WO2021157457A1 - Blonanserin-containing patch and method for manufacturing same - Google Patents

Blonanserin-containing patch and method for manufacturing same Download PDF

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Publication number
WO2021157457A1
WO2021157457A1 PCT/JP2021/002958 JP2021002958W WO2021157457A1 WO 2021157457 A1 WO2021157457 A1 WO 2021157457A1 JP 2021002958 W JP2021002958 W JP 2021002958W WO 2021157457 A1 WO2021157457 A1 WO 2021157457A1
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WO
WIPO (PCT)
Prior art keywords
adhesive layer
sensitive adhesive
pressure
patch
acid
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PCT/JP2021/002958
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French (fr)
Japanese (ja)
Inventor
徳紀 松尾
弘幸 荻野
後藤　正興
Original Assignee
株式会社カネカ
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Application filed by 株式会社カネカ filed Critical 株式会社カネカ
Priority to CN202180012756.6A priority Critical patent/CN115279350A/en
Priority to JP2021575752A priority patent/JPWO2021157457A1/ja
Publication of WO2021157457A1 publication Critical patent/WO2021157457A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the present invention relates to a patch containing blonanserin and a method for producing the same. More specifically, the present invention relates to a blonanserin-containing patch having high skin permeability and a method for producing the same.
  • Patent Document 1 describes a patch that uses an acrylic pressure-sensitive adhesive as a pressure-sensitive adhesive, and when lactic acid is added as a permeation accelerator, the permeation amount of blonanserin is dramatically improved in a rat skin permeability test.
  • Patent Document 2 by requiring the addition of lactic acid, all the pressure-sensitive adhesives of silicone-based pressure-sensitive adhesives, rubber-based (styrene / isoprene / styrene block copolymer) pressure-sensitive adhesives, and acrylic-based pressure-sensitive adhesives are used.
  • a technology that can realize an unprecedentedly high amount of styrenerin permeation is disclosed.
  • Non-Patent Document 1 the drug utilization rate of Lonasen® tape is low (Non-Patent Document 1), and it is necessary to increase the size of the preparation in order to absorb a sufficient amount of the drug through the skin and obtain the drug blood concentration required for treatment. was there. Considering that the application site of Blonanserin (registered trademark) tape must be changed every day, it can be said that an excessively large formulation size is extremely inconvenient for the patient and extremely difficult to use.
  • a blonanserin-containing patch having high skin permeability and a method for producing the same are not known at all, and the provision of these is strongly required.
  • An object of the present invention is to solve the above-mentioned problems in the past and to achieve the following objects. That is, an object of the present invention is to provide a blonanserin-containing patch having high skin permeability and a method for producing the same.
  • the present inventors have a support and a pressure-sensitive adhesive layer on the support, and the pressure-sensitive adhesive layer is bronanceline or a salt thereof, thermoplastic.
  • a patch containing an elastomer and a non-volatile hydrocarbon oil, and the amount of lactic acid in the pressure-sensitive adhesive layer is 1.5 mol equivalent or less with respect to the bronanceline contained in the pressure-sensitive adhesive layer. It was found that the agent can be provided.
  • the present invention is based on the above-mentioned findings by the present inventors, and the means for solving the above-mentioned problems are as follows. That is, ⁇ 1>
  • the pressure-sensitive adhesive comprises a support and a pressure-sensitive adhesive layer on the support, wherein the pressure-sensitive adhesive layer contains bronanceline or a salt thereof, a thermoplastic elastomer, lactic acid, and a non-volatile hydrocarbon oil.
  • the patch is characterized in that the amount of lactic acid in the layer is more than 0 molar equivalent and 1.5 molar equivalent or less with respect to the bronanceline contained in the pressure-sensitive adhesive layer.
  • ⁇ 2> It has a support and a pressure-sensitive adhesive layer on the support, and the pressure-sensitive adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, and a non-volatile hydrocarbon oil, and does not contain lactic acid. It is a patch characterized by.
  • ⁇ 3> The method for producing a patch according to ⁇ 1> or ⁇ 2>, which comprises a step of laminating the support and the pressure-sensitive adhesive layer.
  • the patch may have a support, an adhesive layer on the support, and other elements.
  • the support is not particularly limited and may be appropriately selected depending on the intended purpose.
  • a pressure-sensitive adhesive sheet for skin application a general-purpose support for transdermal absorption preparation, or the like can be used.
  • the material of the support is not particularly limited and may be appropriately selected depending on the intended purpose.
  • polyester such as polyethylene terephthalate, polyolefin such as polyethylene and polypropylene, polyurethane, ethylene vinyl acetate copolymer and polyvinyl chloride Vinyl and the like can be mentioned.
  • the structure of the support may be a one-layer structure or a multi-layer structure. Further, it may be a knitted fabric, a woven fabric, a non-woven fabric, a film, a foam, a porous material, a mesh structure, a sheet shape, or a flat plate shape.
  • the woven fabric, the non-woven fabric, the film and the like constituting the support may contain an antistatic agent.
  • a non-woven fabric or woven fabric as a support, or a laminate of these and a film can be used.
  • the thickness of the support is not particularly limited and may be appropriately selected depending on the intended purpose.
  • the film is preferably 10 ⁇ m or more and 100 ⁇ m or less, more preferably 15 ⁇ m or more and 50 ⁇ m or less, and is woven fabric, non-woven fabric, or foam.
  • a porous sheet such as a sex support, 50 ⁇ m or more and 2,000 ⁇ m or less is preferable, and 100 ⁇ m or more and 1,000 ⁇ m or less is more preferable.
  • the pressure-sensitive adhesive layer contains (a) bronanserin or a salt thereof, (b) a thermoplastic elastomer, and (c) a non-volatile hydrocarbon oil, and the amount of lactic acid in the pressure-sensitive adhesive layer is contained in the pressure-sensitive adhesive layer. It is 1.5 molar equivalents or less, and can further have other components.
  • Bronanserin or a salt thereof
  • the chemical name of "bronanserin” is 2- (4-ethyl-1-piperanidyl) -4- (4-fluorophenyl) -5,6,7,8,9,10-hexa. It is a compound represented as hydroxycroocta [b] pyridine, is classified as SDA (serotonin / dopamine antagonist), and is commercially available as an antipsychotic drug (atypical antipsychotic drug).
  • SDA serotonin / dopamine antagonist
  • the blonanserin contained in the pressure-sensitive adhesive layer may be a free form or a pharmaceutically acceptable salt, and is not particularly limited.
  • the pharmaceutically acceptable salt is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a pharmaceutically acceptable acid addition salt, and even an inorganic salt is organic. It may be salt.
  • the pharmaceutically acceptable salt may be used alone or in combination of two or more. Further, the free form and the salt may be mixed and used.
  • the inorganic salt is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include hydrochloride, hydrobromide, nitrate, sulfate and phosphate.
  • examples of the organic acid salt include formate, acetate, trifluoroacetate, propionate, lactate, tartrate, oxalate, fumarate, maleate, citrate, malonate, and methanesulfone. Examples include acid salts. From the viewpoint of availability, a free form or hydrochloride is preferable, and from the viewpoint of skin permeability, it is more preferable to use a free form.
  • the content of bronanserin or a salt thereof in the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the intended purpose.
  • the lower limit is preferably 0.5% by mass or more, more preferably 0.75% by mass or more, and 1% by mass. % Or more is more preferable, 1.5% by mass or more is particularly preferable, and the upper limit value is preferably 30% by mass or less, more preferably 25% by mass or less, further preferably 20% by mass or less, and particularly preferably 15% by mass or more. ..
  • thermoplastic elastomer is an elastomer that softens when heat is applied and exhibits fluidity, and returns to a rubber-like elastic body when cooled.
  • the thermoplastic elastomer is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include various thermoplastic elastomers such as urethane-based, acrylic-based, styrene-based and olefin-based.
  • a styrene-based thermoplastic elastomer, particularly a styrene-based block copolymer is preferable from the viewpoint of achieving both sufficient skin adhesiveness and low skin irritation.
  • the styrene-based block copolymer is not particularly limited and may be appropriately selected depending on the intended purpose.
  • a styrene / butadiene block copolymer a styrene / butadiene / styrene block copolymer, or a styrene / isoprene block.
  • ethylene / butylene indicates a copolymer block of ethylene and butylene
  • ethylene / propylene indicates a copolymer block of ethylene and propylene
  • styrene-based block copolymers styrene / isoprene / styrene block copolymers from the viewpoints of both sufficient skin adhesion of the pressure-sensitive adhesive layer and suppression of adhesive residue by improving cohesiveness, as well as availability and handleability.
  • styrene / isoprene block copolymers and particularly preferably a mixture of styrene / isoprene block copolymers and styrene / isoprene / styrene block copolymers.
  • the lower limit of the proportion of the styrene / isoprene block copolymer in the mixture is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 10% by mass or more, more preferably 15% by mass or more. 20% by mass or more is more preferable, 40% by mass or more is particularly preferable, and 50% by mass or more is most preferable.
  • the upper limit of the proportion of the styrene / isoprene block copolymer in the mixture is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 95% by mass or less, more preferably 90% by mass or less. It is more preferably 85% by mass or less, and particularly preferably 80% by mass or less.
  • the styrene content in the styrene / isoprene / styrene block copolymer is not particularly limited and may be appropriately selected depending on the intended purpose, but the styrene content in the copolymer is 5% by mass or more and 60% by mass or less. Is preferable, and more preferably 10% by mass or more and 50% by mass or less.
  • the molecular weight of the styrene / isoprene / styrene block copolymer is not particularly limited and may be appropriately selected depending on the intended purpose, but the weight average molecular weight measured by gel permeation chromatography (GPC) is 20,000 or more. It is preferably 500,000 or less, and more preferably 30,000 or more and 300,000 or less.
  • GPC gel permeation chromatography
  • the styrene content in the styrene / isoprene block copolymer is not particularly limited and may be appropriately selected depending on the intended purpose, but the styrene content in the copolymer is 5% by mass or more and 50% by mass or less. It is preferably 10% by mass or more and 40% by mass or less.
  • the molecular weight of the styrene / isoprene block copolymer is not particularly limited and may be appropriately selected depending on the intended purpose, but the weight average molecular weight measured by GPC is preferably 10,000 or more and 500,000 or less. More preferably, it is 20,000 or more and 300,000 or less.
  • the viscosity of the styrene-based block copolymer is not particularly limited and may be appropriately selected depending on the intended purpose. However, from the viewpoint of improving the balance of adhesive properties, a 25 mass% toluene solution at 25 ° C.
  • the lower limit of the viscosity is preferably 500 mPa ⁇ s or more, more preferably 900 mPa ⁇ s or more, and the upper limit value is preferably 2000 mPa ⁇ s or less, more preferably 1800 mPa ⁇ s or less.
  • the “solution viscosity of a 25 mass% toluene solution at 25 ° C.” is the method for measuring the viscosity of a styrene / isoprene / styrene block copolymer described on page 395 of "Pharmaceutical Additives Standard 2013" (published by Pharmaceutical Affairs Daily). It is a value measured based on.
  • styrene / isoprene / styrene block copolymer and the styrene / isoprene block copolymer respectively, a copolymer produced by a known method can be used. Further, as the styrene / isoprene / styrene block copolymer and the styrene / isoprene block copolymer, commercially available products satisfying the above characteristics can be used.
  • a mixture of the styrene / isoprene / styrene block copolymer and the styrene / isoprene block copolymer is also commercially available, and the styrene / isoprene / styrene block copolymer and the styrene / isoprene block satisfying the above characteristics are also commercially available.
  • a commercially available product of a mixture in which the copolymer and the copolymer are mixed at the above mixing ratio can be preferably used.
  • Examples of commercially available products of the styrene-based block copolymer include "KRATON (registered trademark) D1111”, “KRATON (registered trademark) D1163”, “KRATON (registered trademark) D1113”, and “KRATON (registered trademark)” manufactured by KRATON POLYMERS.
  • the content of the thermoplastic elastomer in the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the intended purpose.
  • the lower limit value is preferably 10% by mass or more, more preferably 15% by mass or more, further preferably 20% by mass or more
  • the upper limit value is preferably 70% by mass or less, more preferably 65% by mass or less, and 60% by mass. More preferably, it is by mass or less.
  • the ratio is 10% by mass or more, the shape of the pressure-sensitive adhesive layer can be maintained more reliably, and when the ratio is 70% by mass or less, the adhesiveness of the pressure-sensitive adhesive layer to the skin is more reliably exhibited.
  • Non-volatile hydrocarbon oil is not particularly limited and may be appropriately selected depending on the intended purpose, but is a saturated hydrocarbon having about 10 to 200 carbon atoms or having 10 to 10 carbon atoms.
  • a substance that is liquid at room temperature and is composed of about 200 unsaturated hydrocarbons is preferable, and examples thereof include liquid paraffin, squalene, squalene, and pristan. Among these, liquid paraffin is more preferable from the viewpoint of availability.
  • the normal temperature is in the range of 15 ° C. to 25 ° C. according to the general rules of the Japanese Pharmacopoeia. The same applies to the following description.
  • the liquid paraffin is a mixture of colorless, odorless and liquid saturated hydrocarbons, but in the present invention, those conforming to the standards specified in the Japanese Pharmacopoeia, the United States Pharmacopeia, etc. can be preferably used.
  • the non-volatile hydrocarbon oil preferably has a high viscosity, and it is particularly preferable to use liquid paraffin having a high viscosity from the viewpoint of adhesiveness.
  • the non-volatile hydrocarbon oil preferably has a kinematic viscosity at 40 ° C. of 60 mm 2 / s or more, more preferably 70 mm 2 / s or more, and further preferably 80 mm 2 / s or more.
  • the upper limit of the kinematic viscosity is not particularly limited, but for example, from the viewpoint of ease of handling, availability, and the like, 500 mm 2 / s or less is preferable, and 250 mm 2 / s or less is more preferable.
  • kinematic viscosity means the “second method rotational viscometer method (2.12 single cylindrical rotation)" in the “2.53 viscosity measurement method” of the general test method of the "17th revised Japanese Pharmacy”. It is a value obtained by converting the viscosity (mPa ⁇ s) measured according to the “viscosity meter (Brookfield type viscometer)” into kinematic viscosity.
  • the content of the non-volatile hydrocarbon oil in the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the intended purpose, but exceeds 50 parts by weight with respect to 100 parts by weight of the thermoplastic elastomer. It is preferably contained in an amount of 800 parts by weight or less. If the content of the non-volatile hydrocarbon oil with respect to 100 parts by weight of the thermoplastic elastomer is more than 800 parts by weight, it becomes difficult to maintain the shape of the pressure-sensitive adhesive layer. On the other hand, if the content of the non-volatile hydrocarbon oil is less than 50 parts by weight, the adhesive tends to be too hard to obtain sufficient skin adhesiveness, and in particular, the ability to follow the movement of the skin during application.
