nitrogen environment.
  • Each formulation for transdermal administration packaged in a packaging material was stored at 40 ° C or 60 ° C.
  • the content of ropinirole analogue (Propylidene ropinirole) in the preparation for transdermal administration at the time of the start of storage (initial) and at each time point 2 months after the start of storage was measured by HPLC (UV 250 nm). The result is shown in FIG. The lower the amount of ropinirole analog detected, the higher the drug stability of ropinirole in the transdermal formulation.
  • MBI mercaptobenzimidazole
  • BHT dibutylhydroxytoluene
  • % In FIG. 6 refers to mass%.
  • Example 7 Stability evaluation of ropinirole in a transdermal preparation containing ropinirole (15% by mass) packaged in a packaging material-V>
  • the acrylic pressure-sensitive adhesive used in this example was prepared in the same manner as in Example 1.
  • Mercaptobenzimidazole 0.0 mass%, 0.3 mass%, or 0.6 mass%
  • Dibutylhydroxytoluene 0.0 mass%, 0.5 mass%, 1.0 mass%, or 2.0 mass%
  • Ropinirole 15% by mass
  • Isopropyl myristate 20% by mass
  • Acrylic adhesive 100- (Mixed amount of mercaptobenzimidazole, dibutylhydroxytoluene, ropinirole and isopropyl myristate) (unit: mass%)
  • Each obtained preparation for transdermal administration is individually put in a packaging material having a configuration of PAN / AL / PET, (1) sealing the packaging material in a nitrogen environment, and (2) an oxygen scavenger into the packaging material. (Pharmakeep KD-20, manufactured by Mitsubishi Gas Chemical Co., Ltd.) Sealing after sealing, or (3) Sealing in a nitrogen environment and sealing without removing oxygen scavenger Went.
  • Each formulation for transdermal administration packaged in a packaging material was stored at 60 ° C.
  • the content of ropinirole analogue (4E-indolene) in the transdermal administration preparation at the time of storage start (initial) and at each time point 1 week, 2 weeks, or 1 month after the start of storage was measured by HPLC (UV 250 nm). It was measured. The result is shown in FIG. The lower the amount of ropinirole analog detected, the higher the drug stability of ropinirole in the transdermal formulation.
  • MBI mercaptobenzimidazole
  • BHT dibutylhydroxytoluene
  • N2 indicates that the inside of the packaging material is replaced with nitrogen.
  • Oxygen scavenger means that the oxygen scavenger is enclosed in the packaging material.
  • % In FIG. 7 refers to mass%.
  • transdermal preparation when packaged in a nitrogen-substituted packaging material, or when an oxygen scavenger is enclosed in the packaging material together with the transdermal preparation, ropinirole analogues in the transdermal preparation are markedly produced. There was a tendency to be suppressed.
  • Example 8 Stability evaluation of ropinirole in a preparation for transdermal administration containing ropinirole (15% by mass) packaged in a packaging material-VI>
  • PET polyethylene terephthalate
  • Each obtained preparation for transdermal administration is individually put in a packaging material having a configuration of PAN / AL / PET, (1) sealing the packaging material in a nitrogen environment, and (2) an oxygen scavenger into the packaging material. (Pharmakeep KD-20, manufactured by Mitsubishi Gas Chemical Co., Ltd.) Sealing after sealing, or (3) Sealing in a nitrogen environment and sealing without removing oxygen scavenger Went.
  • Each formulation for transdermal administration packaged in a packaging material was stored at 60 ° C.
  • Content of ropinirole analogues (Monopropyl ropirirole, 4E-indolelone, propylidene ropinirole, Unknown-1) in the preparation for transdermal administration at the time of the start of storage (initial) and 2 weeks or 1 month after the start of storage was measured by HPLC (UV 250 nm). The result is shown in FIG. The lower the amount of ropinirole analog detected, the higher the drug stability of ropinirole in the transdermal formulation.
  • MBI mercaptobenzimidazole
  • BHT dibutylhydroxytoluene
  • N2 indicates that the inside of the packaging material is replaced with nitrogen.
  • Oxygen scavenger means that the oxygen scavenger is enclosed in the packaging material.
  • % In FIG. 8 indicates mass%.
  • transdermal administration preparation when packaged in a nitrogen-substituted packaging material or an oxygen scavenger is enclosed in the packaging material together with the transdermal administration preparation, ropinirole analogues in the transdermal administration preparation are further generated. There was a tendency to be suppressed.

Abstract

The purpose of the present invention is to provide a method for preventing the degeneration of ropinirole in a ropinirole-containing preparation for percutaneous administration. A preparation for percutaneous administration, said preparation comprising a support and an adhesive layer disposed on the support, wherein the adhesive layer contains ropinirole or a pharmacologically acceptable salt thereof and mercaptobenzimidazole. The content of mercaptobenzimidazole may be 0.10-5.00 mass% relative to the adhesive layer.

Description

経皮投与製剤及び包装体Transdermal administration preparation and package
　本発明は、経皮投与製剤及び包装体に関する。 The present invention relates to a preparation for transdermal administration and a package.
　ロピニロールは、パーキンソン病の症状の改善薬として知られる。ロピニロールを含む製剤は、ロピニロール含有経皮投与製剤等の剤形として調製されている。ロピニロール含有経皮投与製剤に含まれるロピニロールは、製剤の保存中に、酸素、光等によって変性してしまう可能性があるので、ロピニロールの変性を防ぐための、製剤の保存方法が検討されている。このような保存方法として、例えば、特定の相対湿度に維持された包装袋中にロピニロール含有経皮投与製剤を封入する方法（特許文献１）が挙げられる。 Ropinirole is known as a remedy for symptoms of Parkinson's disease. The preparation containing ropinirole is prepared as a dosage form such as a preparation for transdermal administration containing ropinirole. Since ropinirole contained in a ropinirole-containing transdermal preparation may be denatured by oxygen, light, etc. during storage of the formulation, a method for storing the formulation to prevent denaturation of ropinirole is being investigated. . As such a storage method, for example, there is a method (Patent Document 1) in which a ropinirole-containing transdermal preparation is enclosed in a packaging bag maintained at a specific relative humidity.
国際公開第２０１０／１２３１０３号パンフレットInternational Publication No. 2010/123103 Pamphlet
　しかし、経皮投与製剤中の粘着剤層の組成の調整によってロピニロールの変性を防ぐことのできる、ロピニロール含有経皮投与製剤が求められていた。 However, there has been a need for a ropinirole-containing transdermal preparation capable of preventing the degeneration of ropinirole by adjusting the composition of the adhesive layer in the transdermal preparation.
　本発明は、上記課題を解決するためになされたものであり、ロピニロール含有経皮投与製剤中のロピニロールの変性を防ぐ方法を提供することを目的とする。 The present invention has been made to solve the above-described problems, and an object of the present invention is to provide a method for preventing the degeneration of ropinirole in a ropinirole-containing transdermal preparation.
　本発明者らは、ロピニロールとともに特定の抗酸化剤を含む粘着剤層を備える経皮投与製剤によれば上記課題を解決できる点を見出し、本発明を完成するに至った。具体的には、本発明は下記のものを提供する。 The present inventors have found that the above-mentioned problems can be solved by a transdermal preparation comprising an adhesive layer containing a specific antioxidant together with ropinirole, and have completed the present invention. Specifically, the present invention provides the following.
　（１）　支持体と、前記支持体上に位置する粘着剤層と、を備える経皮投与製剤であって、
　前記粘着剤層は、ロピニロール又はその薬理学的に許容できる塩、及びメルカプトベンズイミダゾールを含む経皮投与製剤。 (1) A transdermal administration preparation comprising a support and an adhesive layer positioned on the support,
The pressure-sensitive adhesive layer is a transdermal preparation containing ropinirole or a pharmacologically acceptable salt thereof and mercaptobenzimidazole.
　（２）　前記メルカプトベンズイミダゾールの含量は、前記粘着剤層に対して０．１０～５．００質量％である（１）に記載の経皮投与製剤。 (2) The transdermal administration preparation according to (1), wherein the content of the mercaptobenzimidazole is 0.10 to 5.00% by mass with respect to the pressure-sensitive adhesive layer.
　（３）　さらに、ジブチルヒドロキシトルエンを含む（１）又は（２）に記載の経皮投与製剤。 (3) The transdermal administration preparation according to (1) or (2), further comprising dibutylhydroxytoluene.
　（４）　前記ジブチルヒドロキシトルエンの含量は、前記粘着剤層に対して０．１０～１０．０質量％である（３）に記載の経皮投与製剤。 (4) The transdermal preparation according to (3), wherein the content of dibutylhydroxytoluene is 0.10 to 10.0% by mass with respect to the pressure-sensitive adhesive layer.
　（５）　前記粘着剤層は、アクリル系粘着剤を含む（１）から（４）のいずれかに記載の経皮投与製剤。 (5) The transdermal administration preparation according to any one of (1) to (4), wherein the pressure-sensitive adhesive layer contains an acrylic pressure-sensitive adhesive.
　（６）　包装材と、前記包装材内に封入された（１）から（５）のいずれかに記載の経皮投与製剤と、を備え、
　前記包装材内は窒素置換されている、包装体。 (6) A packaging material, and the transdermal administration preparation according to any one of (1) to (5) enclosed in the packaging material,
A packaging body in which the inside of the packaging material is substituted with nitrogen.
　本発明によれば、ロピニロール含有経皮投与製剤中のロピニロールの変性を防ぐ方法が提供される。 According to the present invention, there is provided a method for preventing the degeneration of ropinirole in a ropinirole-containing transdermal preparation.
本発明の経皮投与製剤の安定性を示す図である。It is a figure which shows stability of the transdermal administration formulation of this invention. 本発明の経皮投与製剤の安定性を示す図である。It is a figure which shows stability of the transdermal administration formulation of this invention. 本発明の経皮投与製剤の安定性を示す図である。It is a figure which shows stability of the transdermal administration formulation of this invention. 本発明の経皮投与製剤の安定性を示す図である。It is a figure which shows stability of the transdermal administration formulation of this invention. 本発明の経皮投与製剤の安定性を示す図である。It is a figure which shows stability of the transdermal administration formulation of this invention. 本発明の経皮投与製剤の安定性を示す図である。It is a figure which shows stability of the transdermal administration formulation of this invention. 本発明の経皮投与製剤の安定性を示す図である。It is a figure which shows stability of the transdermal administration formulation of this invention. 本発明の経皮投与製剤の安定性を示す図である。It is a figure which shows stability of the transdermal administration formulation of this invention.
　以下、本発明の実施形態について説明する。なお、本発明は以下の実施形態に限定されない。 Hereinafter, embodiments of the present invention will be described. In addition, this invention is not limited to the following embodiment.