  • the lower limit of the content of the non-volatile hydrocarbon oil in the pressure-sensitive adhesive layer is preferably 50 parts by weight or more, more preferably 60 parts by weight or more, and 70 parts by weight, based on 100 parts by weight of the thermoplastic elastomer. More than parts are particularly preferable, and the upper limit value is preferably 800 parts by weight or less, more preferably 600 parts by weight or less, and particularly preferably 500 parts by weight or less. Further, even within this range, if the content of the non-volatile hydrocarbon oil is high, the peeling stress tends to be low in the adhesive performance, and the adhesive squeezes out during storage or application. There is a tendency for defects to adhere to materials and clothing.
  • the content of the non-volatile hydrocarbon oil in the pressure-sensitive adhesive layer is preferably 80 parts by weight or more and 400 parts by weight or less, and more preferably 90 parts by weight or more and 350 parts by weight with respect to 100 parts by weight of the thermoplastic elastomer. Parts or less, particularly preferably 100 parts by weight or more and 300 parts by weight or less.
  • the amount of lactic acid in the pressure-sensitive adhesive layer is not particularly limited as long as it does not reduce the skin permeability of the drug, and is intended as long as it is 1.5 molar equivalents or less with respect to bronanceline contained in the pressure-sensitive adhesive layer. It can be appropriately selected depending on the situation, but is preferably 1.4 molar equivalents or less, more preferably 1.25 molar equivalents or less, still more preferably 1 molar equivalent or less, still more preferably 0.75 molar equivalents or less, and 0. 5 molar equivalents or less are particularly preferred, and 0 molar equivalents are most preferred.
  • the amount of lactic acid in the pressure-sensitive adhesive layer is measured according to the method described in JIS K 8726: 2014.
  • the pressure-sensitive adhesive layer contains (d) polyisobutylene, (e) aliphatic dicarboxylic acid ester, (f) glycerin monoether, and (g) a liquid organic acid excluding lactic acid, as other components.
  • (H1) Polyhydric alcohol fatty acid monoester, (h2) higher alcohol, (h3) alcohol solvent, (h4) amide solvent, (h5) ester solvent, (h6) carboxylate, (h7) lactone, (H8) solvent, (h9) filler, (h10) crystal precipitation inhibitor, (i) tackifier and the like can be blended.
  • Polyisobutylene can be added to adjust the adhesive properties.
  • the "polyisobutylene" used in the pressure-sensitive adhesive layer of the present invention is a polymer of isobutylene, which is an elastic rubbery semi-solid or a viscous substance, and in the present invention, imparts sufficient skin adhesiveness. Add to.
  • the polyisobutylene is a low molecular weight polyisobutylene having a viscosity average molecular weight of 30,000 to 100,000, a medium molecular weight polyisobutylene having a viscosity average molecular weight of 100,000 to 500,000, and a viscosity average molecular weight of 500,000 to 5,000,000.
  • High molecular weight polyisobutylene can be used alone or in combination. In particular, it is preferable to use a mixture of the low molecular weight polyisobutylene and the high molecular weight polyisobutylene, or the medium molecular weight polyisobutylene alone in order to balance low skin irritation and high skin adhesiveness.
  • polystyrene resin a polymer of isobutylene produced by a method known per se can be used.
  • the adhesive layer of the present invention for skin application those conforming to the standards for pharmaceutical additives and the standards specified in the United States Pharmacopeia and the like can be preferably used.
  • polyisobutylene commercially available products satisfying the above-mentioned viscosity average molecular weight can be used.
  • Examples of the commercially available low molecular weight polyisobutylene include “Oppanol (registered trademark) B10SFN", “Oppanol (registered trademark) B10N", “Oppanol (registered trademark) B12SFN", and “Oppanol (registered trademark)” manufactured by BASF.
  • Examples of the high-molecular-weight polyisobutylene include "Oppanol (registered trademark) N80", “Oppanol (registered trademark) N100", and “Oppanol (registered trademark) N150” manufactured by BASF.
  • the low molecular weight polyisobutylene has a viscosity average molecular weight of 50,000 to 100,000 "Oppanol (registered).
  • (Registered trademark) N80 ” is particularly preferable.
  • the content of polyisobutylene in the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the intended purpose. However, if the content of polyisobutylene in the pressure-sensitive adhesive layer is too small, the skin adhesiveness is enhanced. If the amount is too large, there may be problems such as deterioration of skin irritation due to excessive strengthening of skin adhesiveness, adhesive residue at the time of peeling, and poor drug solubility. Therefore, the lower limit of the content of polyisobutylene in the pressure-sensitive adhesive layer is 0.1 part by weight or more, preferably 0.3 part by weight or more, and more preferably 0 part by weight with respect to 100 parts by weight of the thermoplastic elastomer.
  • the upper limit of the content of polyisobutylene in the pressure-sensitive adhesive layer is 300 parts by weight or less with respect to 100 parts by weight of the thermoplastic elastomer, and 200 parts by weight.
  • the following is preferable, more preferably 150 parts by weight or less, still more preferably 100 parts by weight or less.
  • the polyisobutylene content in the pressure-sensitive adhesive layer can be 0.1% by mass to 50% by mass, more preferably 0.2% by mass to 40% by mass, and further. It is preferably 0.3% by mass to 30% by mass, and particularly preferably 0.5% by mass to 25% by mass.
  • (E) Aliup dicarboxylic acid ester The aliphatic dicarboxylic acid ester is not particularly limited and may be appropriately selected depending on the intended purpose. For example, diethyl adipic acid, diisopropyl adipate, diisobutyl adipate and the like at room temperature. Dicarboxylic acids with 2 to 12 carbon atoms and monovalents with 1 to 20 carbon atoms, such as liquid sebacic acid diesters such as liquid adipic acid diester, diethyl sebacate, diisopropyl sebacate, and dioctyldodecyl sebacate, which are liquid at room temperature.
  • Examples thereof include a diester which is liquid at room temperature with an aliphatic alcohol.
  • diisopropyl adipate and diisobutyl adipate are preferable from the viewpoint of enhancing the solubility and absorption promoting effect of the drug.
  • the lower limit of the content of the aliphatic dicarboxylic acid ester in the total 100% by mass of the constituent components of the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the intended purpose, but is 0.2% by mass. % Or more is preferable, 0.5% by mass or more is more preferable, 0.7% by mass or more is further preferable, and 1% by mass or more is particularly preferable.
  • the upper limit of the content of the aliphatic dicarboxylic acid ester in the total 100% by mass of the constituent components of the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the intended purpose, but is 20% by mass or less. Is preferable, 10% by mass or less is more preferable, 5% by mass or less is further preferable, and 3% by mass or less is particularly preferable.
  • the glycerin monoether is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include ⁇ -monoisostearyl glyceryl ether.
  • the lower limit of the content of the glycerin monoether in the total 100% by mass of the constituent components of the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the intended purpose, but is 0.01% by mass or more. Is more preferable, 0.03% by mass or more is more preferable, 0.05% by mass or more is further preferable, and 0.07% by mass or more is particularly preferable.
  • the upper limit of the content of the glycerin monoether in the total 100% by mass of the constituent components of the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 10% by mass or less. 5, 5% by mass or less is more preferable, 1.5% by mass or less is further preferable, and 1.0% by mass or less is particularly preferable.
  • the liquid organic acid excluding lactic acid is not particularly limited as long as it is an organic acid liquid at room temperature, and can be appropriately selected depending on the intended purpose.
  • acetic acid. Propionic acid, butyric acid, valeric acid, isovaleric acid, caproic acid, isostearic acid, enanthic acid (heptanic acid), capric acid, pelargonic acid (nonanoic acid) and other aliphatic monocarboxylic acids; oleic acid, linoleic acid, arachidone Alibo unsaturated monocarboxylic acids such as acids and docosahexaenoic acid; liquid carboxylic acids substituted with alkoxy groups such as methoxyacetic acid; carboxylic acids having carbonyl groups such as leveric acid; sulfonic acids such as methanesulfonic acid, etc.
  • liquid organic acids have a function of assisting the dissolution of the basic drug, can contain the basic drug in a high concentration in the pressure-sensitive adhesive layer, can improve the dispersibility, and further. It has the effect of improving transdermal absorbability. From this point of view, among these liquid organic acids, oleic acid, isostearic acid, and levulinic acid are preferable.
  • one or more of the liquid organic acids excluding lactic acid can be selected and contained, if necessary.
  • Preferred combinations of the organic acids include levulinic acid and isostearic acid, levulinic acid and oleic acid, and isostearic acid and oleic acid.
  • the content of the liquid organic acid excluding lactic acid is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 0.1% by mass or more and 20% by weight with respect to the total amount of the pressure-sensitive adhesive layer. It is more preferably 0.3% by mass or more, 15% by weight or less, further preferably 0.5% by mass or more and 10% by weight or less, and particularly preferably 1% by mass or more and 5% by weight or less.
  • bronanceline contained in the pressure-sensitive adhesive layer it is preferably more than 0 molar equivalents and 10 molar equivalents or less, more preferably 0.3 molar equivalents or more and 5 molar equivalents or less, still more preferably 0.5 molar equivalents or more. It is 3 molar equivalents or less.
  • the "fatty acid monoester of polyhydric alcohol” is an ester bond between one hydroxyl group of a polyhydric alcohol such as ethylene glycol, propylene glycol and glycerin and a fatty acid. It is a compound.
  • the fatty acid monoester of a polyhydric alcohol contributes to the improvement of drug solubility and has an absorption promoting effect without extremely reducing the cohesive force of the pressure-sensitive adhesive base.
  • the polyhydric alcohol constituting the fatty acid monoester of the polyhydric alcohol is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include ethylene glycol, propylene glycol, butylene glycol and glycerin.
  • the fatty acid constituting the fatty acid monoester of the polyhydric alcohol is not particularly limited and may be appropriately selected depending on the intended purpose. However, fatty acids having 8 to 18 carbon atoms are preferable, and capric acid, caprylic acid and myristine are preferable. Acids, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid and the like can be mentioned.
  • the polyhydric alcohol fatty acid monoester are propylene glycol monocaprilate and propylene glycol monolaurate.
  • the fatty acid monoester content of the polyhydric alcohol is preferably 1% by mass or more, more preferably 2% by mass or more, particularly based on the total amount of the pressure-sensitive adhesive component. It is preferably 5% by weight or more.
  • the content of the fatty acid monoester of the polyhydric alcohol is 30% by mass or less based on the total amount of the pressure-sensitive adhesive component. It is preferably 20% by weight or less, and particularly preferably 10% by weight or less.
  • the higher alcohol is not particularly limited and may be appropriately selected depending on the intended purpose.
  • lauryl alcohol, isostearyl alcohol, etc. which have 12 to 20 carbon atoms and are liquid at room temperature, are higher grade.
  • Saturated fatty alcohols Higher unsaturated aliphatic alcohols such as oleyl alcohol, which have 12 or more and 20 or less carbon atoms and are liquid at room temperature, can be mentioned.
  • lauryl alcohol and oleyl alcohol are preferable from the viewpoint of enhancing the solubility and absorption promoting effect of the drug.
  • the alcohol-based solvent is not particularly limited and may be appropriately selected depending on the intended purpose.
  • examples include the following polyhydric alcohols that are liquid at room temperature such as polyethylene glycol, monoalkyl ethers of polyhydric alcohols such as diethylene glycol monoethyl ether, monofatty acid esters of polyhydric alcohols such as glycerol monolinolete and glycerol monooleate. Be done.
  • ethylene glycol, propylene glycol, glycerin, 1,3-butanediol, and diethylene glycol monoethyl ether are preferable from the viewpoint of improving the solubility of the drug.
  • the amide-based solvent is not particularly limited and may be appropriately selected depending on the intended purpose.
  • pyrrolidone such as N-methyl-2-pyrrolidone and 2-pyrrolidone
  • 1,3- Imidazolidinone such as dimethyl-2-imidazolidinone
  • N-substituted toluidine such as crotamitone
  • formamide N-methylformamide, N, N-dimethylformamide, N-methylacetamide, N, N-dimethylacetamide, N-methyl
  • alkaneamide such as propaneamide.
  • N-methyl-2-pyrrolidone, crotamiton, N, N-dimethylformamide, and N, N-dimethylacetamide are preferable from the viewpoint of improving the solubility, dispersibility, and transdermal absorbability of the drug.
  • N-Methyl-2-pyrrolidone, crotamiton are more preferred.
  • ester-based solvent is not particularly limited and may be appropriately selected depending on the intended purpose.
  • a diester of a dihydric alcohol and a carboxylic acid a medium chain fatty acid triglyceride, and a polyvalent carboxylic acid.
  • examples include esters with monovalent aliphatic alcohols and carbonate esters.
  • the diester of the dihydric alcohol and the carboxylic acid is not particularly limited and may be appropriately selected depending on the intended purpose.
  • it is composed of propylene glycol, caprylic acid, capric acid, lauric acid, oleic acid and the like. Diester and the like.
  • the medium-chain fatty acid triglyceride is a triglyceride composed of glycerin and fatty acids having 6 to 12 carbon atoms such as caproic acid, caprylic acid, caprylic acid, and lauric acid.
  • the caprylic acid triglyceride is liquid at room temperature.
  • a triglyceride mixture of caprylic acid and capric acid, a triglyceride mixture of caprylic acid, caproic acid and lauric acid, and the like can be used. It is also possible to use oils and fats that are liquid at room temperature and contain a large amount of these.
  • oils and fats include olive oil (olib oil), almond oil, saflower oil, soybean oil, corn oil, sesame oil, palm oil, orange oil, ginger oil, peppermint oil, rapeseed oil, sunflower oil, sunflower oil, cotton seed oil, etc.
  • oils and fats include olive oil (olib oil), almond oil, saflower oil, soybean oil, corn oil, sesame oil, palm oil, orange oil, ginger oil, peppermint oil, rapeseed oil, sunflower oil, sunflower oil, cotton seed oil, etc.
  • peanut oil examples include peanut oil.
  • a product commercially available for pharmaceutical use can also be used as a medium-chain fatty acid triglyceride that is liquid at room temperature or a medium-chain fatty acid triglyceride-containing fat or oil that is liquid at room temperature.
  • the carbonic acid ester is not particularly limited and may be appropriately selected depending on the intended purpose. Cyclic carbonic acid ester of carbonic acid and a diol having 2 or more and 10 or less carbon atoms, for example, ethylene carbonate, propylene carbonate, vinylene carbonate and the like can be used. As mentioned above, propylene carbonate is preferable.
  • ester-based solvents a medium-chain fatty acid triglyceride mixture and a carbonic acid ester are preferable, and a triglyceride mixture of caprylic acid and capric acid and propylene carbonate are more preferable.
  • the alcohol-based solvent, the amide-based solvent, and the ester-based solvent can be used by selecting one or more of them, if necessary.
  • the content of these solvents is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 0.1% by mass or more and 20% by mass or less, more preferably 0, based on the total amount of the pressure-sensitive adhesive layer. It is 5.5% by mass or more and 15% by mass or less.
  • the carboxylic acid salt is not particularly limited and may be appropriately selected depending on the intended purpose.
  • an aliphatic monocarboxylic acid, an alicyclic monocarboxylic acid, an aliphatic dicarboxylic acid and the like can be selected.
  • Examples include salt.
  • the aliphatic monocarboxylic acid is not particularly limited and may be appropriately selected depending on the intended purpose. For example, short-chain fatty acids having 2 or more and 7 or less carbon atoms such as acetic acid, butyric acid and hexanoic acid, octanoic acid, etc.
  • Medium-chain fatty acids with 8 to 11 carbon atoms such as decanoic acid, long-chain fatty acids with 12 or more carbon atoms such as lauric acid, myristic acid, stearic acid, isostearic acid, and oleic acid, glycolic acid, lactic acid, 3-hydroxybutyric acid, Examples thereof include hydroxymonocarboxylic acids such as mandelic acid, monocarboxylic acids substituted with alkoxy groups such as methoxyacetic acid, and ketomonocarboxylic acids such as levulinic acid.
  • the alicyclic monocarboxylic acid is not particularly limited and may be appropriately selected depending on the intended purpose.
  • Examples thereof include an alicyclic monocarboxylic acid having 6 or more and 8 or less carbon atoms such as cyclohexanecarboxylic acid. Be done.
  • the aliphatic dicarboxylic acid is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include sebacic acid, adipic acid, malic acid, maleic acid and fumaric acid.
  • Preferred carboxylic acids include long-chain fatty acids having 12 or more carbon atoms and hydroxymonocarboxylic acids, and examples thereof include myristic acid, stearic acid, isostearic acid, lauric acid, and oleic acid. More preferably, it is lauric acid or oleic acid.
  • the salt of the carboxylic acid is not particularly limited and may be appropriately selected depending on the intended purpose. For example, an alkali metal salt such as a sodium salt or a potassium salt, an alkaline earth metal salt such as a calcium salt, or an amine salt. However, a sodium salt is preferable from the viewpoint of easy availability and an effect of improving transdermal absorbability.
  • the lactone is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include 5-membered ring lactones such as ascorbic acid and isoascorbic acid.
  • the carboxylate or lactone is preferably sodium oleate, sodium lactate, ascorbic acid, or isoascorbic acid in consideration of the effect of improving the stability of the drug or the effect of improving transdermal absorbability. ..
  • the content in the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably selected with respect to 1 mol of the drug. It is 0.1 mol or more and 5 mol or less, more preferably 0.2 mol or more and 3 mol or less.
  • the amount added to 1 mol of the drug is less than 0.1 mol, a sufficient effect of improving transdermal absorbability may not be obtained, and when the amount added to 1 mol of the drug is more than 5 mol, the adhesive property The physical characteristics of the drug may deteriorate.
  • the surfactant is not particularly limited and may be appropriately selected depending on the intended purpose.
  • a polyoxyethylene fatty acid ester such as polyoxyethylene monolaurate, or a polyoxyethylene sorbit tetra.
  • Polyoxyethylene sorbitan fatty acid ester such as oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan monopalmitate, sorbitan monolaurate, sorbitan mono Sorbitane fatty acid esters such as oleate, sorbitan sesquioleate, sorbitan trioleate, glycerin monooleate, polyoxyethylene castor oil derivatives, glycerin fatty acid esters such as polyoxyethylene hydrogenated castor oil, polyoxyethylene lauryl ether, polyoxyethylene Polyoxyethylene higher aliphatic alcohol ethers such as oleyl ether, polyoxyethylene
  • Nonionic surfactants such as polyoxyethylene polyoxypropylene copolymers such as L-31 and Pluronic® L-44, and anionic surfactants such as sodium alkyl sulfates such as sodium lauryl sulfate.
  • Agents cationic surfactants such as alkyltrimethylammonium salt and alkyldimethylammonium salt, amphoteric surfactants such as alkyldimethylamine oxide and alkylcarboxybetaine, etc., and one or more selected from these. Can be used.
  • nonionic surfactants that are liquid at room temperature are preferable, and polyoxyethylene higher aliphatic alcohol ethers and sorbitan fatty acid esters that are liquid at room temperature are more preferable, and poly Oxyethylene lauryl ether and sorbitan monolaurate are particularly preferred.
  • the content in the pressure-sensitive adhesive layer when the surfactant is contained is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 0.01% by mass or more. It is 10% by mass or less, more preferably 0.1% by mass or more and 5% by mass or less.
  • (H9) Filler A filler can be contained to control the flexibility of the pressure-sensitive adhesive layer.
  • the filler is not particularly limited and may be appropriately selected depending on the intended purpose.
  • silicon compounds such as silicic acid anhydride, light silicic acid anhydride and hydrous silicic acid, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose and hydroxy
  • examples thereof include cellulose derivatives such as propylmethyl cellulose, water-soluble polymers such as polyvinyl alcohol, dry aluminum hydroxide gel, aluminum compounds such as hydrous aluminum silicate, kaolin and titanium oxide.
  • the filler may be used alone or in combination of two or more.
  • the content of the filler is not particularly limited and can be appropriately selected depending on the intended purpose, and can be contained within a range in which high skin permeability and sufficient cohesive force and adhesive force can be maintained as a patch. .. Above all, it is preferably 10% by mass or less, more preferably 5% by mass or less, and most preferably 2% by mass or less with respect to the total amount of the pressure-sensitive adhesive component.
  • the crystal precipitation inhibitor is not particularly limited and may be appropriately selected depending on the intended purpose.
  • the crystal precipitation inhibitor may be used alone or in combination of two or more.
  • the content of the crystal precipitation suppression is not particularly limited and can be appropriately selected depending on the purpose, and can be contained as a patch within a range in which the adhesive strength is maintained. Above all, it is preferably 0.01% by mass or more and 10% by mass or less, and more preferably 0.1% by mass or more and 5% by mass or less with respect to the total amount of the pressure-sensitive adhesive component.
  • the patch may contain a tackifier from the viewpoint of enhancing the adhesive strength of the pressure-sensitive adhesive layer.
  • the "tackiness-imparting agent" is a tackifier that is generally used in the field of patches, and is not particularly limited and may be appropriately selected depending on the intended purpose.
  • a rosin-based resin or a polyterpene examples thereof include based resins, kumaron-inden resins, petroleum resins, terpene resins, terpene-phenol resins, and alicyclic saturated hydrocarbon resins.
  • the tackifier may be added in order to achieve the adhesive strength required to obtain a sufficient medicinal effect, but if a large amount of the tackifier is added, the release property of the drug is lowered or the skin is irritating. Since it increases, the content of the tackifier is preferably 50% by mass or less, more preferably 30% by mass or less, still more preferably 20% by mass or less, still more preferably 10% by mass, based on the total amount of the pressure-sensitive adhesive component. % Or less, particularly preferably 5% by mass or less, and most preferably no tackifier.
  • the patch may also include a release liner that is common in the art. That is, the patch of the present invention may be one in which a support, an adhesive layer, and a release liner are laminated in this order.
  • the release liner is not particularly limited and may be appropriately selected depending on the intended purpose. For example, glassin paper, polyolefin such as polyethylene and polypropylene, polyester such as polyethylene terephthalate, resin film such as polystyrene; aluminum film; foaming. Polystyrene film or expanded polypropylene film; two or more kinds of laminates among the above can be used.
  • the release liner one that has been subjected to silicone processing, fluororesin processing, embossing processing, hydrophilic processing, hydrophobic processing, or the like can also be used.
  • the thickness of the release liner is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 10 ⁇ m or more and 200 ⁇ m or less, and more preferably 15 ⁇ m or more and 150 ⁇ m or less.
  • the method for producing the patch is a method for producing the patch, which may include a step of laminating the support and the pressure-sensitive adhesive layer, and may further include other steps.
  • the pressure-sensitive adhesive layer and the support are as described above.
  • the step of laminating the support and the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the intended purpose. For example, a method of crimping the support to the pressure-sensitive adhesive layer and laminating the support can be mentioned. Be done.
  • the other steps are not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a step of laminating a release liner.
  • the release liner is as described above.
  • the laminating step of the release liner is not particularly limited and may be appropriately selected depending on the intended purpose.
  • the coating for forming the pressure-sensitive adhesive layer is performed before the laminating step of the support and the pressure-sensitive adhesive layer.
  • a step of crimping the release liner to the pressure-sensitive adhesive layer and laminating can be mentioned.
  • the spreading / drying step is not particularly limited and may be appropriately selected depending on the intended purpose.
  • bronanceline or a salt thereof (b) a thermoplastic elastomer, and (c) a non-volatile hydrocarbon oil.
  • a solvent such as toluene
  • the coating is not particularly limited and may be appropriately selected depending on the intended purpose.
  • roll coater die coater, gravure roll coater, reverse roll coater, kiss roll coater, dip roll coater, bar coater, knife coater.
  • a conventional coater such as a spray coater can be used.
  • the solvent used in the coating liquid is not particularly limited and may be appropriately selected depending on the intended purpose.
  • the components (a), (b) and (c) may be uniformly dissolved or dissolved.
  • Those that can be dispersed are preferable, for example, aromatic hydrocarbons such as toluene, alicyclic hydrocarbons such as cyclohexane and methylcyclohexane, aliphatic hydrocarbons such as hexane and heptane, tetrahydrofuran, diethyl ether and t-butyl methyl.
  • Examples include ethers such as ethers, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, alcohols such as ethanol, propanol and butanol, and acetate esters such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate. Be done. These solvents can be used alone or in combination of two or more.
  • aromatic hydrocarbons such as toluene, alicyclic hydrocarbons such as cyclohexane and methylcyclohexane, and aliphatic hydrocarbons such as hexane and heptane can be used. It can be used alone or in combination, or it can be used alone or in combination with aromatic hydrocarbons such as toluene, aliphatic hydrocarbons such as hexane and heptane, and acetates such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate. It is preferable to use them in combination.
  • the drying is not particularly limited and may be appropriately selected depending on the intended purpose, but it is preferably carried out under heating, for example, at a temperature of about 40 ° C. or higher and 150 ° C. or lower, depending on the solvent used and the amount used.
  • the drying temperature, drying time, and drying method may be adjusted.
  • the weight per unit area of the adhesive layer after drying may be adjusted according to the required skin adhesiveness and transdermal absorption performance.
  • the range that can be produced while obtaining skin adhesiveness is not particularly limited and may be appropriately selected depending on the intended purpose, but the pressure-sensitive adhesive layer after drying is preferably 10 g / m 2 or more and 1,000 g / g. It is m 2 or less, more preferably 20 g / m 2 or more and 800 g / m 2 or less, and further preferably 30 g / m 2 or more and 600 g / m 2 or less.
  • Example 1 Production of patch> Each component constituting the pressure-sensitive adhesive layer was weighed according to the formulation shown in Table 1. The numerical value of each component in Table 1 is mass%. First, a styrene-based block copolymer was dissolved in toluene, bronancerin and liquid paraffin were added, and the mixture was mixed and stirred to prepare a coating liquid for forming an adhesive layer. The above coating liquid was applied to a silicone-treated polyethylene terephthalate (PET) film which is a release liner. After drying in an oven at 50 ° C. for 60 minutes, a PET film (support) was laminated on the surface of the pressure-sensitive adhesive layer and cut into a size of 15 cm ⁇ 30 cm to obtain a patch.
  • PET polyethylene terephthalate
  • ⁇ Test Example 1 Evaluation of skin permeability> The abdominal excised skin of a depilated male hairless rat (HWY / Slc, SPF, 5 weeks old) was punched into a circle with a diameter of 2.5 cm. The patch prepared in the example was punched into a circle with a diameter of 1.3 cm, attached onto rat skin, set in a vertical diffusion cell, and tested with a percutaneous absorption test automatic sampling device (manufactured by Cosmedy). It started. A buffer solution was used as the receptor solution, and the test was conducted at a solution temperature of 32 ° C.
  • Example 2 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 1. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.
  • Example 3 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 1. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.
  • Example 4 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 1. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.
  • Example 5 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 1. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.
  • Example 6 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 1. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.
  • Example 7 Production of patch> A patch was produced in the same manner as in Comparative Example 2 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 1. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.
  • Example 8 Production of patch> Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 1, a styrene-based block copolymer and polyisobutylene were dissolved in toluene, and then bronanceline, liquid paraffin and each additive were added.
  • the patch was manufactured in the same manner as in the above. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.
  • Example 1 Manufacture of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 1, an acrylic pressure-sensitive adhesive and ethyl acetate were mixed, and then blonanserin was added. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.
  • Example 1 using the styrene / isoprene / styrene block copolymer as the pressure-sensitive adhesive base polymer is based on Comparative Example 1 of an acrylic pressure-sensitive adhesive base using the formulation technology of Patent Document 1.
  • Example 7 excluding lactic acid showed high permeability, and the addition of a large amount of lactic acid tended to reduce the skin permeability.
  • the patches of Examples 2 and 8 to which the additive was added to Example 1 showed skin permeability that was more than 3 times higher than that of the existing preparation.
  • Example 9 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 2. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.
  • Example 10 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 2. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.
  • Example 11 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 2. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.
  • Example 12 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 2. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.
  • Example 13 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 2. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.
  • Example 14 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 2. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.
  • Example 15 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 2. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.
  • Example 16 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 2. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.
  • Example 17 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 3. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 3.
  • Example 18 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 3. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 3.
  • Example 19 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 3. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 3.
  • Example 20 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 4. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 4.
  • Example 21 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 4. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 4.
  • Example 22 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 4. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 4.
  • Examples 20 to 22 to which a liquid organic acid excluding lactic acid was added showed the same permeability as Example 5 to which lactic acid was added, and a phenomenon of suppressing crystal precipitation of blonanserin. It was observed.