＜経皮投与製剤＞ <Dermal preparation>
　本発明の経皮投与製剤は、支持体と、該支持体上に位置し、ロピニロール又はその薬理学的に許容できる塩、メルカプトベンズイミダゾール、及び粘着剤を含む粘着剤層とを備える。経皮投与製剤は、公知の皮膚接着層（ポリイソブチレン等）や放出制御膜、剥離ライナ（酸素不透過性ライナ等）を粘着剤層に積層させたものであってもよい。 The preparation for transdermal administration of the present invention comprises a support and a pressure-sensitive adhesive layer located on the support and containing ropinirole or a pharmacologically acceptable salt thereof, mercaptobenzimidazole, and a pressure-sensitive adhesive. The preparation for transdermal administration may be one obtained by laminating a known skin adhesive layer (such as polyisobutylene), a release controlling film, or a release liner (such as an oxygen-impermeable liner) on the adhesive layer.
［ロピニロール］
　本発明の経皮投与製剤は、その粘着剤層中にロピニロールを含む。ロピニロールとしては、ドパミンアゴニストとして作用するロピニロールの遊離体又はその薬学的に許容できる塩を使用できる。ロピニロールの塩としては、ロピニロール塩酸塩等が挙げられる。上記のうち、皮膚透過性が良好である点でロピニロールの遊離体が好ましい。 [Ropinirole]
The preparation for transdermal administration of the present invention contains ropinirole in the adhesive layer. As ropinirole, a free form of ropinirole acting as a dopamine agonist or a pharmaceutically acceptable salt thereof can be used. Examples of ropinirole salts include ropinirole hydrochloride. Of the above, ropinirole free form is preferable in terms of good skin permeability.
　粘着剤層中のロピニロールの含有量は、得ようとする治療効果に応じて適宜調整でき、特に限定されない。例えば、ロピニロールは、粘着剤層中に１．０質量％以上、好ましくは５．０質量％以上、さらに好ましくは１０質量％以上、さらにより好ましくは１５質量％以上含まれていてもよい。また、本発明においてはロピニロールの変性が抑制されるので、過度な量のロピニロールを配合しなくともよく、ロピニロールは、粘着剤層中に３５質量％以下、好ましくは３０質量％以下、さらに好ましくは２５質量％以下、さらにより好ましくは２０質量％以下含まれていてもよい。 The content of ropinirole in the pressure-sensitive adhesive layer can be appropriately adjusted according to the therapeutic effect to be obtained, and is not particularly limited. For example, ropinirole may be contained in the pressure-sensitive adhesive layer in an amount of 1.0% by mass or more, preferably 5.0% by mass or more, more preferably 10% by mass or more, and still more preferably 15% by mass or more. Further, in the present invention, ropinirole is prevented from being modified, so that an excessive amount of ropinirole may not be blended, and ropinirole is 35% by mass or less, preferably 30% by mass or less, more preferably in the pressure-sensitive adhesive layer. It may be contained in an amount of 25% by mass or less, more preferably 20% by mass or less.
　粘着剤層中のロピニロールの含有量は、ＨＰＬＣによって特定する。 The content of ropinirole in the pressure-sensitive adhesive layer is specified by HPLC.
　本発明においては、ロピニロールの一部又は全部の代わりに、ロピニロール以外の薬剤も使用し得る。本発明において使用し得る薬剤としては、特に限定されないが、アナストロゾール、プラミペキソール、ニコチン、ツロブテロール、リドカイン、フェンタニル、イミダフェナシン、リバスチグミン、オキシブチニン、デュロキセチン、ガランタミン、アセナピン、ラサジリン、フルオキセチン、ドネペジル、アトモキセチン等の遊離体又はその薬学的に許容できる塩が挙げられる。 In the present invention, a drug other than ropinirole may be used instead of part or all of ropinirole. The drug that can be used in the present invention is not particularly limited. The free form or a pharmaceutically acceptable salt thereof may be mentioned.
［メルカプトベンズイミダゾール］
　本発明の経皮投与製剤は、その粘着剤層中にメルカプトベンズイミダゾールを含む。メルカプトベンズイミダゾールはロピニロールの安定性を高めることができる。本発明においては、粘着剤層中にメルカプトベンズイミダゾールを配合することで、経皮投与製剤中のロピニロールの変性を抑制できる。 [Mercaptobenzimidazole]
The preparation for transdermal administration of the present invention contains mercaptobenzimidazole in the adhesive layer. Mercaptobenzimidazole can increase the stability of ropinirole. In this invention, modification | denaturation of ropinirole in a transdermal administration formulation can be suppressed by mix | blending mercaptobenzimidazole in an adhesive layer.
　粘着剤層中のメルカプトベンズイミダゾールの含有量は、得ようとするロピニロールの安定性に応じて適宜調整でき、特に限定されない。例えば、メルカプトベンズイミダゾールは、粘着剤層中に０．１０質量％以上、好ましくは０．１５質量％以上、さらに好ましくは０．２０質量％以上含まれていてもよい。また、メルカプトベンズイミダゾールは、粘着剤層中に５．００質量％以下、好ましくは３．００質量％以下、さらに好ましくは２．００質量％以下、最も好ましくは１．００質量％以下含まれていてもよい。 The content of mercaptobenzimidazole in the pressure-sensitive adhesive layer can be appropriately adjusted according to the stability of ropinirole to be obtained, and is not particularly limited. For example, mercaptobenzimidazole may be contained in the pressure-sensitive adhesive layer by 0.10% by mass or more, preferably 0.15% by mass or more, and more preferably 0.20% by mass or more. Further, mercaptobenzimidazole is contained in the pressure-sensitive adhesive layer at 5.00% by mass or less, preferably 3.00% by mass or less, more preferably 2.00% by mass or less, and most preferably 1.00% by mass or less. May be.
　本発明の経皮投与製剤は、その粘着剤層中にジブチルヒドロキシトルエンを含んでいてもよい。粘着剤層中に、メルカプトベンズイミダゾールとともにジブチルヒドロキシトルエンを配合すると、メルカプトベンズイミダゾールによる抗酸化作用を増強できる。 The transdermal administration preparation of the present invention may contain dibutylhydroxytoluene in the adhesive layer. When dibutylhydroxytoluene is blended with mercaptobenzimidazole in the pressure-sensitive adhesive layer, the antioxidant action by mercaptobenzimidazole can be enhanced.
　粘着剤層中のジブチルヒドロキシトルエンの含有量は、得ようとするロピニロールの安定性に応じて適宜調整でき、特に限定されない。例えば、ジブチルヒドロキシトルエンは、粘着剤層中に０．１０質量％以上、好ましくは０．１５質量％以上、さらに好ましくは０．２０質量％以上含まれていてもよい。また、ジブチルヒドロキシトルエンは、粘着剤層中に１０．０質量％以下、好ましくは８．００質量％以下、さらに好ましくは６．００質量％以下、最も好ましくは５．００質量％以下含まれていてもよい。 The content of dibutylhydroxytoluene in the pressure-sensitive adhesive layer can be appropriately adjusted according to the stability of ropinirole to be obtained, and is not particularly limited. For example, dibutylhydroxytoluene may be contained in the pressure-sensitive adhesive layer by 0.10% by mass or more, preferably 0.15% by mass or more, and more preferably 0.20% by mass or more. Further, dibutylhydroxytoluene is contained in the pressure-sensitive adhesive layer in an amount of 10.0% by mass or less, preferably 8.00% by mass or less, more preferably 6.00% by mass or less, and most preferably 5.00% by mass or less. May be.
　粘着剤層中のメルカプトベンズイミダゾール又はジブチルヒドロキシトルエンの含有量は、ＨＰＬＣ又はＧＣ（ガスクロマトグラフィー）によって特定する。 The content of mercaptobenzimidazole or dibutylhydroxytoluene in the pressure-sensitive adhesive layer is specified by HPLC or GC (gas chromatography).
［粘着剤］
　粘着剤層に含まれる粘着剤としては、皮膚に適用される経皮投与製剤において一般的に使用されるものであれば特に限定されず、アクリル系粘着剤、ゴム系粘着剤又はシリコン系粘着剤のうち１種以上であってもよい。 [Adhesive]
The pressure-sensitive adhesive contained in the pressure-sensitive adhesive layer is not particularly limited as long as it is generally used in a preparation for transdermal administration applied to the skin, and is an acrylic pressure-sensitive adhesive, rubber-based pressure-sensitive adhesive, or silicon-based pressure-sensitive adhesive. 1 or more types may be sufficient.
　従来、ロピニロール含有経皮投与製剤において、粘着剤としてアクリル系粘着剤を使用すると、ロピニロールの安定性を損なう可能性があった。しかし、本発明の経皮投与製剤においては、粘着剤としてアクリル系粘着剤を使用しても、ロピニロールの安定性を損ないにくい。したがって、本発明においては、アクリル系粘着剤を好ましく使用できる。アクリル系粘着剤のうち、ロピニロールとの反応性が低く、ロピニロールの経皮吸収性の低下を抑制でき、酸素による影響を受けにくいという点で、実質的にカルボキシル基（カルボキシ基）を含まないアクリル系粘着剤が好ましい。「実質的にカルボキシル基を含まない」とは、全くカルボキシル基を含まないものだけではなく、設計上、全てのカルボキシル基がエステル結合等の置換基に変換されているものも意味し、その中には、例えば、ごく一部のエステル結合等が加水分解により遊離カルボキシル基に変換されている場合や、原材料由来の不純物として遊離カルボキシル基を含む場合も含まれる。 Conventionally, when an acrylic pressure-sensitive adhesive is used as a pressure-sensitive adhesive in a ropinirole-containing transdermal preparation, the stability of ropinirole may be impaired. However, in the percutaneous preparation of the present invention, even if an acrylic adhesive is used as the adhesive, the stability of ropinirole is hardly impaired. Therefore, in the present invention, an acrylic pressure-sensitive adhesive can be preferably used. Among acrylic pressure-sensitive adhesives, an acrylic that does not substantially contain a carboxyl group (carboxy group) in that it has a low reactivity with ropinirole, can suppress a decrease in transdermal absorbability of ropinirole, and is hardly affected by oxygen. System adhesives are preferred. “Substantially free of carboxyl groups” means not only those that do not contain any carboxyl groups, but also those in which all carboxyl groups are converted into substituents such as ester bonds by design. For example, the case where a very small part of ester bond or the like is converted to a free carboxyl group by hydrolysis or the case where a free carboxyl group is contained as an impurity derived from the raw material is included.