  • Example 23 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 5. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.
  • Example 24 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 5. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.
  • Example 25 Production of patch> A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 5. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.
  • Example 26 Production of patch> A patch was produced in the same manner as in Example 8 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 5. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.
  • Example 27 Production of patch> A patch was produced in the same manner as in Example 8 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 5. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.
  • Example 28 Production of patch> A patch was produced in the same manner as in Example 8 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 5. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.
  • Example 29 Production of patch> A patch was produced in the same manner as in Example 8 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 5. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.
  • Example 30 Production of patch> A patch was produced in the same manner as in Example 8 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 5. Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.
  • the pressure-sensitive adhesive comprises a support and a pressure-sensitive adhesive layer on the support, wherein the pressure-sensitive adhesive layer contains bronanceline or a salt thereof, a thermoplastic elastomer, lactic acid, and a non-volatile hydrocarbon oil.
  • the patch is characterized in that the amount of lactic acid in the layer is more than 0 molar equivalent and 1.5 molar equivalent or less with respect to the bronanceline contained in the pressure-sensitive adhesive layer.
  • ⁇ 2> It has a support and a pressure-sensitive adhesive layer on the support, and the pressure-sensitive adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, and a non-volatile hydrocarbon oil, and does not contain lactic acid. It is a patch characterized by. ⁇ 3> The patch according to ⁇ 1> or ⁇ 2>, wherein the thermoplastic elastomer contains a styrene-based block copolymer.
  • ⁇ 4> The patch according to ⁇ 3>, wherein the styrene-based block copolymer is a mixture of a styrene / isoprene / styrene block copolymer and a styrene / isoprene block copolymer.
  • ⁇ 5> The patch according to any one of ⁇ 1> to ⁇ 4>, wherein the pressure-sensitive adhesive layer contains polyisobutylene.
  • ⁇ 6> The patch according to any one of ⁇ 1> to ⁇ 5>, wherein the pressure-sensitive adhesive layer contains an aliphatic dicarboxylic acid ester.
  • ⁇ 7> The patch according to any one of ⁇ 1> to ⁇ 6>, wherein the pressure-sensitive adhesive layer contains glycerin monoether.
  • ⁇ 8> The patch according to any one of ⁇ 1> to ⁇ 7> above, wherein the initial pressure-sensitive adhesive layer contains a liquid organic acid other than lactic acid.
  • ⁇ 9> The method for producing a patch according to any one of ⁇ 1> to ⁇ 8>, which comprises a step of laminating the support and the pressure-sensitive adhesive layer.

Abstract

This patch is characterized by including a support and an adhesive layer disposed on the support, and is further characterized in that the adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, lactic acid, and a nonvolatile hydrocarbon oil, and that the amount of lactic acid in the adhesive layer is more than 0 molar equivalent but not more than 1.5 molar equivalent with respect to the blonanserin contained in the adhesive layer. Alternatively, this patch is characterized by including a support and an adhesive layer disposed on the support, and is further characterized in that the adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, and a nonvolatile hydrocarbon oil, but does not contain lactic acid.

Description

ブロナンセリン含有貼付剤、及びその製造方法Blonanserin-containing patch and its manufacturing method
　本発明は、ブロナンセリンを含有する貼付剤、及びその製造方法に関する。さらに詳しくは、皮膚透過性の高いブロナンセリン含有貼付剤、及びその製造方法に関する。 The present invention relates to a patch containing blonanserin and a method for producing the same. More specifically, the present invention relates to a blonanserin-containing patch having high skin permeability and a method for producing the same.
　統合失調症治療において、統合失調症治療薬（経口製剤）の服薬アドヒアランス不良による再発、再燃が問題となっている。２０１９年９月に上市されたロナセン（登録商標）テープは、統合失調症治療薬であるブロナンセリンを有効成分とした貼付剤であり、従来の経口製剤とは異なり、投与状況を目視で確認でき、看護者や介護者が服薬を管理することも容易であることから、服薬アドヒアランスの向上が期待できる製剤である。 In the treatment of schizophrenia, recurrence and relapse due to poor adherence to schizophrenia therapeutic agents (oral preparations) have become a problem. The Lonasen® tape, which was launched in September 2019, is a patch containing blonanserin, which is a therapeutic agent for schizophrenia, as an active ingredient. Unlike conventional oral preparations, the administration status can be visually confirmed. Since it is easy for nurses and caregivers to manage medication, it is a preparation that can be expected to improve medication adherence.
　ロナセン（登録商標）テープには、特許文献１、及び２に記載の製剤技術が用いられている。特許文献１には、粘着基剤にアクリル系粘着剤を用いる貼付剤が記載されており、透過促進剤として乳酸を添加すると、ラット皮膚透過性試験において、ブロナンセリンの透過量が飛躍的に向上する技術が開示されている。
　また、特許文献２には、乳酸添加を必須とすることで、シリコーン系粘着剤、ゴム系（スチレン・イソプレン・スチレンブロック共重合体）粘着剤、アクリル系粘着剤の全ての粘着基剤において、これまでにない程高いブロナンセリンの透過量が実現できる技術が開示されている。 The formulation technology described in Patent Documents 1 and 2 is used for the Blonanserin (registered trademark) tape. Patent Document 1 describes a patch that uses an acrylic pressure-sensitive adhesive as a pressure-sensitive adhesive, and when lactic acid is added as a permeation accelerator, the permeation amount of blonanserin is dramatically improved in a rat skin permeability test. The technology is disclosed.
Further, in Patent Document 2, by requiring the addition of lactic acid, all the pressure-sensitive adhesives of silicone-based pressure-sensitive adhesives, rubber-based (styrene / isoprene / styrene block copolymer) pressure-sensitive adhesives, and acrylic-based pressure-sensitive adhesives are used. A technology that can realize an unprecedentedly high amount of styrenerin permeation is disclosed.
　しかしながら、ロナセン（登録商標）テープの薬物利用率は低く（非特許文献１）、十分量の薬物を皮膚から吸収させ、治療に必要な薬物血中濃度を得るために、製剤サイズを大きくする必要があった。ロナセン（登録商標）テープは貼付部位を毎日変更しなければならないことを考慮すると、製剤サイズが大きすぎることは患者にとって極めて不便であり、極めて使いづらい製剤であると言える。 However, the drug utilization rate of Lonasen® tape is low (Non-Patent Document 1), and it is necessary to increase the size of the preparation in order to absorb a sufficient amount of the drug through the skin and obtain the drug blood concentration required for treatment. was there. Considering that the application site of Blonanserin (registered trademark) tape must be changed every day, it can be said that an excessively large formulation size is extremely inconvenient for the patient and extremely difficult to use.
　したがって、皮膚透過性の高いブロナンセリン含有貼付剤、及びその製造方法は全く知られておらず、これらの提供が強く求められている。 Therefore, a blonanserin-containing patch having high skin permeability and a method for producing the same are not known at all, and the provision of these is strongly required.
特許第５００１２７１号公報Japanese Patent No. 5001271 特許第５８３７５１８号公報Japanese Patent No. 5837518
　本発明は、従来における前記諸問題を解決し、以下の目的を達成することを課題とする。即ち、本発明は、皮膚透過性の高いブロナンセリン含有貼付剤、及びその製造方法を提供することを目的とする。 An object of the present invention is to solve the above-mentioned problems in the past and to achieve the following objects. That is, an object of the present invention is to provide a blonanserin-containing patch having high skin permeability and a method for producing the same.
　本発明者らが、前記目的を達成すべく鋭意研究を重ねた結果、支持体と、前記支持体上の粘着剤層と、を有し、前記粘着剤層が、ブロナンセリン又はその塩、熱可塑性エラストマー、及び不揮発性炭化水素油を含み、前記粘着剤層における乳酸の量が前記粘着剤層に含まれるブロナンセリンに対し１．５モル当量以下である貼付剤により、皮膚透過性の高いブロナンセリン含有貼付剤が提供できることを知見した。 As a result of intensive research to achieve the above object, the present inventors have a support and a pressure-sensitive adhesive layer on the support, and the pressure-sensitive adhesive layer is bronanceline or a salt thereof, thermoplastic. A patch containing an elastomer and a non-volatile hydrocarbon oil, and the amount of lactic acid in the pressure-sensitive adhesive layer is 1.5 mol equivalent or less with respect to the bronanceline contained in the pressure-sensitive adhesive layer. It was found that the agent can be provided.
　本発明は、本発明者らによる前記知見に基づくものであり、前記課題を解決するための手段としては以下の通りである。即ち、
　＜１＞　支持体と、前記支持体上の粘着剤層と、を有し、前記粘着剤層が、ブロナンセリン又はその塩、熱可塑性エラストマー、乳酸、及び不揮発性炭化水素油を含み、前記粘着剤層における乳酸の量が前記粘着剤層に含まれるブロナンセリンに対し０モル当量超１．５モル当量以下であることを特徴とする、貼付剤である。
　＜２＞　支持体と、前記支持体上の粘着剤層と、を有し、前記粘着剤層が、ブロナンセリン又はその塩、熱可塑性エラストマー、及び不揮発性炭化水素油を含み、乳酸を含まないことを特徴とする、貼付剤である。
　＜３＞　前記＜１＞又は＜２＞に記載の貼付剤を製造する方法であって、前記支持体と前記粘着剤層を積層する工程を含む貼付剤の製造方法である。 The present invention is based on the above-mentioned findings by the present inventors, and the means for solving the above-mentioned problems are as follows. That is,
<1> The pressure-sensitive adhesive comprises a support and a pressure-sensitive adhesive layer on the support, wherein the pressure-sensitive adhesive layer contains bronanceline or a salt thereof, a thermoplastic elastomer, lactic acid, and a non-volatile hydrocarbon oil. The patch is characterized in that the amount of lactic acid in the layer is more than 0 molar equivalent and 1.5 molar equivalent or less with respect to the bronanceline contained in the pressure-sensitive adhesive layer.
<2> It has a support and a pressure-sensitive adhesive layer on the support, and the pressure-sensitive adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, and a non-volatile hydrocarbon oil, and does not contain lactic acid. It is a patch characterized by.
<3> The method for producing a patch according to <1> or <2>, which comprises a step of laminating the support and the pressure-sensitive adhesive layer.
　本発明によると、従来における前記諸問題を解決し、前記目的を達成することができ、皮膚透過性の高いブロナンセリン含有貼付剤、及びその製造方法を提供することができる。 According to the present invention, it is possible to solve the above-mentioned problems in the past, achieve the above-mentioned object, and provide a blonanserin-containing patch having high skin permeability and a method for producing the same.
　（貼付剤）
　前記貼付剤は、支持体と、前記支持体上の粘着剤層と、を有し、さらにその他の要素を有することができる。 (Attachment)
The patch may have a support, an adhesive layer on the support, and other elements.
　＜支持体＞
　前記支持体としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、皮膚貼付用粘着シートや経皮吸収製剤に汎用されるものなどを使用することができる。
　前記支持体の材料としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、ポリエチレンテレフタレート等のポリエステル、ポリエチレン、ポリプロピレン等のポリオレフィン、ポリウレタン、エチレン酢酸ビニル共重合体、ポリ塩化ビニルなどが挙げられる。
　前記支持体の構造としては、１層構造であってもよく、多層構造であってもよい。また、編布、織布、不織布、フィルム、発泡体、多孔質、網目構造、シート状、平板状であってもよい。 <Support>
The support is not particularly limited and may be appropriately selected depending on the intended purpose. For example, a pressure-sensitive adhesive sheet for skin application, a general-purpose support for transdermal absorption preparation, or the like can be used.
The material of the support is not particularly limited and may be appropriately selected depending on the intended purpose. For example, polyester such as polyethylene terephthalate, polyolefin such as polyethylene and polypropylene, polyurethane, ethylene vinyl acetate copolymer and polyvinyl chloride Vinyl and the like can be mentioned.
The structure of the support may be a one-layer structure or a multi-layer structure. Further, it may be a knitted fabric, a woven fabric, a non-woven fabric, a film, a foam, a porous material, a mesh structure, a sheet shape, or a flat plate shape.
　更に、支持体に静電気が蓄積することを防止するため、支持体を構成する前記織布、不織布、フィルム等に帯電防止剤を含有させてもよい。また、粘着剤層との良好な投錨性を得るため、支持体として不織布若しくは織布、又はこれらとフィルムの積層体を用いることができる。 Further, in order to prevent static electricity from accumulating on the support, the woven fabric, the non-woven fabric, the film and the like constituting the support may contain an antistatic agent. Further, in order to obtain good anchoring property with the pressure-sensitive adhesive layer, a non-woven fabric or woven fabric as a support, or a laminate of these and a film can be used.
　前記支持体の厚さとしては、特に制限はなく、目的に応じて適宜選択することができるが、フィルムについては１０μｍ以上１００μｍ以下が好ましく、１５μｍ以上５０μｍ以下がより好ましく、織布、不織布、発泡性支持体などの多孔性シートについては５０μｍ以上２，０００μｍ以下が好ましく、１００μｍ以上１，０００μｍ以下がより好ましい。 The thickness of the support is not particularly limited and may be appropriately selected depending on the intended purpose. However, the film is preferably 10 μm or more and 100 μm or less, more preferably 15 μm or more and 50 μm or less, and is woven fabric, non-woven fabric, or foam. For a porous sheet such as a sex support, 50 μm or more and 2,000 μm or less is preferable, and 100 μm or more and 1,000 μm or less is more preferable.
　＜粘着剤層＞
　前記粘着剤層は、（ａ）ブロナンセリン又はその塩、（ｂ）熱可塑性エラストマー、（ｃ）不揮発性炭化水素油、を含み、前記粘着剤層における乳酸の量が前記粘着剤層に含まれるブロナンセリンに対し１．５モル当量以下であり、さらにその他の成分を有することができる。 <Adhesive layer>
The pressure-sensitive adhesive layer contains (a) bronanserin or a salt thereof, (b) a thermoplastic elastomer, and (c) a non-volatile hydrocarbon oil, and the amount of lactic acid in the pressure-sensitive adhesive layer is contained in the pressure-sensitive adhesive layer. It is 1.5 molar equivalents or less, and can further have other components.
　（ａ）ブロナンセリン又はその塩
　前記「ブロナンセリン」は、化学名では２－（４－エチル－１－ピペラニジル）－４－（４－フルオロフェニル）－５，６，７，８，９，１０－ヘキサヒドロキシクロオクタ［ｂ］ピリジンとして表される化合物であり、ＳＤＡ（セロトニン・ドーパミン拮抗薬）に分類され、抗精神病薬（非定型抗精神病薬）として市販されている。
　前記粘着剤層に含まれるブロナンセリンは、フリー体であっても薬学的に許容される塩であってもよく、特に限定されるものではない。 (A) Bronanserin or a salt thereof The chemical name of "bronanserin" is 2- (4-ethyl-1-piperanidyl) -4- (4-fluorophenyl) -5,6,7,8,9,10-hexa. It is a compound represented as hydroxycroocta [b] pyridine, is classified as SDA (serotonin / dopamine antagonist), and is commercially available as an antipsychotic drug (atypical antipsychotic drug).
The blonanserin contained in the pressure-sensitive adhesive layer may be a free form or a pharmaceutically acceptable salt, and is not particularly limited.
　前記薬学的に許容される塩としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、薬学的に許容される酸付加塩などが挙げられ、無機塩であっても有機塩であってもよい。
　前記薬学的に許容される塩は、１種のみ使用してもよく、２種以上を併用してもよい。さらに、フリー体と塩を混合して用いてもよい。 The pharmaceutically acceptable salt is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a pharmaceutically acceptable acid addition salt, and even an inorganic salt is organic. It may be salt.
The pharmaceutically acceptable salt may be used alone or in combination of two or more. Further, the free form and the salt may be mixed and used.
　前記無機塩としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、塩酸塩、臭化水素酸塩、硝酸塩、硫酸塩、リン酸塩などが挙げられる。
　前記有機酸塩としては、ギ酸塩、酢酸塩、トリフルオロ酢酸塩、プロピオン酸塩、乳酸塩、酒石酸塩、シュウ酸塩、フマル酸塩、マレイン酸塩、クエン酸塩、マロン酸塩、メタンスルホン酸塩などが挙げられる。入手し易さの観点から、フリー体又は塩酸塩が好ましく、皮膚透過性の観点から、フリー体を用いることがより好ましい。 The inorganic salt is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include hydrochloride, hydrobromide, nitrate, sulfate and phosphate.
Examples of the organic acid salt include formate, acetate, trifluoroacetate, propionate, lactate, tartrate, oxalate, fumarate, maleate, citrate, malonate, and methanesulfone. Examples include acid salts. From the viewpoint of availability, a free form or hydrochloride is preferable, and from the viewpoint of skin permeability, it is more preferable to use a free form.
　前記粘着剤層におけるブロナンセリン又はその塩の含有量、即ち、前記粘着剤層の構成成分の合計１００質量％に占めるブロナンセリン又はその塩の割合としては、特に制限はなく、目的に応じて適宜選択することができるが、粘着剤層中への分散性及び良好な皮膚透過性を確保する観点から、下限値は、０．５質量％以上が好ましく、０．７５質量％以上がより好ましく、１質量％以上がさらに好ましく、１．５質量％以上が特に好ましく、上限値は、３０質量％以下が好ましく、２５質量％以下がより好ましく、２０質量％以下がさらに好ましく、１５質量％以上が特に好ましい。 The content of bronanserin or a salt thereof in the pressure-sensitive adhesive layer, that is, the ratio of bronanserin or a salt thereof to 100% by mass of the total components of the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the intended purpose. However, from the viewpoint of ensuring dispersibility in the pressure-sensitive adhesive layer and good skin permeability, the lower limit is preferably 0.5% by mass or more, more preferably 0.75% by mass or more, and 1% by mass. % Or more is more preferable, 1.5% by mass or more is particularly preferable, and the upper limit value is preferably 30% by mass or less, more preferably 25% by mass or less, further preferably 20% by mass or less, and particularly preferably 15% by mass or more. ..
　（ｂ）熱可塑性エラストマー
　本発明に係る「熱可塑性エラストマー」とは、熱を加えると軟化して流動性を示し、冷却すればゴム状弾性体に戻る熱可塑性を示すエラストマーである。
　前記熱可塑性エラストマーとしては、特に制限はなく、目的に応じて適宜選択することができ、例えば、ウレタン系、アクリル系、スチレン系、オレフィン系など、各種の熱可塑性エラストマーが挙げられる。特に、十分な皮膚粘着性と低皮膚刺激性を両立させる観点から、スチレン系熱可塑性エラストマー、特にスチレン系ブロック共重合体が好ましい。 (B) Thermoplastic Elastomer The "thermoplastic elastomer" according to the present invention is an elastomer that softens when heat is applied and exhibits fluidity, and returns to a rubber-like elastic body when cooled.
The thermoplastic elastomer is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include various thermoplastic elastomers such as urethane-based, acrylic-based, styrene-based and olefin-based. In particular, a styrene-based thermoplastic elastomer, particularly a styrene-based block copolymer, is preferable from the viewpoint of achieving both sufficient skin adhesiveness and low skin irritation.
　前記スチレン系ブロック共重合体としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、スチレン・ブタジエンブロック共重合体、スチレン・ブタジエン・スチレンブロック共重合体、スチレン・イソプレンブロック共重合体、スチレン・イソプレン・スチレンブロック共重合体、スチレン・エチレン／ブチレンブロック共重合体、スチレン・エチレン／ブチレン・スチレンブロック共重合体、スチレン・エチレン／プロピレンブロック共重合体、スチレン・エチレン／プロピレン・スチレンブロック共重合体、スチレン・イソブチレンブロック共重合体、スチレン・イソブチレン・スチレンブロック共重合体などが挙げられる。なお、前記「エチレン／ブチレン」は、エチレンとブチレンの共重合体ブロックを示し、前記「エチレン／プロピレン」は、エチレンとプロピレンの共重合体ブロックを示す。これらスチレン系ブロック共重合体は、１種のみを用いても、２種以上を組合せて用いてもよい。 The styrene-based block copolymer is not particularly limited and may be appropriately selected depending on the intended purpose. For example, a styrene / butadiene block copolymer, a styrene / butadiene / styrene block copolymer, or a styrene / isoprene block. Styrene, styrene / isoprene / styrene block copolymer, styrene / ethylene / butylene block copolymer, styrene / ethylene / butylene / styrene block copolymer, styrene / ethylene / propylene block copolymer, styrene / ethylene / Examples thereof include a propylene / styrene block copolymer, a styrene / isobutylene block copolymer, and a styrene / isobutylene / styrene block copolymer. The "ethylene / butylene" indicates a copolymer block of ethylene and butylene, and the "ethylene / propylene" indicates a copolymer block of ethylene and propylene. These styrene-based block copolymers may be used alone or in combination of two or more.
　前記スチレン系ブロック共重合体のうち、粘着剤層の十分な皮膚粘着性と凝集力向上による糊残り抑制の両立のほか、入手性や取り扱い性の観点から、スチレン・イソプレン・スチレンブロック共重合体、及びスチレン・イソプレンブロック共重合体からなる群より選択される１種又は２種以上が好ましく、特にスチレン・イソプレンブロック共重合体とスチレン・イソプレン・スチレンブロック共重合体との混合物が好ましい。 Among the styrene-based block copolymers, styrene / isoprene / styrene block copolymers from the viewpoints of both sufficient skin adhesion of the pressure-sensitive adhesive layer and suppression of adhesive residue by improving cohesiveness, as well as availability and handleability. , And one or more selected from the group consisting of styrene / isoprene block copolymers, and particularly preferably a mixture of styrene / isoprene block copolymers and styrene / isoprene / styrene block copolymers.
　前記混合物におけるスチレン・イソプレンブロック共重合体の割合の下限値としては、特に制限はなく、目的に応じて適宜選択することができるが、１０質量％以上が好ましく、１５質量％以上がより好ましく、２０質量％以上がさらに好ましく、４０質量％以上が特に好ましく、５０質量％以上が最も好ましい。
　前記混合物におけるスチレン・イソプレンブロック共重合体の割合の上限値としては、特に制限はなく、目的に応じて適宜選択することができるが、９５質量％以下が好ましく、９０質量％以下がより好ましく、８５質量％以下がさらに好ましく、８０質量％以下が特に好ましい。 The lower limit of the proportion of the styrene / isoprene block copolymer in the mixture is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 10% by mass or more, more preferably 15% by mass or more. 20% by mass or more is more preferable, 40% by mass or more is particularly preferable, and 50% by mass or more is most preferable.
The upper limit of the proportion of the styrene / isoprene block copolymer in the mixture is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 95% by mass or less, more preferably 90% by mass or less. It is more preferably 85% by mass or less, and particularly preferably 80% by mass or less.
　前記スチレン・イソプレン・スチレンブロック共重合体におけるスチレン含有量としては、特に制限はなく、目的に応じて適宜選択することができるが、共重合体におけるスチレン含有量が５質量％以上６０質量％以下であるものが好ましく、１０質量％以上５０質量％以下であるものがより好ましい。 The styrene content in the styrene / isoprene / styrene block copolymer is not particularly limited and may be appropriately selected depending on the intended purpose, but the styrene content in the copolymer is 5% by mass or more and 60% by mass or less. Is preferable, and more preferably 10% by mass or more and 50% by mass or less.
　前記スチレン・イソプレン・スチレンブロック共重合体の分子量としては、特に制限はなく、目的に応じて適宜選択することができるが、ゲル浸透クロマトグラフィー（ＧＰＣ）により測定した重量平均分子量が２０，０００以上５００，０００以下であるものが好ましく、３０，０００以上３００，０００以下であるものがより好ましい。 The molecular weight of the styrene / isoprene / styrene block copolymer is not particularly limited and may be appropriately selected depending on the intended purpose, but the weight average molecular weight measured by gel permeation chromatography (GPC) is 20,000 or more. It is preferably 500,000 or less, and more preferably 30,000 or more and 300,000 or less.
　前記スチレン・イソプレンブロック共重合体におけるスチレン含有量としては、特に制限はなく、目的に応じて適宜選択することができるが、共重合体におけるスチレン含有量が５質量％以上５０質量％以下であるものが好ましく、１０質量％以上４０質量％以下であるものがより好ましい。 The styrene content in the styrene / isoprene block copolymer is not particularly limited and may be appropriately selected depending on the intended purpose, but the styrene content in the copolymer is 5% by mass or more and 50% by mass or less. It is preferably 10% by mass or more and 40% by mass or less.
　スチレン・イソプレンブロック共重合体の分子量としては、特に制限はなく、目的に応じて適宜選択することができるが、ＧＰＣにより測定した重量平均分子量が１０，０００以上５００，０００以下であるものが好ましく、２０，０００以上３００，０００以下であるものがより好ましい。 The molecular weight of the styrene / isoprene block copolymer is not particularly limited and may be appropriately selected depending on the intended purpose, but the weight average molecular weight measured by GPC is preferably 10,000 or more and 500,000 or less. More preferably, it is 20,000 or more and 300,000 or less.
　前記スチレン系ブロック共重合体の粘度としては、特に制限はなく、目的に応じて適宜選択することができるが、粘着物性のバランスを良好にする観点から、２５質量％トルエン溶液の２５℃における溶液粘度の下限値は、５００ｍＰａ・ｓ以上が好ましく、９００ｍＰａ・ｓ以上がより好ましく、上限値は、２０００ｍＰａ・ｓ以下が好ましく、１８００ｍＰａ・ｓ以下がより好ましい。なお、前記「２５質量％トルエン溶液の２５℃における溶液粘度」は、「医薬品添加物規格２０１３」（薬事日報社発行）の３９５頁に記載のスチレン・イソプレン・スチレンブロック共重合体の粘度測定方法に基づいて測定される値である。 The viscosity of the styrene-based block copolymer is not particularly limited and may be appropriately selected depending on the intended purpose. However, from the viewpoint of improving the balance of adhesive properties, a 25 mass% toluene solution at 25 ° C. The lower limit of the viscosity is preferably 500 mPa · s or more, more preferably 900 mPa · s or more, and the upper limit value is preferably 2000 mPa · s or less, more preferably 1800 mPa · s or less. The "solution viscosity of a 25 mass% toluene solution at 25 ° C." is the method for measuring the viscosity of a styrene / isoprene / styrene block copolymer described on page 395 of "Pharmaceutical Additives Standard 2013" (published by Pharmaceutical Affairs Daily). It is a value measured based on.
　前記スチレン・イソプレン・スチレンブロック共重合体と前記スチレン・イソプレンブロック共重合体は、それぞれ、公知の方法により製造した共重合体を用いることができる。また、前記スチレン・イソプレン・スチレンブロック共重合体と前記スチレン・イソプレンブロック共重合体は、それぞれ、上記の特性を満たす市販の製品を使用することがきる。また、前記スチレン・イソプレン・スチレンブロック共重合体と前記スチレン・イソプレンブロック共重合体の混合物も市販されており、上記の特性を満たす前記スチレン・イソプレン・スチレンブロック共重合体と前記スチレン・イソプレンブロック共重合体とが上記の混合比率で混合された混合物の市販品を好適に使用することができる。 As the styrene / isoprene / styrene block copolymer and the styrene / isoprene block copolymer, respectively, a copolymer produced by a known method can be used. Further, as the styrene / isoprene / styrene block copolymer and the styrene / isoprene block copolymer, commercially available products satisfying the above characteristics can be used. Further, a mixture of the styrene / isoprene / styrene block copolymer and the styrene / isoprene block copolymer is also commercially available, and the styrene / isoprene / styrene block copolymer and the styrene / isoprene block satisfying the above characteristics are also commercially available. A commercially available product of a mixture in which the copolymer and the copolymer are mixed at the above mixing ratio can be preferably used.
　前記スチレン系ブロック共重合体の市販品としては、例えば、ＫＲＡＴＯＮ　ＰＯＬＹＭＥＲＳ社製の「ＫＲＡＴＯＮ（登録商標）　Ｄ１１１１」、「ＫＲＡＴＯＮ（登録商標）　Ｄ１１６３」、「ＫＲＡＴＯＮ（登録商標）　Ｄ１１１３」、「ＫＲＡＴＯＮ（登録商標）　Ｄ１１１９」；ＪＳＲ社製の「ＪＳＲ（登録商標）　ＳＩＳ５２２９」、「ＪＳＲ（登録商標）　ＳＩＳ５００２」、「ＪＳＲ（登録商標）　ＳＩＳ５４０３」、「ＪＳＲ（登録商標）　ＳＩＳ５５０５」；日本ゼオン社製の「Ｑｕｉｎｔａｃ（登録商標）　３４２１」、「Ｑｕｉｎｔａｃ（登録商標）　３４３３Ｎ」、「Ｑｕｉｎｔａｃ（登録商標）　３５２０」、「Ｑｕｉｎｔａｃ（登録商標）　３４５０」、「Ｑｕｉｎｔａｃ（登録商標）　３２７０」などが挙げられる。 Examples of commercially available products of the styrene-based block copolymer include "KRATON (registered trademark) D1111", "KRATON (registered trademark) D1163", "KRATON (registered trademark) D1113", and "KRATON (registered trademark)" manufactured by KRATON POLYMERS. Registered trademark) D1119 "; JSR (registered trademark) SIS5229", "JSR (registered trademark) SIS5002", "JSR (registered trademark) SIS5403", "JSR (registered trademark) SIS5505"; manufactured by Nippon Zeon "Quintac (registered trademark) 3421", "Quintac (registered trademark) 3433N", "Quintac (registered trademark) 3520", "Quintac (registered trademark) 3450", "Quintac (registered trademark) 3270" and the like.