　実質的にカルボキシル基を含まないアクリル系粘着剤としては、特に限定されないが、例えば、特開２００５－３２５１０１号公報、特許３８０９４６２号等に記載された粘着剤を使用できる。これらのうち、特開２００５－３２５１０１号公報に記載されたアクリル系粘着剤を特に好適に使用できる。 The acrylic pressure-sensitive adhesive which does not substantially contain a carboxyl group is not particularly limited, but for example, pressure-sensitive adhesives described in JP-A-2005-325101, Patent 3809462 and the like can be used. Of these, the acrylic pressure-sensitive adhesive described in JP-A-2005-325101 can be used particularly preferably.
　本発明におけるアクリル系粘着剤としては、ロピニロールとの反応性がより低く、ロピニロールの経皮吸収性の低下をより抑制でき、酸素による影響をより受けにくいという点で、実質的にカルボキシル基及びヒドロキシ基を含まないアクリル系粘着剤が特に好ましい。 As the acrylic pressure-sensitive adhesive in the present invention, the reactivity with ropinirole is lower, the decrease in the transdermal absorbability of ropinirole can be further suppressed, and the carboxyl group and hydroxy group are substantially reduced in that they are less susceptible to oxygen. An acrylic pressure-sensitive adhesive containing no group is particularly preferable.
　経皮投与製剤中には、必要に応じて上記以外の成分が含まれていてもよい。このような成分としては、粘着付与剤、可塑剤（ミリスチン酸イソプロピル等）、防腐剤、ｐＨ調整剤、キレート剤、経皮吸収促進剤、賦形剤、香料、色剤、脂肪酸、油脂等が挙げられる。 In the preparation for transdermal administration, components other than the above may be contained as necessary. Such components include tackifiers, plasticizers (such as isopropyl myristate), preservatives, pH adjusters, chelating agents, transdermal absorption promoters, excipients, fragrances, colorants, fatty acids, fats and oils, etc. Can be mentioned.
［支持体］
　本発明における支持体としては、特に限定されず、ポリエチレン、ポリプロピレン等から製造された伸縮性もしくは非伸縮性の織布又は不織布、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、塩化ビニル等から製造されたフィルム、あるいはウレタン、ポリウレタン等から製造された発泡性支持体が挙げられ、これらを１種単独で又は複数種が積層されたものが使用できる。 [Support]
The support in the present invention is not particularly limited, and is manufactured from stretchable or non-stretchable woven or non-woven fabrics made from polyethylene, polypropylene, etc., polyethylene, polypropylene, ethylene vinyl acetate copolymer, vinyl chloride, etc. Film, or a foamable support produced from urethane, polyurethane, or the like, and these may be used alone or in a laminate of plural kinds.
［剥離ライナ］
　本発明の経皮投与製剤は、支持体と、この支持体の片面に積層された粘着剤層と、を備えるが、通常、粘着剤層の支持体との接触面とは反対の面に、剥離可能なライナ（剥離ライナ）をさらに備える形態で提供されてもよい。 [Peeling liner]
The preparation for transdermal administration of the present invention comprises a support and a pressure-sensitive adhesive layer laminated on one side of the support, but usually on the surface opposite to the contact surface of the pressure-sensitive adhesive layer with the support, You may provide with the form further provided with the peelable liner (peeling liner).
　剥離可能なライナとしては、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、塩化ビニル等から製造されたフィルム、アルミニウム蒸着の金属性のフィルム等が使用できる。ライナ表面にシリコン処理等の剥離処理が施されたものを使用してもよい。さらに、ライナには、剥離を容易にするため、直線又は曲線状の切れ込みが設けられていてもよく、２以上のライナが一部重畳されたものや、折返し部を有するものでもよい。 As the peelable liner, there can be used a film made of polyethylene, polypropylene, ethylene vinyl acetate copolymer, vinyl chloride or the like, an aluminum-deposited metallic film, or the like. A liner surface that has been subjected to a peeling treatment such as a silicon treatment may be used. Further, in order to facilitate peeling, the liner may be provided with a straight or curved cut, or may have two or more liners partially overlapped or may have a folded portion.
＜経皮投与製剤の製造方法＞
　経皮投与製剤の調製方法は特に限定されず、公知の経皮投与製剤の調製方法によって調製できる。例えば、粘着剤層を構成する成分を均一に撹拌し、得られた組成物を、塗工機を用いて支持体表面上に塗工乾燥した後に経皮投与製剤を得る方法等が挙げられる。 <Method for producing transdermal preparation>
The preparation method of a transdermal administration formulation is not specifically limited, It can prepare by the known preparation method of a transdermal administration formulation. For example, the component which comprises an adhesive layer is stirred uniformly, The method of obtaining a transdermal administration formulation after coating and drying the obtained composition on the support surface using a coating machine etc. is mentioned.
＜包装材＞
　本発明の経皮投与製剤は、包装材内に包装されていてもよい。本発明において「包装材」とは、経皮投与製剤をその内部に封入させるものであり、包装袋等とも呼ばれ得るものである。包装材としては、気体を密封できるものであれば特に限定されず、テープ剤、パップ剤等の経皮投与製剤の包装材として通常使用されるものであってもよい。また、包装材内に経皮投与製剤を包装する際には、不活性ガス（窒素等）によって置換された包装材内に経皮投与製剤を封入してもよいし、置換されない包装材内に経皮投与製剤を封入してもよい。封入はシーリング等によって行うことができる。シーリングとしては、ヒートシール、接着剤によるシール等の公知の方法を適用できる。ロピニロール類縁物質の生成を顕著に抑制できるという観点から、窒素によって置換された包装材内に経皮投与製剤を封入することが好ましい。本発明において、内部に経皮投与製剤が封入された状態の包装材を、「包装体」ともいう。 <Packaging material>
The preparation for transdermal administration of the present invention may be packaged in a packaging material. In the present invention, the “packaging material” encapsulates a preparation for transdermal administration, and can also be called a packaging bag or the like. The packaging material is not particularly limited as long as it can seal a gas, and may be a packaging material for a preparation for transdermal administration such as a tape or a poultice. In addition, when packaging a transdermal preparation in a packaging material, the transdermal administration preparation may be enclosed in a packaging material substituted with an inert gas (such as nitrogen), or in a packaging material that is not replaced. A preparation for transdermal administration may be enclosed. The sealing can be performed by sealing or the like. As the sealing, known methods such as heat sealing and sealing with an adhesive can be applied. From the viewpoint that production of ropinirole analogues can be remarkably suppressed, it is preferable to encapsulate a transdermal preparation in a packaging material substituted with nitrogen. In the present invention, a packaging material in which a preparation for transdermal administration is enclosed is also referred to as a “packaging body”.
　包装材内を不活性ガス（窒素等）によって置換する場合、包装材内の酸素濃度を５．０質量％以下、好ましくは３．０質量％以下（より好ましくは、１．０質量％以下）に調整することが好ましい。不活性ガス（窒素等）による置換は、不活性ガス環境下で包装材を封入することで行うことができる。 When replacing the inside of the packaging material with an inert gas (such as nitrogen), the oxygen concentration in the packaging material is 5.0 mass% or less, preferably 3.0 mass% or less (more preferably 1.0 mass% or less). It is preferable to adjust to. Replacement with an inert gas (such as nitrogen) can be performed by enclosing the packaging material in an inert gas environment.
　本発明の経皮投与製剤は、経皮投与製剤と別体又は一体である脱酸素剤（鉄粉、亜鉛粉、ハイドロサルファイト、アスコルビン酸系剤、多価アルコール系剤、活性炭系剤等の、包装材内の酸素量を低減するために一般的に使用される剤）を包装材内に封入しなくとも、経皮投与製剤中のロピニロールの変性を抑制できる。ただし、脱酸素剤を包装材内に封入することは、本発明の範囲から除外されず、脱酸素剤を包装材内に封入することで、ロピニロールの変性をより効果的に抑制し得る。脱酸素剤は、乾燥剤としての作用を有するもの（例えば、ファーマキープ　ＫＤ－２０、三菱ガス化学（株）製）であってもよい。 The transdermal administration preparation of the present invention comprises oxygen scavengers (iron powder, zinc powder, hydrosulfite, ascorbic acid-based agent, polyhydric alcohol-based agent, activated carbon-based agent, etc., which are separate or integrated with the transdermally administered formulation. The denaturation of ropinirole in the preparation for transdermal administration can be suppressed without enclosing an agent generally used for reducing the amount of oxygen in the packaging material in the packaging material. However, encapsulating the oxygen scavenger in the packaging material is not excluded from the scope of the present invention, and the denaturation of ropinirole can be more effectively suppressed by encapsulating the oxygen scavenger in the packaging material. The oxygen scavenger may be one having an action as a desiccant (for example, Pharmakeep KD-20, manufactured by Mitsubishi Gas Chemical Co., Inc.).
　不活性ガス（窒素等）による包装材内の置換及び包装材内への脱酸素剤の封入は、いずれかのみを行ってもよく、これらを組み合わせて行ってもよい。 The replacement of the inside of the packaging material with an inert gas (nitrogen or the like) and the encapsulation of the oxygen scavenger in the packaging material may be performed either alone or in combination.
　本発明の経皮投与製剤は、酸素濃度が低減された包装材内に包装され得る。本発明の経皮投与製剤は、例えば、包装材内の酸素濃度が５．０質量％以下、好ましくは３．０質量％以下（より好ましくは、１．０質量％以下）に維持される。ただし、本発明の経皮投与製剤は、酸素による影響を受けにくく、ロピニロールの安定性が損なわれにくいため、包装材内の酸素濃度が５．０質量％以上であることは排除されない。 The preparation for transdermal administration of the present invention can be packaged in a packaging material having a reduced oxygen concentration. In the preparation for transdermal administration of the present invention, for example, the oxygen concentration in the packaging material is maintained at 5.0% by mass or less, preferably 3.0% by mass or less (more preferably 1.0% by mass or less). However, since the percutaneous preparation of the present invention is not easily affected by oxygen and the stability of ropinirole is not easily impaired, it is not excluded that the oxygen concentration in the packaging material is 5.0% by mass or more.
　包装材内の酸素濃度は、酸素濃度計（例えば、Ｏｘｙｇｅｎ　Ｍｅｔｅｒ　Ｍｏｄｅｌ　ＲＯ－１０２（飯島電子工業株式会社製））によって特定する。 The oxygen concentration in the packaging material is specified by an oxygen concentration meter (for example, Oxygen Meter Model RO-102 (manufactured by Iijima Electronics Co., Ltd.)).