　このうち、前記スチレン・イソプレン・スチレンブロック共重合体と前記スチレン・イソプレンブロック共重合体の混合比率や溶液粘度の観点から、「ＫＲＡＴＯＮ（登録商標）　Ｄ１１６３」、「ＫＲＡＴＯＮ（登録商標）　Ｄ１１１３」、「ＪＳＲ（登録商標）　ＳＩＳ５４０３」「ＪＳＲ（登録商標）　ＳＩＳ５５０５」、「Ｑｕｉｎｔａｃ（登録商標）　３４３３Ｎ」、及び／又は「Ｑｕｉｎｔａｃ（登録商標）　３５２０」が好ましく、「ＪＳＲ（登録商標）　ＳＩＳ５５０５」及び／又は「Ｑｕｉｎｔａｃ（登録商標）　３５２０」が特に好ましい。 Of these, "KRATON (registered trademark) D1163", "KRATON (registered trademark) D1113", from the viewpoint of the mixing ratio of the styrene / isoprene / styrene block copolymer and the styrene / isoprene block copolymer and the solution viscosity, "JSR (registered trademark) SIS5403", "JSR (registered trademark) SIS5505", "Quintac (registered trademark) 3433N", and / or "Quintac (registered trademark) 3520" are preferable, and "JSR (registered trademark) SIS5505" and / Alternatively, "Quintac® 3520" is particularly preferable.
　前記粘着剤層における前記熱可塑性エラストマーの含有量、即ち、粘着剤層の構成成分の合計１００質量％に占める熱可塑性エラストマーの割合としては、特に制限はなく、目的に応じて適宜選択することができるが、下限値は、１０質量％以上が好ましく、１５質量％以上がより好ましく、２０質量％以上がさらに好ましく、上限値は、７０質量％以下が好ましく、６５質量％以下がより好ましく、６０質量％以下がさらに好ましい。当該割合が１０質量％以上であれば、粘着剤層の形状をより確実に維持することが可能になり、７０質量％以下であれば、皮膚に対する粘着剤層の粘着性がより確実に発揮される。 The content of the thermoplastic elastomer in the pressure-sensitive adhesive layer, that is, the ratio of the thermoplastic elastomer to 100% by mass of the total components of the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the intended purpose. However, the lower limit value is preferably 10% by mass or more, more preferably 15% by mass or more, further preferably 20% by mass or more, and the upper limit value is preferably 70% by mass or less, more preferably 65% by mass or less, and 60% by mass. More preferably, it is by mass or less. When the ratio is 10% by mass or more, the shape of the pressure-sensitive adhesive layer can be maintained more reliably, and when the ratio is 70% by mass or less, the adhesiveness of the pressure-sensitive adhesive layer to the skin is more reliably exhibited. NS.
　（ｃ）不揮発性炭化水素油
　前記不揮発性炭化水素油としては、特に制限はなく、目的に応じて適宜選択することができるが、炭素数が１０～２００程度の飽和炭化水素又は炭素数１０～２００程度の不飽和炭化水素からなる、常温で液状の物質が好ましく、例えば、流動パラフィン、スクアレン、スクアラン、プリスタンなどが挙げられる。これらの中でも入手のしやすさの観点において、流動パラフィンがより好ましい。
　ここで、常温とは、日本薬局方の通則における１５℃～２５℃の範囲である。以下の記載においても、同様である。
　前記流動パラフィンは、無色無臭で液状の飽和炭化水素の混合物であるが、本発明においては、日本薬局方、米国薬局方等に規定する規格に適合するもの等を好ましく用いることができる。不揮発性炭化水素油は粘度の高いものが好ましく、特に粘度の高い流動パラフィンを用いることが、粘着性の観点から好ましい。 (C) Non-volatile hydrocarbon oil The non-volatile hydrocarbon oil is not particularly limited and may be appropriately selected depending on the intended purpose, but is a saturated hydrocarbon having about 10 to 200 carbon atoms or having 10 to 10 carbon atoms. A substance that is liquid at room temperature and is composed of about 200 unsaturated hydrocarbons is preferable, and examples thereof include liquid paraffin, squalene, squalene, and pristan. Among these, liquid paraffin is more preferable from the viewpoint of availability.
Here, the normal temperature is in the range of 15 ° C. to 25 ° C. according to the general rules of the Japanese Pharmacopoeia. The same applies to the following description.
The liquid paraffin is a mixture of colorless, odorless and liquid saturated hydrocarbons, but in the present invention, those conforming to the standards specified in the Japanese Pharmacopoeia, the United States Pharmacopeia, etc. can be preferably used. The non-volatile hydrocarbon oil preferably has a high viscosity, and it is particularly preferable to use liquid paraffin having a high viscosity from the viewpoint of adhesiveness.
　具体的には、不揮発性炭化水素油は４０℃における動粘度が６０ｍｍ２／ｓ以上であるものが好ましく、より好ましくは７０ｍｍ２／ｓ以上、さらに好ましくは８０ｍｍ２／ｓ以上である。なお、動粘度の上限は特に限定されないが、例えば、取扱いのしやすさや、入手のしやすさ等の観点から、５００ｍｍ２／ｓ以下が好ましく、２５０ｍｍ２／ｓ以下がより好ましい。ここでいう「動粘度」とは、「第十七改正日本薬局方」の一般試験法の「２．５３　粘度測定法」における「第２法　回転粘度計法（２．１２　単一円筒形回転粘度計（ブルックフィールド型粘度計）」に準拠して測定した粘度（ｍＰａ・ｓ）を動粘度に換算した値である。 Specifically, the non-volatile hydrocarbon oil preferably has a kinematic viscosity at 40 ° C. of 60 mm 2 / s or more, more preferably 70 mm 2 / s or more, and further preferably 80 mm 2 / s or more. The upper limit of the kinematic viscosity is not particularly limited, but for example, from the viewpoint of ease of handling, availability, and the like, 500 mm 2 / s or less is preferable, and 250 mm 2 / s or less is more preferable. The term "kinematic viscosity" as used herein means the "second method rotational viscometer method (2.12 single cylindrical rotation)" in the "2.53 viscosity measurement method" of the general test method of the "17th revised Japanese Pharmacy". It is a value obtained by converting the viscosity (mPa · s) measured according to the “viscosity meter (Brookfield type viscometer)” into kinematic viscosity.
　前記粘着剤層における、前記不揮発性炭化水素油の含有量としては、特に制限はなく、目的に応じて適宜選択することができるが、熱可塑性エラストマー１００重量部に対して、５０重量部を超えて８００重量部以下で含有することが好ましい。熱可塑性エラストマー１００重量部に対する不揮発性炭化水素油の含有量が８００重量部より多くなると、粘着剤層の形状の維持が困難となる。一方、不揮発性炭化水素油の含有量が５０重量部より少ないと、粘着剤が硬くなりすぎることにより十分な皮膚粘着性が得られない傾向があり、特に、貼付時の皮膚の動きに対する追随性が悪くなり、貼付中に脱落する場合がある。このような観点から、粘着剤層中における不揮発性炭化水素油の含有量の下限値は、熱可塑性エラストマー１００重量部に対し、５０重量部以上が好ましく、６０重量部以上がさらに好ましく、７０重量部以上が特に好ましく、上限値は、８００重量部以下が好ましく、６００重量部以下がさらに好ましく、５００重量部以下が特に好ましい。また、この範囲内においても、不揮発性炭化水素油の含量が多いと、粘着性能のうち、剥離応力が低くなる傾向があり、かつ、保存時や貼付時の粘着剤のはみ出しが見られ、包材や衣服に付着する不具合が出やすい傾向にある。一方、不揮発性炭化水素油の含量が少ないと、特に、発汗時や入浴時の皮膚粘着性が低下し、貼付剤が脱落してしまう可能性がある。このような観点から、粘着剤層中における不揮発性炭化水素油の含有量は、熱可塑性エラストマー１００重量部に対し、８０重量部以上４００重量部以下が好ましく、さらに好ましくは９０重量部以上３５０重量部以下、特に好ましくは１００重量部以上３００重量部以下である。 The content of the non-volatile hydrocarbon oil in the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the intended purpose, but exceeds 50 parts by weight with respect to 100 parts by weight of the thermoplastic elastomer. It is preferably contained in an amount of 800 parts by weight or less. If the content of the non-volatile hydrocarbon oil with respect to 100 parts by weight of the thermoplastic elastomer is more than 800 parts by weight, it becomes difficult to maintain the shape of the pressure-sensitive adhesive layer. On the other hand, if the content of the non-volatile hydrocarbon oil is less than 50 parts by weight, the adhesive tends to be too hard to obtain sufficient skin adhesiveness, and in particular, the ability to follow the movement of the skin during application. May get worse and may fall off during application. From this point of view, the lower limit of the content of the non-volatile hydrocarbon oil in the pressure-sensitive adhesive layer is preferably 50 parts by weight or more, more preferably 60 parts by weight or more, and 70 parts by weight, based on 100 parts by weight of the thermoplastic elastomer. More than parts are particularly preferable, and the upper limit value is preferably 800 parts by weight or less, more preferably 600 parts by weight or less, and particularly preferably 500 parts by weight or less. Further, even within this range, if the content of the non-volatile hydrocarbon oil is high, the peeling stress tends to be low in the adhesive performance, and the adhesive squeezes out during storage or application. There is a tendency for defects to adhere to materials and clothing. On the other hand, if the content of the non-volatile hydrocarbon oil is low, the skin adhesiveness during sweating or bathing may decrease, and the patch may fall off. From this point of view, the content of the non-volatile hydrocarbon oil in the pressure-sensitive adhesive layer is preferably 80 parts by weight or more and 400 parts by weight or less, and more preferably 90 parts by weight or more and 350 parts by weight with respect to 100 parts by weight of the thermoplastic elastomer. Parts or less, particularly preferably 100 parts by weight or more and 300 parts by weight or less.
　－乳酸の量－
　前記粘着剤層における乳酸の量としては、薬物の皮膚透過性が低下しない範囲であれば特に制限はなく、前記粘着剤層に含まれるブロナンセリンに対し１．５モル当量以下である限り、目的に応じて適宜選択することができるが、１．４モル当量以下が好ましく、１．２５モル当量以下がより好ましく、１モル当量以下がさらに好ましく、０．７５モル当量以下がよりさらに好ましく、０．５モル当量以下が特に好ましく、０モル当量が最も好ましい。
　前記粘着剤層における乳酸の量は、ＪＩＳ　Ｋ　８７２６：２０１４に記載の方法に従い測定する。 -Amount of lactic acid-
The amount of lactic acid in the pressure-sensitive adhesive layer is not particularly limited as long as it does not reduce the skin permeability of the drug, and is intended as long as it is 1.5 molar equivalents or less with respect to bronanceline contained in the pressure-sensitive adhesive layer. It can be appropriately selected depending on the situation, but is preferably 1.4 molar equivalents or less, more preferably 1.25 molar equivalents or less, still more preferably 1 molar equivalent or less, still more preferably 0.75 molar equivalents or less, and 0. 5 molar equivalents or less are particularly preferred, and 0 molar equivalents are most preferred.
The amount of lactic acid in the pressure-sensitive adhesive layer is measured according to the method described in JIS K 8726: 2014.
　－その他の成分－
　前記粘着剤層には、必要に応じて、その他の成分として、（ｄ）ポリイソブチレン、（ｅ）脂肪族ジカルボン酸エステル、（ｆ）グリセリンモノエーテル、（ｇ）乳酸を除く液状の有機酸、（ｈ１）多価アルコールの脂肪酸モノエステル、（ｈ２）高級アルコール、（ｈ３）アルコール系溶媒、（ｈ４）アミド系溶媒、（ｈ５）エステル系溶媒、（ｈ６）カルボン酸塩、（ｈ７）ラクトン、（ｈ８）界面活性剤、（ｈ９）充填剤、（ｈ１０）結晶析出抑制剤、（ｉ）粘着付与剤などを配合することができる。 -Other ingredients-
If necessary, the pressure-sensitive adhesive layer contains (d) polyisobutylene, (e) aliphatic dicarboxylic acid ester, (f) glycerin monoether, and (g) a liquid organic acid excluding lactic acid, as other components. (H1) Polyhydric alcohol fatty acid monoester, (h2) higher alcohol, (h3) alcohol solvent, (h4) amide solvent, (h5) ester solvent, (h6) carboxylate, (h7) lactone, (H8) solvent, (h9) filler, (h10) crystal precipitation inhibitor, (i) tackifier and the like can be blended.
　（ｄ）ポリイソブチレン
　粘着物性調整のため、ポリイソブチレンを添加することができる。
　本発明の粘着剤層において用いる「ポリイソブチレン」とは、イソブチレンの重合物であり、弾力性のあるゴム性の半固体又は粘稠な物質で、本発明においては、十分な皮膚粘着性を付与するために添加する。 (D) Polyisobutylene Polyisobutylene can be added to adjust the adhesive properties.
The "polyisobutylene" used in the pressure-sensitive adhesive layer of the present invention is a polymer of isobutylene, which is an elastic rubbery semi-solid or a viscous substance, and in the present invention, imparts sufficient skin adhesiveness. Add to.
　前記ポリイソブチレンは、粘度平均分子量が３０，０００～１００，０００の低分子量ポリイソブチレン、粘度平均分子量が１００，０００～５００，０００の中分子量ポリイソブチレン、粘度平均分子量が５００，０００～５０００，０００の高分子量ポリイソブチレンを、それぞれ単独、もしくは混合して用いることができる。特に、前記低分子量ポリイソブチレンと前記高分子量ポリイソブチレンの混合、もしくは前記中分子量ポリイソブチレン単独で用いることが、低い皮膚刺激性と高い皮膚粘着性のバランスを取る上で好ましい。 The polyisobutylene is a low molecular weight polyisobutylene having a viscosity average molecular weight of 30,000 to 100,000, a medium molecular weight polyisobutylene having a viscosity average molecular weight of 100,000 to 500,000, and a viscosity average molecular weight of 500,000 to 5,000,000. High molecular weight polyisobutylene can be used alone or in combination. In particular, it is preferable to use a mixture of the low molecular weight polyisobutylene and the high molecular weight polyisobutylene, or the medium molecular weight polyisobutylene alone in order to balance low skin irritation and high skin adhesiveness.
　前記ポリイソブチレンは、自体公知の方法で製造したイソブチレンの重合体を用いることができる。特に、皮膚貼付用である本発明の粘着層においては、医薬品添加物規格や米国薬局方等に規定する規格に適合するもの等を好ましく用いることができる。また、ポリイソブチレンは、それぞれ、上記の粘度平均分子量を満たす市販品を使用することがきる。 As the polyisobutylene, a polymer of isobutylene produced by a method known per se can be used. In particular, in the adhesive layer of the present invention for skin application, those conforming to the standards for pharmaceutical additives and the standards specified in the United States Pharmacopeia and the like can be preferably used. Further, as polyisobutylene, commercially available products satisfying the above-mentioned viscosity average molecular weight can be used.
　前記市販品としては、前記低分子量ポリイソブチレンとしては、例えば、ＢＡＳＦ社製の「Ｏｐｐａｎｏｌ（登録商標）　Ｂ１０ＳＦＮ」、「Ｏｐｐａｎｏｌ（登録商標）　Ｂ１０Ｎ」、「Ｏｐｐａｎｏｌ（登録商標）　Ｂ１２ＳＦＮ」、「Ｏｐｐａｎｏｌ（登録商標）　Ｂ１５ＳＦＮ」、「Ｏｐｐａｎｏｌ（登録商標）　Ｂ１５Ｎ」などが、前記中分子量ポリイソブチレンとしては、例えば、ＢＡＳＦ社製の「Ｏｐｐａｎｏｌ（登録商標）　Ｎ５０ＳＦ」、「Ｏｐｐａｎｏｌ（登録商標）　Ｎ５０」などが、前記高分子量ポリイソブチレンとしては、例えば、ＢＡＳＦ社製の「Ｏｐｐａｎｏｌ（登録商標）　Ｎ８０」、「Ｏｐｐａｎｏｌ（登録商標）　Ｎ１００」、「Ｏｐｐａｎｏｌ（登録商標）　Ｎ１５０」などが挙げられる。 Examples of the commercially available low molecular weight polyisobutylene include "Oppanol (registered trademark) B10SFN", "Oppanol (registered trademark) B10N", "Oppanol (registered trademark) B12SFN", and "Oppanol (registered trademark)" manufactured by BASF. "Registered trademark" B15SFN "," Oppanol (registered trademark) B15N ", etc., and as the medium molecular weight polyisobutylene, for example," Oppanol (registered trademark) N50SF "," Oppanol (registered trademark) N50 "manufactured by BASF, etc. Examples of the high-molecular-weight polyisobutylene include "Oppanol (registered trademark) N80", "Oppanol (registered trademark) N100", and "Oppanol (registered trademark) N150" manufactured by BASF.
　これらのうち、塗工液とする際の溶解度や、得られた貼付剤の粘着物性バランスの観点から、前記低分子量ポリイソブチレンとしては粘度平均分子量が５０，０００～１００，０００の「Ｏｐｐａｎｏｌ（登録商標）　Ｂ１５ＳＦＮ」、「Ｏｐｐａｎｏｌ（登録商標）　Ｂ１５Ｎ」が、前記中分子量ポリイソブチレンとしては「Ｏｐｐａｎｏｌ（登録商標）　Ｎ５０ＳＦ」、「Ｏｐｐａｎｏｌ（登録商標）　Ｎ５０」が、前記高分子量ポリイソブチレンとしては「Ｏｐｐａｎｏｌ（登録商標）　Ｎ８０」が、特に好ましい。 Of these, from the viewpoint of the solubility in the coating liquid and the balance of the adhesive properties of the obtained patch, the low molecular weight polyisobutylene has a viscosity average molecular weight of 50,000 to 100,000 "Oppanol (registered). "B15SFN" and "Oppanol (registered trademark) B15N", "Oppanol (registered trademark) N50SF" and "Oppanol (registered trademark) N50" as the medium molecular weight polyisobutylene, and "Oppanol (registered trademark) N50" as the high molecular weight polyisobutylene. (Registered trademark) N80 ”is particularly preferable.
　前記粘着剤層におけるポリイソブチレンの含有量としては、特に制限はなく、目的に応じて適宜選択することができるが、前記粘着剤層におけるポリイソブチレンの含有量が少な過ぎると、皮膚粘着性の強化が不十分となり、多過ぎると過度の皮膚粘着性強化による皮膚刺激性の悪化や、剥離時の糊残り、薬剤溶解性不良などが問題となる場合がある。従って、前記粘着剤層中におけるポリイソブチレンの含有量の下限値は、熱可塑性エラストマー１００重量部に対して０．１重量部以上であり、０．３重量部以上が好ましく、より好ましくは０．５重量部以上、さらに好ましくは１重量部以上であり、前記粘着剤層中におけるポリイソブチレンの含有量の上限値は、熱可塑性エラストマー１００重量部に対して３００重量部以下であり、２００重量部以下が好ましく、より好ましくは１５０重量部以下、さらに好ましくは１００重量部以下である。 The content of polyisobutylene in the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the intended purpose. However, if the content of polyisobutylene in the pressure-sensitive adhesive layer is too small, the skin adhesiveness is enhanced. If the amount is too large, there may be problems such as deterioration of skin irritation due to excessive strengthening of skin adhesiveness, adhesive residue at the time of peeling, and poor drug solubility. Therefore, the lower limit of the content of polyisobutylene in the pressure-sensitive adhesive layer is 0.1 part by weight or more, preferably 0.3 part by weight or more, and more preferably 0 part by weight with respect to 100 parts by weight of the thermoplastic elastomer. It is 5 parts by weight or more, more preferably 1 part by weight or more, and the upper limit of the content of polyisobutylene in the pressure-sensitive adhesive layer is 300 parts by weight or less with respect to 100 parts by weight of the thermoplastic elastomer, and 200 parts by weight. The following is preferable, more preferably 150 parts by weight or less, still more preferably 100 parts by weight or less.
　なお、より具体的な好適態様として、粘着剤層中におけるポリイソブチレン含有量は、０．１質量％～５０質量％を挙げることができ、より好ましくは０．２質量％～４０質量％、さらに好ましくは０．３質量％～３０質量％、特に好ましくは０．５質量％～２５質量％である。 As a more specific preferred embodiment, the polyisobutylene content in the pressure-sensitive adhesive layer can be 0.1% by mass to 50% by mass, more preferably 0.2% by mass to 40% by mass, and further. It is preferably 0.3% by mass to 30% by mass, and particularly preferably 0.5% by mass to 25% by mass.
　（ｅ）脂肪族ジカルボン酸エステル
　前記脂肪族ジカルボン酸エステルとしては、特に制限はなく、目的に応じて適宜選択することができ、例えば、アジピン酸ジエチル、アジピン酸ジイソプロピル、アジピン酸ジイソブチル等の常温で液状のアジピン酸ジエステル、セバシン酸ジエチル、セバシン酸ジイソプロピル、セバシン酸ジオクチルドデシル等の常温で液状のセバシン酸ジエステルなど、炭素数２以上１２以下のジカルボン酸と、炭素数１以上２０以下の一価の脂肪族アルコールとの常温で液状のジエステルなどが挙げられる。なかでも、薬物の溶解性や吸収促進効果を高める観点から、アジピン酸ジイソプロピル、アジピン酸ジイソブチルが好ましい。 (E) Aliup dicarboxylic acid ester The aliphatic dicarboxylic acid ester is not particularly limited and may be appropriately selected depending on the intended purpose. For example, diethyl adipic acid, diisopropyl adipate, diisobutyl adipate and the like at room temperature. Dicarboxylic acids with 2 to 12 carbon atoms and monovalents with 1 to 20 carbon atoms, such as liquid sebacic acid diesters such as liquid adipic acid diester, diethyl sebacate, diisopropyl sebacate, and dioctyldodecyl sebacate, which are liquid at room temperature. Examples thereof include a diester which is liquid at room temperature with an aliphatic alcohol. Of these, diisopropyl adipate and diisobutyl adipate are preferable from the viewpoint of enhancing the solubility and absorption promoting effect of the drug.
　前記粘着剤層の構成成分の合計１００質量％に占める前記脂肪族ジカルボン酸エステルの含有量の下限値としては、特に制限はなく、目的に応じて適宜選択することができるが、０．２質量％以上が好ましく、０．５質量％以上がより好ましく、０．７質量％以上がさらに好ましく、１質量％以上が特に好ましい。
　記粘着剤層の構成成分の合計１００質量％に占める前記脂肪族ジカルボン酸エステルの含有量の上限値としては、特に制限はなく、目的に応じて適宜選択することができるが、２０質量％以下が好ましく、１０質量％以下がより好ましく、５質量％以下がさらに好ましく、３質量％以下が特に好ましい。 The lower limit of the content of the aliphatic dicarboxylic acid ester in the total 100% by mass of the constituent components of the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the intended purpose, but is 0.2% by mass. % Or more is preferable, 0.5% by mass or more is more preferable, 0.7% by mass or more is further preferable, and 1% by mass or more is particularly preferable.
The upper limit of the content of the aliphatic dicarboxylic acid ester in the total 100% by mass of the constituent components of the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the intended purpose, but is 20% by mass or less. Is preferable, 10% by mass or less is more preferable, 5% by mass or less is further preferable, and 3% by mass or less is particularly preferable.
　（ｆ）グリセリンモノエーテル
　前記グリセリンモノエーテルとしては、特に制限はなく、目的に応じて適宜選択することができ、例えば、α－モノイソステアリルグリセリルエーテルなどが挙げられる。 (F) Glycerin monoether The glycerin monoether is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include α-monoisostearyl glyceryl ether.
　前記粘着剤層の構成成分の合計１００質量％に占める前記グリセリンモノエーテルの含有量の下限値としては、特に制限はなく、目的に応じて適宜選択することができるが、０．０１質量％以上が好ましく、０．０３質量％以上がより好ましく、０．０５質量％以上がさらに好ましく、０．０７質量％以上が特に好ましい。
　記粘着剤層の構成成分の合計１００質量％に占める前記グリセリンモノエーテルの含有量の上限値としては、特に制限はなく、目的に応じて適宜選択することができるが、１０質量％以下が好ましく、５質量％以下がより好ましく、１．５質量％以下がさらに好ましく、１．０質量％以下が特に好ましい。 The lower limit of the content of the glycerin monoether in the total 100% by mass of the constituent components of the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the intended purpose, but is 0.01% by mass or more. Is more preferable, 0.03% by mass or more is more preferable, 0.05% by mass or more is further preferable, and 0.07% by mass or more is particularly preferable.
The upper limit of the content of the glycerin monoether in the total 100% by mass of the constituent components of the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 10% by mass or less. 5, 5% by mass or less is more preferable, 1.5% by mass or less is further preferable, and 1.0% by mass or less is particularly preferable.
　（ｇ）乳酸を除く液状の有機酸
　前記乳酸を除く液状の有機酸としては、常温で液状の有機酸である限り、特に制限はなく、目的に応じて適宜選択することができ、例えば、酢酸、プロピオン酸、酪酸、吉草酸、イソ吉草酸、カプロン酸、イソステアリン酸、エナント酸（ヘプタン酸）、カプリル酸、ペラルゴン酸（ノナン酸）等の脂肪族モノカルボン酸；オレイン酸、リノール酸、アラキドン酸、ドコサヘキサエン酸等の脂肪族不飽和モノカルボン酸；メトキシ酢酸等のアルコキシ基で置換された液状のカルボン酸；レブリン酸等のカルボニル基を有するカルボン酸；メタンスルホン酸等のスルホン酸などが挙げられる。
　これらの液状の有機酸は、塩基性薬物の溶解を補助する機能を有し、塩基性薬物を粘着剤層中において高濃度に含有させることができるとともに、分散性も向上させることができ、さらに経皮吸収性を向上させる効果を有する。このような観点から、これら液状の有機酸のうち、オレイン酸、イソステアリン酸、レブリン酸が好ましい。 (G) Liquid organic acid excluding lactic acid The liquid organic acid excluding lactic acid is not particularly limited as long as it is an organic acid liquid at room temperature, and can be appropriately selected depending on the intended purpose. For example, acetic acid. , Propionic acid, butyric acid, valeric acid, isovaleric acid, caproic acid, isostearic acid, enanthic acid (heptanic acid), capric acid, pelargonic acid (nonanoic acid) and other aliphatic monocarboxylic acids; oleic acid, linoleic acid, arachidone Alibo unsaturated monocarboxylic acids such as acids and docosahexaenoic acid; liquid carboxylic acids substituted with alkoxy groups such as methoxyacetic acid; carboxylic acids having carbonyl groups such as leveric acid; sulfonic acids such as methanesulfonic acid, etc. Be done.
These liquid organic acids have a function of assisting the dissolution of the basic drug, can contain the basic drug in a high concentration in the pressure-sensitive adhesive layer, can improve the dispersibility, and further. It has the effect of improving transdermal absorbability. From this point of view, among these liquid organic acids, oleic acid, isostearic acid, and levulinic acid are preferable.
　本発明においては、必要に応じて前記乳酸を除く液状の有機酸から１種又は２種以上を選択して含有させることができる。上記有機酸の好ましい組み合わせとしては、レブリン酸とイソステアリン酸、レブリン酸とオレイン酸、イソステアリン酸とオレイン酸を挙げることができる。
　前記乳酸を除く液状の有機酸の含有量としては、特に制限はなく、目的に応じて適宜選択することができるが、粘着剤層全量に対し、好ましくは０．１質量％以上、２０重量％以下であり、より好ましくは０．３質量％以上、１５重量％以下、さらに好ましくは０．５質量％以上、１０重量％以下、特に好ましくは１質量％以上、５重量％以下である。
　また、粘着剤層に含まれるブロナンセリンに対し、好ましくは０モル当量超１０モル当量以下であり、より好ましくは０．３モル当量以上、５モル当量以下、さらに好ましくは０．５モル当量以上、３モル当量以下である。 In the present invention, one or more of the liquid organic acids excluding lactic acid can be selected and contained, if necessary. Preferred combinations of the organic acids include levulinic acid and isostearic acid, levulinic acid and oleic acid, and isostearic acid and oleic acid.