＜経皮投与製剤中のロピニロールの安定性＞
　本発明の経皮投与製剤においては、経皮投与製剤中のロピニロールの変性が抑制され、薬物安定性が良好である。本発明において、「ロピニロールの変性」とは、ロピニロールが分解等することで、ロピニロール量が減少したり、ロピニロールの分解物や類縁物質等が増加したりすることを指す。経皮投与製剤中のロピニロールの変性が抑制されているかどうかは、ＨＰＬＣ等によって、経皮投与製剤中のロピニロール又はロピニロールの類縁物質等を検出することによって特定される。ロピニロールの類縁物質は、ロピニロールが酸素や光によって変性等することで生じる物質であり、ロピニロール本来の薬効が低下した物質、又は、ロピニロール本来の薬効を有さない物質である。そのため、経皮投与製剤中から検出される類縁物質の量が低いほど、ロピニロールの薬物安定性が高いことを示す。ロピニロールの類縁物質としては、例えば、４Ｅ－ｉｎｄｏｌｏｎｅ、Ｍｏｎｏｐｒｏｐｙｌ　ｒｏｐｉｎｉｒｏｌｅ、Ｐｒｏｐｙｌｉｄｅｎｅ　ｒｏｐｉｎｉｒｏｌｅ、Ｕｎｋｎｏｗｎ　１、Ｕｎｋｎｏｗｎ　２が挙げられる。これらの物質の量は、ＨＰＬＣによって特定する。 <Stability of ropinirole in transdermal administration>
In the transdermal preparation of the present invention, the degeneration of ropinirole in the transdermal preparation is suppressed, and the drug stability is good. In the present invention, “modification of ropinirole” means that ropinirole is decomposed or the like, thereby reducing the amount of ropinirole or increasing the decomposition product or related substances of ropinirole. Whether or not the degeneration of ropinirole in the preparation for transdermal administration is suppressed is specified by detecting ropinirole or a related substance of ropinirole in the preparation for transdermal administration by HPLC or the like. A related substance of ropinirole is a substance that is produced by denaturation of ropinirole by oxygen or light, and is a substance that has reduced the original medicinal effect of ropinirole or a substance that does not have the original medicinal effect of ropinirole. Therefore, it shows that the drug stability of ropinirole is so high that the amount of the related substance detected from a transdermal administration formulation is low. Examples of the related substances of ropinirole include 4E-indolelone, Monopropyl ropirile, propylidene ropirirole, Unknown 1, and Unknown 2. The amount of these substances is determined by HPLC.
　以下、実施例により本発明をさらに詳しく説明するが、本発明はこれらに限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
＜実施例１：包装材中に包装されたロピニロール（１５質量％）含有経皮投与製剤中のロピニロールの安定性評価－Ｉ＞
　メルカプトベンズイミダゾール、ロピニロール、ミリスチン酸イソプロピル及びアクリル系粘着剤を、下記割合で配合した組成物を作製し、これをＰＥＴ（ポリエチレンテレフタレート）フィルム上に塗工乾燥（８０℃、１５分）することによって粘着剤層を形成し、この粘着剤層上に支持体を積層させ、経皮投与製剤を得た。なお、支持体としてＰＥＴ不織布とＰＥＴフィルムとを積層したものを使用した。
　メルカプトベンズイミダゾール：０．０質量％、０．１質量％、０．３質量％、又は０．６質量％
　ロピニロール：１５質量％
　ミリスチン酸イソプロピル：２０質量％
　アクリル系粘着剤：１００－（メルカプトベンズイミダゾール、ロピニロール及びミリスチン酸イソプロピルの配合量）（単位：質量％） <Example 1: Ropinirole (15 mass%)-containing transdermal administration formulation packaged in a packaging material-Ropinirole stability evaluation-I>
By preparing a composition in which mercaptobenzimidazole, ropinirole, isopropyl myristate and an acrylic pressure-sensitive adhesive were blended in the following proportions and coating and drying (80 ° C., 15 minutes) on a PET (polyethylene terephthalate) film An adhesive layer was formed, and a support was laminated on the adhesive layer to obtain a preparation for transdermal administration. In addition, what laminated | stacked PET nonwoven fabric and PET film was used as a support body.
Mercaptobenzimidazole: 0.0 mass%, 0.1 mass%, 0.3 mass%, or 0.6 mass%
Ropinirole: 15% by mass
Isopropyl myristate: 20% by mass
Acrylic adhesive: 100- (Mixed amount of mercaptobenzimidazole, ropinirole and isopropyl myristate) (unit: mass%)
　なお、本実施例で用いたアクリル系粘着剤は、下記のように調製した。すなわち、以下に示す合成方法によって得られた共重合体（Ａ）の溶液と、共重合体（Ｂ）の溶液とを、質量比１００：５（共重合体（Ａ）：共重合体（Ｂ））の割合で混合し、アクリル系粘着剤を得た。 The acrylic pressure-sensitive adhesive used in this example was prepared as follows. That is, the copolymer (A) solution obtained by the synthesis method shown below and the copolymer (B) solution were mixed at a mass ratio of 100: 5 (copolymer (A): copolymer (B )) To obtain an acrylic pressure-sensitive adhesive.
［共重合体（Ａ）］
　アクリル酸２－エチルヘキシル２００質量部、アクリル酸ブチル１００質量部、ジアセトンアクリルアミド５０質量部、及び酢酸エチル３００質量部を加えて混合した。この混合物を、撹拌装置及び還流冷却装置を備えるセパラブルフラスコに供給し、撹拌及び窒素置換しながら、７５℃に昇温した。過酸化ベンゾイル２質量部を酢酸エチル２０質量部に溶解した溶液を５分割し、その１部をセパラブルフラスコに添加して、重合を開始した。残りの４部を、反応開始後２時間目から１時間間隔で１部ずつ添加し、添加を終了した後、さらに２時間反応させた。なお、粘度調節のため、反応開始後、２時間ごとに酢酸エチルを５０質量部ずつ４回添加した。反応終了後、冷却し、次いで酢酸エチルを添加することで、固形分濃度３０質量％の共重合体（Ａ）を得た。 [Copolymer (A)]
200 parts by mass of 2-ethylhexyl acrylate, 100 parts by mass of butyl acrylate, 50 parts by mass of diacetone acrylamide, and 300 parts by mass of ethyl acetate were added and mixed. This mixture was supplied to a separable flask equipped with a stirring device and a reflux cooling device, and the temperature was raised to 75 ° C. while stirring and purging with nitrogen. A solution in which 2 parts by mass of benzoyl peroxide was dissolved in 20 parts by mass of ethyl acetate was divided into 5 parts, and 1 part thereof was added to a separable flask to initiate polymerization. The remaining 4 parts were added one by one at intervals of 1 hour from the 2nd hour after the start of the reaction, and after the addition was completed, the reaction was continued for another 2 hours. In order to adjust the viscosity, 50 parts by mass of ethyl acetate was added 4 times every 2 hours after the start of the reaction. After completion of the reaction, the mixture was cooled and then ethyl acetate was added to obtain a copolymer (A) having a solid concentration of 30% by mass.
［共重合体（Ｂ）］
　アクリル酸エチル６６０質量部、ジアセトンアクリルアミド７０質量部、分子量調節剤としてドデシルメルカプタン４０質量部及び酢酸エチル４００質量部を加えて混合した。この混合物を、撹拌装置及び還流冷却装置を備えるセパラブルフラスコに供給し、撹拌及び窒素置換しながら、７０℃に昇温した。アゾビスイソブチロニトリル５質量部を酢酸エチル１００質量部に溶解した溶液を５分割し、その１部をセパラブルフラスコに添加して、重合を開始した。残りの４部を、反応開始後２時間目から１時間間隔で１部ずつ添加し、添加を終了した後、さらに２時間反応させた。なお、粘度調節のため、反応開始後、２時間ごとに酢酸エチルを５０質量部ずつ３回添加した。その後、アジピン酸ジヒドラジド４０質量部を、精製水４０質量部、メタノール１６００質量部、酢酸エチル２６０質量部の混合液に溶解したものを添加し、さらに濃塩酸５質量部を加えた後、７０℃に昇温した。反応終了後、冷却し、精製水で３回洗浄した後、生成物を酢酸エチル７００質量部、アセトン１４００質量部、メタノール４００質量部の混合溶媒に溶解させることで、固形分濃度３０質量％の共重合体（Ｂ）を得た。 [Copolymer (B)]
660 parts by mass of ethyl acrylate, 70 parts by mass of diacetone acrylamide, 40 parts by mass of dodecyl mercaptan and 400 parts by mass of ethyl acetate as a molecular weight regulator were added and mixed. This mixture was supplied to a separable flask equipped with a stirring device and a reflux cooling device, and the temperature was raised to 70 ° C. while stirring and purging with nitrogen. A solution in which 5 parts by mass of azobisisobutyronitrile was dissolved in 100 parts by mass of ethyl acetate was divided into 5 parts, and 1 part thereof was added to a separable flask to initiate polymerization. The remaining 4 parts were added one by one at intervals of 1 hour from the 2nd hour after the start of the reaction, and after the addition was completed, the reaction was continued for another 2 hours. In order to adjust the viscosity, 50 parts by mass of ethyl acetate was added three times every 2 hours after the start of the reaction. Thereafter, 40 parts by mass of adipic acid dihydrazide dissolved in a mixed solution of 40 parts by mass of purified water, 1600 parts by mass of methanol and 260 parts by mass of ethyl acetate was added, and further 5 parts by mass of concentrated hydrochloric acid was added. The temperature was raised to. After completion of the reaction, the mixture is cooled and washed three times with purified water, and then the product is dissolved in a mixed solvent of 700 parts by mass of ethyl acetate, 1400 parts by mass of acetone, and 400 parts by mass of methanol, so that the solid content concentration is 30% by mass. A copolymer (B) was obtained.
　得られた各経皮投与製剤を、ポリアクリロニトリル（以下、「ＰＡＮ」ともいう）／アルミニウム（以下、「ＡＬ」ともいう）／ポリエチレンテレフタレート（以下、「ＰＥＴ」ともいう）という構成を有する包装材に個別に入れ、包装材内をガス置換せずにそのままシーリングした。 Each of the obtained preparations for transdermal administration is a packaging material having a configuration of polyacrylonitrile (hereinafter also referred to as “PAN”) / aluminum (hereinafter also referred to as “AL”) / polyethylene terephthalate (hereinafter also referred to as “PET”). The packaging material was sealed as it was without replacing the gas.
　包装材中に包装された各経皮投与製剤を６０℃にて保存した。保存開始時点（イニシャル）、及び保存開始から１週間後、２週間後、又は１ヶ月後の各時点における経皮投与製剤中のロピニロール類縁物質（４Ｅ－ｉｎｄｏｌｏｎｅ）の含有量をＨＰＬＣ（ＵＶ２５０ｎｍ）で測定した。その結果を図１に示す。検出されたロピニロール類縁物質の量が低いほど、経皮投与製剤中のロピニロールの薬物安定性が高いことを示す。 Each formulation for transdermal administration packaged in a packaging material was stored at 60 ° C. The content of ropinirole analogue (4E-indolene) in the transdermal administration preparation at the time of storage start (initial) and at each time point 1 week, 2 weeks, or 1 month after the start of storage was measured by HPLC (UV 250 nm). It was measured. The result is shown in FIG. The lower the amount of ropinirole analog detected, the higher the drug stability of ropinirole in the transdermal formulation.
　なお、図１中、「ＭＢＩ」とはメルカプトベンズイミダゾールを指す。図１中の「％」とは質量％を指す。 In FIG. 1, “MBI” refers to mercaptobenzimidazole. “%” In FIG. 1 refers to mass%.
　図１に示される通り、メルカプトベンズイミダゾールを含む経皮投与製剤（「ＭＢＩ　０．１％」、「ＭＢＩ　０．３％」、「ＭＢＩ　０．６％」を参照。）は、メルカプトベンズイミダゾールを含まない経皮投与製剤（「ＭＢＩ　０％」を参照。）と比較して、経皮投与製剤中のロピニロール類縁物質の生成が抑制されていた。また、経皮投与製剤中のメルカプトベンズイミダゾールの濃度が高いほど、ロピニロール類縁物質の生成が抑制される傾向にあった。 As shown in FIG. 1, a transdermal preparation containing mercaptobenzimidazole (see “MBI 0.1%”, “MBI 0.3%”, “MBI 0.6%”) contains mercaptobenzimidazole. The production of ropinirole-related substances in the preparation for transdermal administration was suppressed as compared with the preparation for percutaneous administration (see “MBI 0%”). In addition, the higher the concentration of mercaptobenzimidazole in the preparation for transdermal administration, the more the production of ropinirole analogues tended to be suppressed.
＜実施例２：包装材中に包装されたロピニロール（１５質量％）含有経皮投与製剤中のロピニロールの安定性評価－ＩＩ＞
　メルカプトベンズイミダゾール、ロピニロール、ミリスチン酸イソプロピル及びアクリル系粘着剤を、下記の割合で配合した組成物を作製し、これをＰＥＴ（ポリエチレンテレフタレート）フィルム上に塗工乾燥（８０℃、１５分）することによって粘着剤層を形成し、この粘着剤層上に支持体を積層させ、経皮投与製剤を得た。なお、支持体としてＰＥＴ不織布とＰＥＴフィルムとを積層したものを使用した。本実施例で用いたアクリル系粘着剤は、実施例１と同様に調製した。
　メルカプトベンズイミダゾール：０．０質量％、０．１質量％、０．３質量％、又は０．６質量％
　ロピニロール：１５質量％
　ミリスチン酸イソプロピル：２０質量％
　アクリル系粘着剤：１００－（メルカプトベンズイミダゾール、ロピニロール及びミリスチン酸イソプロピルの配合量）（単位：質量％） <Example 2: Evaluation of stability of ropinirole in a transdermal preparation containing ropinirole (15% by mass) packaged in a packaging material-II>
A composition in which mercaptobenzimidazole, ropinirole, isopropyl myristate and an acrylic pressure-sensitive adhesive are blended in the following proportions is prepared, and this is coated on a PET (polyethylene terephthalate) film and dried (80 ° C., 15 minutes). Was used to form a pressure-sensitive adhesive layer, and a support was laminated on the pressure-sensitive adhesive layer to obtain a preparation for transdermal administration. In addition, what laminated | stacked PET nonwoven fabric and PET film was used as a support body. The acrylic pressure-sensitive adhesive used in this example was prepared in the same manner as in Example 1.
Mercaptobenzimidazole: 0.0 mass%, 0.1 mass%, 0.3 mass%, or 0.6 mass%
Ropinirole: 15% by mass
Isopropyl myristate: 20% by mass
Acrylic adhesive: 100- (Mixed amount of mercaptobenzimidazole, ropinirole and isopropyl myristate) (unit: mass%)
　得られた各経皮投与製剤を、ＰＡＮ／ＡＬ／ＰＥＴという構成を有する包装材に個別に入れ、包装材内を窒素環境下でシーリングした。 Each obtained transdermal preparation was individually put into a packaging material having a configuration of PAN / AL / PET, and the inside of the packaging material was sealed in a nitrogen environment.
　包装材中に包装された各経皮投与製剤を６０℃にて保存した。保存開始時点（イニシャル）、及び保存開始から０．５ヶ月後、１ヶ月後、２ヶ月後の各時点における経皮投与製剤中のロピニロール類縁物質（Ｐｒｏｐｙｌｉｄｅｎｅ　ｒｏｐｉｎｉｒｏｌｅ）の含有量をＨＰＬＣ（ＵＶ２５０ｎｍ）で測定した。その結果を図２に示す。検出されたロピニロール類縁物質の量が低いほど、経皮投与製剤中のロピニロールの薬物安定性が高いことを示す。 Each formulation for transdermal administration packaged in a packaging material was stored at 60 ° C. The content of ropinirole analogue (Propydine ropinirole) in the transdermal preparation at 0.5 months, 1 month, and 2 months after the start of storage was measured by HPLC (UV 250 nm). It was measured. The result is shown in FIG. The lower the amount of ropinirole analog detected, the higher the drug stability of ropinirole in the transdermal dosage formulation.
　なお、図２中、「ＭＢＩ」とはメルカプトベンズイミダゾールを指す。図２の「％」とは質量％を指す。 In FIG. 2, “MBI” refers to mercaptobenzimidazole. “%” In FIG. 2 refers to mass%.
　図２に示される通り、メルカプトベンズイミダゾールを含む経皮投与製剤においては、メルカプトベンズイミダゾールを含まない経皮投与製剤と比較して、ロピニロール類縁物質の生成が抑制されていた。このような抑制効果は、メルカプトベンズイミダゾールの濃度依存的に奏され、経皮投与製剤の保存期間が長期であっても認められた。 As shown in FIG. 2, in the transdermal preparation containing mercaptobenzimidazole, the production of ropinirole analogues was suppressed as compared with the transdermal preparation containing no mercaptobenzimidazole. Such an inhibitory effect was exhibited depending on the concentration of mercaptobenzimidazole, and was observed even when the storage period of the transdermal preparation was long.
＜実施例３：包装材中に包装されたロピニロール（２５質量％）含有経皮投与製剤中のロピニロールの安定性評価－Ｉ＞
　実施例１と同様の試験を、ロピニロールの配合量を増やして下記の通り行った。
　メルカプトベンズイミダゾール、ロピニロール、ミリスチン酸イソプロピル及びアクリル系粘着剤を、下記の割合で配合した組成物を作製し、これをＰＥＴ（ポリエチレンテレフタレート）フィルム上に塗工乾燥（８０℃、１５分）することによって粘着剤層を形成し、この粘着剤層上に支持体を積層させ、経皮投与製剤を得た。なお、支持体としてＰＥＴ不織布とＰＥＴフィルムとを積層したものを使用した。本実施例で用いたアクリル系粘着剤は、実施例１と同様に調製した。
　メルカプトベンズイミダゾール：０．０質量％、０．１質量％、０．３質量％、又は０．６質量％
　ロピニロール：２５質量％
　ミリスチン酸イソプロピル：２０質量％
　アクリル系粘着剤：１００－（メルカプトベンズイミダゾール、ロピニロール及びミリスチン酸イソプロピルの配合量）（単位：質量％） <Example 3: Evaluation of stability of ropinirole in a transdermal preparation containing ropinirole (25% by mass) packaged in a packaging material-I>
The same test as in Example 1 was performed as follows by increasing the amount of ropinirole.
A composition in which mercaptobenzimidazole, ropinirole, isopropyl myristate and an acrylic pressure-sensitive adhesive are blended in the following proportions is prepared, and this is coated on a PET (polyethylene terephthalate) film and dried (80 ° C., 15 minutes). Was used to form a pressure-sensitive adhesive layer, and a support was laminated on the pressure-sensitive adhesive layer to obtain a preparation for transdermal administration. In addition, what laminated | stacked PET nonwoven fabric and PET film was used as a support body. The acrylic pressure-sensitive adhesive used in this example was prepared in the same manner as in Example 1.
Mercaptobenzimidazole: 0.0 mass%, 0.1 mass%, 0.3 mass%, or 0.6 mass%
Ropinirole: 25% by mass
Isopropyl myristate: 20% by mass
Acrylic adhesive: 100- (Mixed amount of mercaptobenzimidazole, ropinirole and isopropyl myristate) (unit: mass%)
　得られた各経皮投与製剤を、ＰＡＮ／ＡＬ／ＰＥＴという構成を有する包装材に個別に入れ、包装材内を窒素環境下でシーリングした。 Each obtained transdermal preparation was individually put into a packaging material having a configuration of PAN / AL / PET, and the inside of the packaging material was sealed in a nitrogen environment.
　包装材中に包装された各経皮投与製剤を６０℃にて保存した。保存開始時点（イニシャル）、及び保存開始から０．５ヶ月後、１ヶ月後、２ヶ月後の各時点における経皮投与製剤中のロピニロール類縁物質（４Ｅ－ｉｎｄｏｌｏｎｅ）の含有量をＨＰＬＣ（ＵＶ２５０ｎｍ）で測定した。その結果を図３に示す。検出されたロピニロール類縁物質の量が低いほど、経皮投与製剤中のロピニロールの薬物安定性が高いことを示す。 Each formulation for transdermal administration packaged in a packaging material was stored at 60 ° C. The content of ropinirole-related substance (4E-indolene) in the preparation for transdermal administration at the time of the start of storage (initial) and 0.5 months, 1 month, and 2 months after the start of storage is HPLC (UV 250 nm) Measured with The result is shown in FIG. The lower the amount of ropinirole analog detected, the higher the drug stability of ropinirole in the transdermal formulation.
　なお、図３中、「ＭＢＩ」とはメルカプトベンズイミダゾールを指す。図３の「％」とは質量％を指す。 In FIG. 3, “MBI” refers to mercaptobenzimidazole. “%” In FIG. 3 refers to mass%.
　図３に示される通り、メルカプトベンズイミダゾールを含む経皮投与製剤においては、メルカプトベンズイミダゾールを含まない経皮投与製剤と比較して、ロピニロール類縁物質の生成が抑制されていた。このような抑制効果は、メルカプトベンズイミダゾールの濃度依存的に奏され、経皮投与製剤の保存期間が長期であっても認められた。 As shown in FIG. 3, in the transdermal administration formulation containing mercaptobenzimidazole, the production of ropinirole analogues was suppressed as compared to the transdermal administration formulation not containing mercaptobenzimidazole. Such an inhibitory effect was exhibited depending on the concentration of mercaptobenzimidazole, and was observed even when the storage period of the transdermal preparation was long.
＜実施例４：包装材中に包装されたロピニロール（１５質量％）含有経皮投与製剤中のロピニロールの安定性評価－ＩＩＩ＞
　メルカプトベンズイミダゾール、ジブチルヒドロキシトルエン、ロピニロール、ミリスチン酸イソプロピル及びアクリル系粘着剤を、下記の割合で配合した組成物を作製し、これをＰＥＴ（ポリエチレンテレフタレート）フィルム上に塗工乾燥（８０℃、１５分）することによって粘着剤層を形成し、この粘着剤層上に支持体を積層させ、経皮投与製剤を得た。なお、支持体としてＰＥＴ不織布とＰＥＴフィルムとを積層したものを使用した。本実施例で用いたアクリル系粘着剤は、実施例１と同様に調製した。
　メルカプトベンズイミダゾール：０．０質量％、０．１質量％、０．３質量％、又は０．６質量％
　ジブチルヒドロキシトルエン：０．０質量％、０．５質量％、１．０質量％、又は２．０質量％
　ロピニロール：１５質量％
　ミリスチン酸イソプロピル：２０質量％
　アクリル系粘着剤：１００－（メルカプトベンズイミダゾール、ジブチルヒドロキシトルエン、ロピニロール及びミリスチン酸イソプロピルの配合量）（単位：質量％） <Example 4: Evaluation of stability of ropinirole in a preparation for transdermal administration containing ropinirole (15% by mass) packaged in a packaging material-III>
A composition in which mercaptobenzimidazole, dibutylhydroxytoluene, ropinirole, isopropyl myristate and an acrylic pressure-sensitive adhesive were blended in the following proportions was prepared, and this was applied onto a PET (polyethylene terephthalate) film and dried (80 ° C., 15 To form a pressure-sensitive adhesive layer, and a support was laminated on the pressure-sensitive adhesive layer to obtain a preparation for transdermal administration. In addition, what laminated | stacked PET nonwoven fabric and PET film was used as a support body. The acrylic pressure-sensitive adhesive used in this example was prepared in the same manner as in Example 1.
Mercaptobenzimidazole: 0.0 mass%, 0.1 mass%, 0.3 mass%, or 0.6 mass%
Dibutylhydroxytoluene: 0.0 mass%, 0.5 mass%, 1.0 mass%, or 2.0 mass%
Ropinirole: 15% by mass
Isopropyl myristate: 20% by mass
Acrylic adhesive: 100- (Mixed amount of mercaptobenzimidazole, dibutylhydroxytoluene, ropinirole and isopropyl myristate) (unit: mass%)
　得られた各経皮投与製剤を、ＰＡＮ／ＡＬ／ＰＥＴという構成を有する包装材に個別に入れ、包装材内をガス置換せずにそのままシーリングした。 Each obtained transdermal preparation was individually put into a packaging material having a configuration of PAN / AL / PET, and the inside of the packaging material was sealed as it was without replacing the gas.
　包装材中に包装された各経皮投与製剤を６０℃にて保存した。保存開始時点（イニシャル）、及び保存開始から１週間後の各時点における経皮投与製剤中のロピニロール類縁物質（４Ｅ－ｉｎｄｏｌｏｎｅ）の含有量をＨＰＬＣ（ＵＶ２５０ｎｍ）で測定した。その結果を図４に示す。検出されたロピニロール類縁物質の量が低いほど、経皮投与製剤中のロピニロールの薬物安定性が高いことを示す。 Each formulation for transdermal administration packaged in a packaging material was stored at 60 ° C. The content of ropinirole analogue (4E-indolene) in the preparation for transdermal administration at the time of starting storage (initial) and at each time one week after the start of storage was measured by HPLC (UV 250 nm). The result is shown in FIG. The lower the amount of ropinirole analog detected, the higher the drug stability of ropinirole in the transdermal formulation.
　なお、図４中、「ＭＢＩ」とはメルカプトベンズイミダゾールを指す。「ＢＨＴ」とはジブチルヒドロキシトルエンを指す。図４中の「％」とは質量％を指す。 In FIG. 4, “MBI” refers to mercaptobenzimidazole. “BHT” refers to dibutylhydroxytoluene. “%” In FIG. 4 refers to mass%.
　図４に示される通り、メルカプトベンズイミダゾールを含む経皮投与製剤においては、メルカプトベンズイミダゾールを含まない経皮投与製剤と比較して、ロピニロール類縁物質の生成が抑制されていた。経皮投与製剤中に、メルカプトベンズイミダゾールとともにジブチルヒドロキシトルエンが配合されていると、経皮投与製剤中のロピニロール類縁物質の生成がより抑制される傾向にあった。 As shown in FIG. 4, in the transdermal administration formulation containing mercaptobenzimidazole, the production of ropinirole analogues was suppressed as compared to the transdermal administration formulation not containing mercaptobenzimidazole. When dibutylhydroxytoluene was blended with mercaptobenzimidazole in a transdermal administration preparation, the production of ropinirole-related substances in the transdermal administration preparation tended to be further suppressed.
＜実施例５：包装材中に包装されたロピニロール（１５質量％）含有経皮投与製剤中のロピニロールの安定性評価－ＩＶ＞
　メルカプトベンズイミダゾール、ジブチルヒドロキシトルエン、ロピニロール、ミリスチン酸イソプロピル及びアクリル系粘着剤を、下記の割合で配合した組成物を作製し、これをＰＥＴ（ポリエチレンテレフタレート）フィルム上に塗工乾燥（８０℃、１５分）することによって粘着剤層を形成し、この粘着剤層上に支持体を積層させ、経皮投与製剤を得た。なお、支持体としてＰＥＴ不織布とＰＥＴフィルムとを積層したものを使用した。本実施例で用いたアクリル系粘着剤は、実施例１と同様に調製した。
　メルカプトベンズイミダゾール：０．０質量％、０．１質量％、又は０．３質量％
　ジブチルヒドロキシトルエン：０．０質量％、０．５質量％、１．０質量％、又は２．０質量％
　ロピニロール：１５質量％
　ミリスチン酸イソプロピル：２０質量％
　アクリル系粘着剤：１００－（メルカプトベンズイミダゾール、ジブチルヒドロキシトルエン、ロピニロール及びミリスチン酸イソプロピルの配合量）（単位：質量％） <Example 5: Stability evaluation of ropinirole in a transdermal preparation containing ropinirole (15% by mass) packaged in a packaging material-IV>
A composition in which mercaptobenzimidazole, dibutylhydroxytoluene, ropinirole, isopropyl myristate and an acrylic pressure-sensitive adhesive were blended in the following proportions was prepared, and this was applied onto a PET (polyethylene terephthalate) film and dried (80 ° C., 15 To form a pressure-sensitive adhesive layer, and a support was laminated on the pressure-sensitive adhesive layer to obtain a preparation for transdermal administration. In addition, what laminated | stacked PET nonwoven fabric and PET film was used as a support body. The acrylic pressure-sensitive adhesive used in this example was prepared in the same manner as in Example 1.
Mercaptobenzimidazole: 0.0 mass%, 0.1 mass%, or 0.3 mass%
Dibutylhydroxytoluene: 0.0 mass%, 0.5 mass%, 1.0 mass%, or 2.0 mass%
Ropinirole: 15% by mass
Isopropyl myristate: 20% by mass
Acrylic adhesive: 100- (Mixed amount of mercaptobenzimidazole, dibutylhydroxytoluene, ropinirole and isopropyl myristate) (unit: mass%)
　得られた各経皮投与製剤を、ＰＡＮ／ＡＬ／ＰＥＴという構成を有する包装材に個別に入れ、包装材内を窒素環境下でシーリングした。 Each obtained transdermal preparation was individually put into a packaging material having a configuration of PAN / AL / PET, and the inside of the packaging material was sealed in a nitrogen environment.
　包装材中に包装された各経皮投与製剤を６０℃にて保存した。保存開始時点（イニシャル）、及び、保存開始から２ヶ月後の各時点における経皮投与製剤中のロピニロール類縁物質（Ｐｒｏｐｙｌｉｄｅｎｅ　ｒｏｐｉｎｉｒｏｌｅ）の含有量をＨＰＬＣ（ＵＶ２５０ｎｍ）で測定した。その結果を図５に示す。検出されたロピニロール類縁物質の量が低いほど、経皮投与製剤中のロピニロールの薬物安定性が高いことを示す。 Each formulation for transdermal administration packaged in a packaging material was stored at 60 ° C. The content of ropinirole analogue (Propylidene ropinirole) in the preparation for transdermal administration at the time of the start of storage (initial) and at each time point 2 months after the start of storage was measured by HPLC (UV 250 nm). The result is shown in FIG. The lower the amount of ropinirole analog detected, the higher the drug stability of ropinirole in the transdermal formulation.
　なお、図５中、「ＭＢＩ」とはメルカプトベンズイミダゾールを指す。「ＢＨＴ」とはジブチルヒドロキシトルエンを指す。図５中の「％」とは質量％を指す。 In FIG. 5, “MBI” refers to mercaptobenzimidazole. “BHT” refers to dibutylhydroxytoluene. “%” In FIG. 5 refers to mass%.
　図５に示される通り、メルカプトベンズイミダゾールを含む経皮投与製剤においては、メルカプトベンズイミダゾールを含まない経皮投与製剤と比較して、ロピニロール類縁物質の生成が抑制されていた。このような抑制効果は、メルカプトベンズイミダゾールの濃度依存的に奏され、経皮投与製剤の保存期間が長期であっても認められた。経皮投与製剤中に、メルカプトベンズイミダゾールとともにジブチルヒドロキシトルエンが配合されていると、経皮投与製剤中のロピニロール類縁物質の生成がより抑制される傾向にあった。 As shown in FIG. 5, in the transdermal preparation containing mercaptobenzimidazole, the production of ropinirole analogues was suppressed as compared with the transdermal preparation containing no mercaptobenzimidazole. Such an inhibitory effect was exhibited depending on the concentration of mercaptobenzimidazole, and was observed even when the storage period of the transdermal preparation was long. When dibutylhydroxytoluene was blended with mercaptobenzimidazole in a transdermal administration preparation, the production of ropinirole-related substances in the transdermal administration preparation tended to be further suppressed.
＜実施例６：包装材中に包装されたロピニロール（２５質量％）含有経皮投与製剤中のロピニロールの安定性評価－ＩＩ＞
　メルカプトベンズイミダゾール、ジブチルヒドロキシトルエン、ロピニロール、ミリスチン酸イソプロピル及びアクリル系粘着剤を、下記の割合で配合した組成物を作製し、これをＰＥＴ（ポリエチレンテレフタレート）フィルム上に塗工乾燥（８０℃、１５分）することによって粘着剤層を形成し、この粘着剤層上に支持体を積層させ、経皮投与製剤を得た。なお、支持体としてＰＥＴ不織布とＰＥＴフィルムとを積層したものを使用した。本実施例で用いたアクリル系粘着剤は、実施例１と同様に調製した。
　メルカプトベンズイミダゾール：０．０質量％、０．１質量％、０．３質量％、又は０．６質量％
　ジブチルヒドロキシトルエン：０．０質量％、０．５質量％、１．０質量％、又は２．０質量％
　ロピニロール：２５質量％
　ミリスチン酸イソプロピル：２０質量％
　アクリル系粘着剤：１００－（メルカプトベンズイミダゾール、ジブチルヒドロキシトルエン、ロピニロール及びミリスチン酸イソプロピルの配合量）（単位：質量％） <Example 6: Stability evaluation of ropinirole in a preparation for transdermal administration containing ropinirole (25% by mass) packaged in a packaging material-II>
A composition in which mercaptobenzimidazole, dibutylhydroxytoluene, ropinirole, isopropyl myristate and an acrylic pressure-sensitive adhesive were blended in the following proportions was prepared, and this was applied onto a PET (polyethylene terephthalate) film and dried (80 ° C., 15 To form a pressure-sensitive adhesive layer, and a support was laminated on the pressure-sensitive adhesive layer to obtain a preparation for transdermal administration. In addition, what laminated | stacked PET nonwoven fabric and PET film was used as a support body. The acrylic pressure-sensitive adhesive used in this example was prepared in the same manner as in Example 1.
Mercaptobenzimidazole: 0.0 mass%, 0.1 mass%, 0.3 mass%, or 0.6 mass%
Dibutylhydroxytoluene: 0.0 mass%, 0.5 mass%, 1.0 mass%, or 2.0 mass%
Ropinirole: 25% by mass
Isopropyl myristate: 20% by mass
Acrylic adhesive: 100- (Mixed amount of mercaptobenzimidazole, dibutylhydroxytoluene, ropinirole and isopropyl myristate) (unit: mass%)
　得られた各経皮投与製剤を、ＰＡＮ／ＡＬ／ＰＥＴという構成を有する包装材に個別に入れ、包装材内を窒素環境下でシーリングした。 Each obtained transdermal preparation was individually put into a packaging material having a configuration of PAN / AL / PET, and the inside of the packaging material was sealed in a nitrogen environment.
　包装材中に包装された各経皮投与製剤を４０℃又は６０℃にて保存した。保存開始時点（イニシャル）、及び、保存開始から２ヶ月後の各時点における経皮投与製剤中のロピニロール類縁物質（Ｐｒｏｐｙｌｉｄｅｎｅ　ｒｏｐｉｎｉｒｏｌｅ）の含有量をＨＰＬＣ（ＵＶ２５０ｎｍ）で測定した。その結果を図６に示す。検出されたロピニロール類縁物質の量が低いほど、経皮投与製剤中のロピニロールの薬物安定性が高いことを示す。 Each formulation for transdermal administration packaged in a packaging material was stored at 40 ° C or 60 ° C. The content of ropinirole analogue (Propylidene ropinirole) in the preparation for transdermal administration at the time of the start of storage (initial) and at each time point 2 months after the start of storage was measured by HPLC (UV 250 nm). The result is shown in FIG. The lower the amount of ropinirole analog detected, the higher the drug stability of ropinirole in the transdermal formulation.
　なお、図６中、「ＭＢＩ」とはメルカプトベンズイミダゾールを指す。「ＢＨＴ」とはジブチルヒドロキシトルエンを指す。図６中の「％」とは質量％を指す。 In FIG. 6, “MBI” refers to mercaptobenzimidazole. “BHT” refers to dibutylhydroxytoluene. “%” In FIG. 6 refers to mass%.
　図６に示される通り、メルカプトベンズイミダゾールを含む経皮投与製剤においては、メルカプトベンズイミダゾールを含まない経皮投与製剤と比較して、ロピニロール類縁物質の生成が抑制されていた。このような抑制効果は、メルカプトベンズイミダゾールの濃度依存的に奏され、経皮投与製剤の保存期間が長期であっても認められた。経皮投与製剤中に、メルカプトベンズイミダゾールとともにジブチルヒドロキシトルエンが配合されていると、経皮投与製剤中のロピニロール類縁物質の生成がより抑制される傾向にあった。 As shown in FIG. 6, in the transdermal preparation containing mercaptobenzimidazole, the production of ropinirole analogues was suppressed as compared with the transdermal preparation containing no mercaptobenzimidazole. Such an inhibitory effect was exhibited depending on the concentration of mercaptobenzimidazole, and was observed even when the storage period of the transdermal preparation was long. When dibutylhydroxytoluene was blended with mercaptobenzimidazole in a transdermal administration preparation, the production of ropinirole-related substances in the transdermal administration preparation tended to be further suppressed.
＜実施例７：包装材中に包装されたロピニロール（１５質量％）含有経皮投与製剤中のロピニロールの安定性評価－Ｖ＞
　メルカプトベンズイミダゾール、ジブチルヒドロキシトルエン、ロピニロール、ミリスチン酸イソプロピル及びアクリル系粘着剤を、下記の割合で配合した組成物を作製し、これをＰＥＴ（ポリエチレンテレフタレート）フィルム上に塗工乾燥（８０℃、１５分）することによって粘着剤層を形成し、この粘着剤層上に支持体を積層させ、経皮投与製剤を得た。なお、支持体としてＰＥＴ不織布とＰＥＴフィルムを積層したものを使用した。本実施例で用いたアクリル系粘着剤は、実施例１と同様に調製した。
　メルカプトベンズイミダゾール：０．０質量％、０．３質量％、又は０．６質量％
　ジブチルヒドロキシトルエン：０．０質量％、０．５質量％、１．０質量％、又は２．０質量％
　ロピニロール：１５質量％
　ミリスチン酸イソプロピル：２０質量％
　アクリル系粘着剤：１００－（メルカプトベンズイミダゾール、ジブチルヒドロキシトルエン、ロピニロール及びミリスチン酸イソプロピルの配合量）（単位：質量％） <Example 7: Stability evaluation of ropinirole in a transdermal preparation containing ropinirole (15% by mass) packaged in a packaging material-V>
A composition in which mercaptobenzimidazole, dibutylhydroxytoluene, ropinirole, isopropyl myristate and an acrylic pressure-sensitive adhesive were blended in the following proportions was prepared, and this was applied onto a PET (polyethylene terephthalate) film and dried (80 ° C., 15 To form a pressure-sensitive adhesive layer, and a support was laminated on the pressure-sensitive adhesive layer to obtain a preparation for transdermal administration. In addition, what laminated | stacked PET nonwoven fabric and PET film was used as a support body. The acrylic pressure-sensitive adhesive used in this example was prepared in the same manner as in Example 1.
Mercaptobenzimidazole: 0.0 mass%, 0.3 mass%, or 0.6 mass%
Dibutylhydroxytoluene: 0.0 mass%, 0.5 mass%, 1.0 mass%, or 2.0 mass%
Ropinirole: 15% by mass
Isopropyl myristate: 20% by mass
Acrylic adhesive: 100- (Mixed amount of mercaptobenzimidazole, dibutylhydroxytoluene, ropinirole and isopropyl myristate) (unit: mass%)
　得られた各経皮投与製剤を、ＰＡＮ／ＡＬ／ＰＥＴという構成を有する包装材に個別に入れ、（１）包装材内を窒素環境下でシーリング、（２）包装材内への脱酸素剤（ファーマキープ　ＫＤ－２０、三菱ガス化学（株）製）の封入後にシーリング、又は、（３）窒素環境下でのシーリング、及び脱酸素剤の封入のいずれも行わずにそのままシーリング、のいずれかを行った。 Each obtained preparation for transdermal administration is individually put in a packaging material having a configuration of PAN / AL / PET, (1) sealing the packaging material in a nitrogen environment, and (2) an oxygen scavenger into the packaging material. (Pharmakeep KD-20, manufactured by Mitsubishi Gas Chemical Co., Ltd.) Sealing after sealing, or (3) Sealing in a nitrogen environment and sealing without removing oxygen scavenger Went.
　包装材中に包装された各経皮投与製剤を６０℃にて保存した。保存開始時点（イニシャル）、及び保存開始から１週間後、２週間後、又は１ヶ月後の各時点における経皮投与製剤中のロピニロール類縁物質（４Ｅ－ｉｎｄｏｌｏｎｅ）の含有量をＨＰＬＣ（ＵＶ２５０ｎｍ）で測定した。その結果を図７に示す。検出されたロピニロール類縁物質の量が低いほど、経皮投与製剤中のロピニロールの薬物安定性が高いことを示す。 Each formulation for transdermal administration packaged in a packaging material was stored at 60 ° C. The content of ropinirole analogue (4E-indolene) in the transdermal administration preparation at the time of storage start (initial) and at each time point 1 week, 2 weeks, or 1 month after the start of storage was measured by HPLC (UV 250 nm). It was measured. The result is shown in FIG. The lower the amount of ropinirole analog detected, the higher the drug stability of ropinirole in the transdermal formulation.
　なお、図７中、「ＭＢＩ」とはメルカプトベンズイミダゾールを指す。「ＢＨＴ」とはジブチルヒドロキシトルエンを指す。「Ｎ２」とは包装材内を窒素置換したことを指す。「脱酸素剤」とは包装材内に脱酸素剤を封入したことを指す。図７中の「％」とは質量％を指す。 In FIG. 7, “MBI” refers to mercaptobenzimidazole. “BHT” refers to dibutylhydroxytoluene. “N2” indicates that the inside of the packaging material is replaced with nitrogen. “Oxygen scavenger” means that the oxygen scavenger is enclosed in the packaging material. “%” In FIG. 7 refers to mass%.
　図７に示される通り、メルカプトベンズイミダゾールを含む経皮投与製剤においては、メルカプトベンズイミダゾールを含まない経皮投与製剤と比較して、ロピニロール類縁物質の生成が抑制されていた。経皮投与製剤中に、メルカプトベンズイミダゾールとともにジブチルヒドロキシトルエンが配合されていると、経皮投与製剤中のロピニロール類縁物質の生成がより抑制される傾向にあった。さらに、窒素置換された包装材内に経皮投与製剤を包装するか、又は、経皮投与製剤とともに脱酸素剤を包装材内に封入すると、経皮投与製剤中のロピニロール類縁物質の生成が顕著に抑制される傾向にあった。 As shown in FIG. 7, in the transdermal administration formulation containing mercaptobenzimidazole, the production of ropinirole analogues was suppressed as compared to the transdermal administration formulation not containing mercaptobenzimidazole. When dibutylhydroxytoluene was blended with mercaptobenzimidazole in a transdermal administration preparation, the production of ropinirole-related substances in the transdermal administration preparation tended to be further suppressed. Furthermore, when a transdermal preparation is packaged in a nitrogen-substituted packaging material, or when an oxygen scavenger is enclosed in the packaging material together with the transdermal preparation, ropinirole analogues in the transdermal preparation are markedly produced. There was a tendency to be suppressed.
＜実施例８：包装材中に包装されたロピニロール（１５質量％）含有経皮投与製剤中のロピニロールの安定性評価－ＶＩ＞
　メルカプトベンズイミダゾール、ジブチルヒドロキシトルエン、ロピニロール、ミリスチン酸イソプロピル及びアクリル系粘着剤を、下記の割合で配合した組成物を作製し、これをＰＥＴ（ポリエチレンテレフタレート）フィルム上に塗工乾燥（８０℃、１５分）することによって粘着剤層を形成し、この粘着剤層上に支持体を積層させ、経皮投与製剤を得た。なお、支持体としてＰＥＴ不織布とＰＥＴフィルムを積層したものを使用した。本実施例で用いたアクリル系粘着剤は、実施例１と同様に調製した。
　メルカプトベンズイミダゾール：０．０質量％、又は０．６質量％
　ジブチルヒドロキシトルエン：０．０質量％、又は２．０質量％
　ロピニロール：１５質量％
　ミリスチン酸イソプロピル：２０質量％
　アクリル系粘着剤：１００－（メルカプトベンズイミダゾール、ジブチルヒドロキシトルエン、ロピニロール及びミリスチン酸イソプロピルの配合量）（単位：質量％） <Example 8: Stability evaluation of ropinirole in a preparation for transdermal administration containing ropinirole (15% by mass) packaged in a packaging material-VI>
A composition in which mercaptobenzimidazole, dibutylhydroxytoluene, ropinirole, isopropyl myristate and an acrylic pressure-sensitive adhesive were blended in the following proportions was prepared, and this was applied onto a PET (polyethylene terephthalate) film and dried (80 ° C., 15 To form a pressure-sensitive adhesive layer, and a support was laminated on the pressure-sensitive adhesive layer to obtain a preparation for transdermal administration. In addition, what laminated | stacked PET nonwoven fabric and PET film was used as a support body. The acrylic pressure-sensitive adhesive used in this example was prepared in the same manner as in Example 1.
Mercaptobenzimidazole: 0.0% by mass or 0.6% by mass
Dibutylhydroxytoluene: 0.0% by mass or 2.0% by mass
Ropinirole: 15% by mass
Isopropyl myristate: 20% by mass
Acrylic adhesive: 100- (Mixed amount of mercaptobenzimidazole, dibutylhydroxytoluene, ropinirole and isopropyl myristate) (unit: mass%)
　得られた各経皮投与製剤を、ＰＡＮ／ＡＬ／ＰＥＴという構成を有する包装材に個別に入れ、（１）包装材内を窒素環境下でシーリング、（２）包装材内への脱酸素剤（ファーマキープ　ＫＤ－２０、三菱ガス化学（株）製）の封入後にシーリング、又は、（３）窒素環境下でのシーリング、及び脱酸素剤の封入のいずれも行わずにそのままシーリング、のいずれかを行った。 Each obtained preparation for transdermal administration is individually put in a packaging material having a configuration of PAN / AL / PET, (1) sealing the packaging material in a nitrogen environment, and (2) an oxygen scavenger into the packaging material. (Pharmakeep KD-20, manufactured by Mitsubishi Gas Chemical Co., Ltd.) Sealing after sealing, or (3) Sealing in a nitrogen environment and sealing without removing oxygen scavenger Went.
　包装材中に包装された各経皮投与製剤を６０℃にて保存した。保存開始時点（イニシャル）、及び保存開始から２週間後、又は１ヶ月後の各時点における経皮投与製剤中のロピニロール類縁物質（Ｍｏｎｏｐｒｏｐｙｌ　ｒｏｐｉｎｉｒｏｌｅ、４Ｅ－ｉｎｄｏｌｏｎｅ、Ｐｒｏｐｙｌｉｄｅｎｅ　ｒｏｐｉｎｉｒｏｌｅ、Ｕｎｋｎｏｗｎ－１）の含有量をＨＰＬＣ（ＵＶ２５０ｎｍ）で測定した。その結果を図８に示す。検出されたロピニロール類縁物質の量が低いほど、経皮投与製剤中のロピニロールの薬物安定性が高いことを示す。 Each formulation for transdermal administration packaged in a packaging material was stored at 60 ° C. Content of ropinirole analogues (Monopropyl ropirirole, 4E-indolelone, propylidene ropinirole, Unknown-1) in the preparation for transdermal administration at the time of the start of storage (initial) and 2 weeks or 1 month after the start of storage Was measured by HPLC (UV 250 nm). The result is shown in FIG. The lower the amount of ropinirole analog detected, the higher the drug stability of ropinirole in the transdermal formulation.
　なお、図８中、「ＭＢＩ」とはメルカプトベンズイミダゾールを指す。「ＢＨＴ」とはジブチルヒドロキシトルエンを指す。「Ｎ２」とは包装材内を窒素置換したことを指す。「脱酸素剤」とは包装材内に脱酸素剤を封入したことを指す。図８中の「％」とは質量％を指す。 In FIG. 8, “MBI” refers to mercaptobenzimidazole. “BHT” refers to dibutylhydroxytoluene. “N2” indicates that the inside of the packaging material is replaced with nitrogen. “Oxygen scavenger” means that the oxygen scavenger is enclosed in the packaging material. “%” In FIG. 8 indicates mass%.
　図８に示される通り、メルカプトベンズイミダゾールを含む経皮投与製剤においては、メルカプトベンズイミダゾールを含まない経皮投与製剤と比較して、様々なロピニロール類縁物質の生成が抑制されていた。経皮投与製剤中に、メルカプトベンズイミダゾールとともにジブチルヒドロキシトルエンが配合されていると、経皮投与製剤中のロピニロール類縁物質の生成がより抑制される傾向にあった。さらに、窒素置換された包装材内に経皮投与製剤を包装するか、又は、経皮投与製剤とともに脱酸素剤を包装材内に封入すると、経皮投与製剤中のロピニロール類縁物質の生成がさらに抑制される傾向にあった。 As shown in FIG. 8, in the preparation for transdermal administration containing mercaptobenzimidazole, the production of various ropinirole analogues was suppressed as compared with the preparation for transdermal administration containing no mercaptobenzimidazole. When dibutylhydroxytoluene was blended with mercaptobenzimidazole in a transdermal administration preparation, the production of ropinirole-related substances in the transdermal administration preparation tended to be further suppressed. Further, when a transdermal administration preparation is packaged in a nitrogen-substituted packaging material or an oxygen scavenger is enclosed in the packaging material together with the transdermal administration preparation, ropinirole analogues in the transdermal administration preparation are further generated. There was a tendency to be suppressed.

Claims (6)

  1. 　支持体と、前記支持体上に位置する粘着剤層と、を備える経皮投与製剤であって、
    　前記粘着剤層は、ロピニロール又はその薬理学的に許容できる塩、及びメルカプトベンズイミダゾールを含む経皮投与製剤。     A transdermal administration preparation comprising a support and an adhesive layer located on the support,
    The pressure-sensitive adhesive layer is a transdermal preparation containing ropinirole or a pharmacologically acceptable salt thereof and mercaptobenzimidazole.
  2. 　前記メルカプトベンズイミダゾールの含量は、前記粘着剤層に対して０．１０～５．００質量％である請求項１に記載の経皮投与製剤。 2. The transdermal administration preparation according to claim 1, wherein the content of the mercaptobenzimidazole is 0.10 to 5.00% by mass with respect to the pressure-sensitive adhesive layer.
  3. 　さらに、ジブチルヒドロキシトルエンを含む請求項１又は２に記載の経皮投与製剤。 The transdermal administration preparation according to claim 1 or 2, further comprising dibutylhydroxytoluene.
  4. 　前記ジブチルヒドロキシトルエンの含量は、前記粘着剤層に対して０．１０～１０．０質量％である請求項３に記載の経皮投与製剤。 The preparation for transdermal administration according to claim 3, wherein a content of the dibutylhydroxytoluene is 0.10 to 10.0% by mass with respect to the pressure-sensitive adhesive layer.
  5. 　前記粘着剤層は、アクリル系粘着剤を含む請求項１から４のいずれかに記載の経皮投与製剤。 The transdermal administration preparation according to any one of claims 1 to 4, wherein the pressure-sensitive adhesive layer contains an acrylic pressure-sensitive adhesive.
  6. 　包装材と、前記包装材内に封入された請求項１から５のいずれかに記載の経皮投与製剤と、を備え、
    　前記包装材内は窒素置換されている、包装体。     A packaging material, and a transdermal administration preparation according to any one of claims 1 to 5 enclosed in the packaging material,
    A packaging body in which the inside of the packaging material is substituted with nitrogen.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017073516A1 (en) * 2015-10-26 2017-05-04 久光製薬株式会社 Adhesive skin patch
EP3616699A4 (en) * 2017-04-25 2020-06-17 Hisamitsu Pharmaceutical Co., Inc. Adhesive patch

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1179979A (en) * 1997-09-05 1999-03-23 Nitto Denko Corp Percutaneously absorbable type preparation
JP2011190204A (en) * 2010-03-12 2011-09-29 Nitto Denko Corp Selegiline-containing adhesive preparation
WO2013081102A1 (en) * 2011-12-01 2013-06-06 帝國製薬株式会社 Ropinirole-containing adhesive patch
JP2013525345A (en) * 2010-04-23 2013-06-20 アイキュア・ファーマシューティカル・インコーポレーテッド Transdermal absorption preparation
JP2014513719A (en) * 2011-05-20 2014-06-05 エスケー ケミカルズ カンパニー，リミテッド Rivastigmine-containing patch

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1179979A (en) * 1997-09-05 1999-03-23 Nitto Denko Corp Percutaneously absorbable type preparation
JP2011190204A (en) * 2010-03-12 2011-09-29 Nitto Denko Corp Selegiline-containing adhesive preparation
JP2013525345A (en) * 2010-04-23 2013-06-20 アイキュア・ファーマシューティカル・インコーポレーテッド Transdermal absorption preparation
JP2014513719A (en) * 2011-05-20 2014-06-05 エスケー ケミカルズ カンパニー，リミテッド Rivastigmine-containing patch
WO2013081102A1 (en) * 2011-12-01 2013-06-06 帝國製薬株式会社 Ropinirole-containing adhesive patch

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017073516A1 (en) * 2015-10-26 2017-05-04 久光製薬株式会社 Adhesive skin patch
US10441551B2 (en) 2015-10-26 2019-10-15 Hisamitsu Pharmaceutical Co., Inc. Patch
EP3616699A4 (en) * 2017-04-25 2020-06-17 Hisamitsu Pharmaceutical Co., Inc. Adhesive patch

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