The content of the liquid organic acid excluding lactic acid is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 0.1% by mass or more and 20% by weight with respect to the total amount of the pressure-sensitive adhesive layer. It is more preferably 0.3% by mass or more, 15% by weight or less, further preferably 0.5% by mass or more and 10% by weight or less, and particularly preferably 1% by mass or more and 5% by weight or less.
Further, with respect to bronanceline contained in the pressure-sensitive adhesive layer, it is preferably more than 0 molar equivalents and 10 molar equivalents or less, more preferably 0.3 molar equivalents or more and 5 molar equivalents or less, still more preferably 0.5 molar equivalents or more. It is 3 molar equivalents or less.
　（ｈ１）多価アルコールの脂肪酸モノエステル
　本発明において、「多価アルコールの脂肪酸モノエステル」とは、エチレングリコール、プロピレングリコール、グリセリンなどの多価アルコールの１つのヒドロキシル基と脂肪酸とがエステル結合した化合物である。多価アルコールの脂肪酸モノエステルは粘着基剤の凝集力を極端に低下させることなく、薬物溶解性の向上に寄与し、吸収促進効果を有する。 (H1) Fatty Acid Monoester of Polyhydric Alcohol In the present invention, the "fatty acid monoester of polyhydric alcohol" is an ester bond between one hydroxyl group of a polyhydric alcohol such as ethylene glycol, propylene glycol and glycerin and a fatty acid. It is a compound. The fatty acid monoester of a polyhydric alcohol contributes to the improvement of drug solubility and has an absorption promoting effect without extremely reducing the cohesive force of the pressure-sensitive adhesive base.
　前記多価アルコールの脂肪酸モノエステルを構成する多価アルコールとしては、特に制限はなく、目的に応じて適宜選択することができ、例えば、エチレングリコール、プロピレングリコール、ブチレングリコール、グリセリンなどが挙げられる。
　前記多価アルコールの脂肪酸モノエステルを構成する脂肪酸としては、特に制限はなく、目的に応じて適宜選択することができるが、炭素数８以上１８以下の脂肪酸が好ましく、カプリン酸、カプリル酸、ミリスチン酸、パルミチン酸、ステアリン酸、イソステアリン酸、オレイン酸、リノール酸などが挙げられる。 The polyhydric alcohol constituting the fatty acid monoester of the polyhydric alcohol is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include ethylene glycol, propylene glycol, butylene glycol and glycerin.
The fatty acid constituting the fatty acid monoester of the polyhydric alcohol is not particularly limited and may be appropriately selected depending on the intended purpose. However, fatty acids having 8 to 18 carbon atoms are preferable, and capric acid, caprylic acid and myristine are preferable. Acids, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid and the like can be mentioned.
　前記多価アルコール脂肪酸モノエステルの好適な具体例としては、プロピレングリコールモノカプリレート、プロピレングリコールモノラウレートである。薬物の溶解性と吸収促進効果を高めるために、多価アルコールの脂肪酸モノエステルの含量は粘着剤成分全量に対し１質量％以上であることが好ましく、さらに好ましくは２質量％以上であり、特に好ましくは５重量％以上である。一方、多価アルコールの脂肪酸モノエステルを大量に添加すると、粘着力の凝集力及び粘着力が低下することから、多価アルコールの脂肪酸モノエステルの含量は粘着剤成分全量に対して３０質量％以下であることが好ましく、さらに好ましくは２０重量％以下であり、特に好ましくは１０重量％以下である。 Preferable specific examples of the polyhydric alcohol fatty acid monoester are propylene glycol monocaprilate and propylene glycol monolaurate. In order to enhance the solubility and absorption promoting effect of the drug, the fatty acid monoester content of the polyhydric alcohol is preferably 1% by mass or more, more preferably 2% by mass or more, particularly based on the total amount of the pressure-sensitive adhesive component. It is preferably 5% by weight or more. On the other hand, when a large amount of the fatty acid monoester of the polyhydric alcohol is added, the cohesive force and the adhesive force of the adhesive force decrease. Therefore, the content of the fatty acid monoester of the polyhydric alcohol is 30% by mass or less based on the total amount of the pressure-sensitive adhesive component. It is preferably 20% by weight or less, and particularly preferably 10% by weight or less.
　（ｈ２）高級アルコール
　前記高級アルコールとしては、特に制限はなく、目的に応じて適宜選択することができ、例えば、ラウリルアルコール、イソステアリルアルコール等の炭素数１２以上２０以下程度の常温で液状の高級飽和脂肪族アルコール；オレイルアルコール等の炭素数１２以上２０以下程度の常温で液状の高級不飽和脂肪族アルコールなどが挙げられる。
　これらの中でも、薬物の溶解性や吸収促進効果を高める観点からラウリルアルコール、オレイルアルコールが好ましい。 (H2) Higher Alcohol The higher alcohol is not particularly limited and may be appropriately selected depending on the intended purpose. For example, lauryl alcohol, isostearyl alcohol, etc., which have 12 to 20 carbon atoms and are liquid at room temperature, are higher grade. Saturated fatty alcohols: Higher unsaturated aliphatic alcohols such as oleyl alcohol, which have 12 or more and 20 or less carbon atoms and are liquid at room temperature, can be mentioned.
Among these, lauryl alcohol and oleyl alcohol are preferable from the viewpoint of enhancing the solubility and absorption promoting effect of the drug.
　（ｈ３）アルコール系溶媒
　前記アルコール系溶媒としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、エチレングリコール、プロピレングリコール、グリセリン、１，３－ブタンジオール、分子量１００以上６００以下程度のポリエチレングリコール等の常温で液状の多価アルコール、ジエチレングリコールモノエチルエーテル等の多価アルコールのモノアルキルエーテル、グリセロールモノリノレート、グリセロールモノオレエート等の多価アルコールのモノ脂肪酸エステルなどが挙げられる。
　これらの中でも、薬物の溶解性を向上させる観点から、エチレングリコール、プロピレングリコール、グリセリン、１，３－ブタンジオール、ジエチレングリコールモノエチルエーテルが好ましい。 (H3) Alcohol-based solvent The alcohol-based solvent is not particularly limited and may be appropriately selected depending on the intended purpose. For example, ethylene glycol, propylene glycol, glycerin, 1,3-butanediol, molecular weight 100 or more and 600 or more. Examples include the following polyhydric alcohols that are liquid at room temperature such as polyethylene glycol, monoalkyl ethers of polyhydric alcohols such as diethylene glycol monoethyl ether, monofatty acid esters of polyhydric alcohols such as glycerol monolinolete and glycerol monooleate. Be done.
Among these, ethylene glycol, propylene glycol, glycerin, 1,3-butanediol, and diethylene glycol monoethyl ether are preferable from the viewpoint of improving the solubility of the drug.
　（ｈ４）アミド系溶媒
　前記アミド系溶媒としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、Ｎ－メチル－２－ピロリドン、２－ピロリドン等のピロリドン；１，３－ジメチル－２－イミダゾリジノン等のイミダゾリジノン；クロタミトン等のＮ－置換トルイジン；ホルムアミド、Ｎ－メチルホルムアミド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチルアセトアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルプロパンアミド等のアルカンアミドなどが挙げられる。
　前記アミド系溶媒のうち、薬物の溶解性、分散性及び経皮吸収性を向上させる観点から、Ｎ－メチル－２－ピロリドン、クロタミトン、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミドが好ましく、Ｎ－メチル－２－ピロリドン、クロタミトンがより好ましい。 (H4) Amide-based solvent The amide-based solvent is not particularly limited and may be appropriately selected depending on the intended purpose. For example, pyrrolidone such as N-methyl-2-pyrrolidone and 2-pyrrolidone; 1,3- Imidazolidinone such as dimethyl-2-imidazolidinone; N-substituted toluidine such as crotamitone; formamide, N-methylformamide, N, N-dimethylformamide, N-methylacetamide, N, N-dimethylacetamide, N-methyl Examples thereof include alkaneamide such as propaneamide.
Of the amide solvents, N-methyl-2-pyrrolidone, crotamiton, N, N-dimethylformamide, and N, N-dimethylacetamide are preferable from the viewpoint of improving the solubility, dispersibility, and transdermal absorbability of the drug. , N-Methyl-2-pyrrolidone, crotamiton are more preferred.
　（ｈ５）エステル系溶媒
　前記エステル系溶媒としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、２価アルコールとカルボン酸のジエステル、中鎖脂肪酸トリグリセリド、多価カルボン酸と一価の脂肪族アルコールとのエステル、炭酸エステルなどが挙げられる。 (H5) Ester-based solvent The ester-based solvent is not particularly limited and may be appropriately selected depending on the intended purpose. For example, a diester of a dihydric alcohol and a carboxylic acid, a medium chain fatty acid triglyceride, and a polyvalent carboxylic acid. Examples include esters with monovalent aliphatic alcohols and carbonate esters.
　前記２価アルコールとカルボン酸のジエステルとしては、特に制限はなく、目的に応じて適宜選択することができ、例えば、プロピレングリコールと、カプリル酸、カプリン酸、ラウリン酸、オレイン酸等から構成されるジエステルなどが挙げられる。 The diester of the dihydric alcohol and the carboxylic acid is not particularly limited and may be appropriately selected depending on the intended purpose. For example, it is composed of propylene glycol, caprylic acid, capric acid, lauric acid, oleic acid and the like. Diester and the like.
　前記中鎖脂肪酸トリグリセリドは、カプロン酸、カプリル酸、カプリン酸、ラウリン酸等の炭素数６以上１２以下程度の脂肪酸と、グリセリンよりなるトリグリセリドであり、本発明においては、常温で液状のカプリル酸トリグリセリド、カプリル酸及びカプリン酸のトリグリセリド混合物、カプリル酸、カプリン酸及びラウリン酸のトリグリセリド混合物などを用いることができる。また、これらを多く含む常温で液状の油脂を用いることもできる。かかる油脂としては、オリーブ油（オリブ油）、アルモンド油、サフラワー油、ダイズ油、トウモロコシ油、ゴマ油、ヤシ油、オレンジ油、ショウキョウ油、トウヒ油、ナタネ油、ヒマシ油、ヒマワリ油、綿実油、落花生油などが挙げられる。
　なお、本発明においては、常温で液状の中鎖脂肪酸トリグリセリド、又は常温で液状の中鎖脂肪酸トリグリセリド含有油脂として、医薬品用として市販されている製品を用いることもできる。 The medium-chain fatty acid triglyceride is a triglyceride composed of glycerin and fatty acids having 6 to 12 carbon atoms such as caproic acid, caprylic acid, caprylic acid, and lauric acid. In the present invention, the caprylic acid triglyceride is liquid at room temperature. , A triglyceride mixture of caprylic acid and capric acid, a triglyceride mixture of caprylic acid, caproic acid and lauric acid, and the like can be used. It is also possible to use oils and fats that are liquid at room temperature and contain a large amount of these. Such oils and fats include olive oil (olib oil), almond oil, saflower oil, soybean oil, corn oil, sesame oil, palm oil, orange oil, ginger oil, peppermint oil, rapeseed oil, sunflower oil, sunflower oil, cotton seed oil, etc. Examples include peanut oil.
In the present invention, a product commercially available for pharmaceutical use can also be used as a medium-chain fatty acid triglyceride that is liquid at room temperature or a medium-chain fatty acid triglyceride-containing fat or oil that is liquid at room temperature.
　前記炭酸エステルとしては、特に制限はなく、目的に応じて適宜選択することができ、炭酸と炭素数２以上１０以下のジオールとの環状炭酸エステル、例えば、炭酸エチレン、炭酸プロピレン、炭酸ビニレンなどが挙げられ、炭酸プロピレンが好ましい。 The carbonic acid ester is not particularly limited and may be appropriately selected depending on the intended purpose. Cyclic carbonic acid ester of carbonic acid and a diol having 2 or more and 10 or less carbon atoms, for example, ethylene carbonate, propylene carbonate, vinylene carbonate and the like can be used. As mentioned above, propylene carbonate is preferable.
　上記のエステル系溶媒のなかでも、中鎖脂肪酸トリグリセリド混合物、炭酸エステルが好ましく、カプリル酸及びカプリン酸のトリグリセリド混合物、炭酸プロピレンがより好ましい。 Among the above ester-based solvents, a medium-chain fatty acid triglyceride mixture and a carbonic acid ester are preferable, and a triglyceride mixture of caprylic acid and capric acid and propylene carbonate are more preferable.
　本発明においては、前記アルコール系溶媒、前記アミド系溶媒及び前記エステル系溶媒は、必要に応じてこれらより１種又は２種以上を選択して用いることができる。
　これら溶媒の含有量としては、特に制限はなく、目的に応じて適宜選択することができるが、粘着剤層全量に対し好ましくは０．１質量％以上２０質量％以下であり、より好ましくは０．５質量％以上１５質量％以下である。 In the present invention, the alcohol-based solvent, the amide-based solvent, and the ester-based solvent can be used by selecting one or more of them, if necessary.
The content of these solvents is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 0.1% by mass or more and 20% by mass or less, more preferably 0, based on the total amount of the pressure-sensitive adhesive layer. It is 5.5% by mass or more and 15% by mass or less.
　（ｈ６）カルボン酸塩
　前記カルボン酸塩としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、脂肪族モノカルボン酸、脂環式モノカルボン酸、脂肪族ジカルボン酸等の塩が挙げられる。
　前記脂肪族モノカルボン酸としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、酢酸、酪酸、ヘキサン酸等の炭素数が２以上７以下の短鎖脂肪酸、オクタン酸、デカン酸等の炭素数８以上１１以下の中鎖脂肪酸、ラウリン酸、ミリスチン酸、ステアリン酸、イソステアリン酸、オレイン酸等の炭素数１２以上の長鎖脂肪酸、グリコール酸、乳酸、３－ヒドロキシ酪酸、マンデル酸等のヒドロキシモノカルボン酸、メトキシ酢酸等のアルコキシ基で置換されたモノカルボン酸、レブリン酸等のケトモノカルボン酸などが挙げられる。
　前記脂環式モノカルボン酸としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、シクロヘキサンカルボン酸等の炭素数が６以上８以下の脂環式モノカルボン酸などが挙げられる。
　前記脂肪族ジカルボン酸としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、セバシン酸、アジピン酸、リンゴ酸、マレイン酸、フマル酸などが挙げられる。 (H6) Carboxylate The carboxylic acid salt is not particularly limited and may be appropriately selected depending on the intended purpose. For example, an aliphatic monocarboxylic acid, an alicyclic monocarboxylic acid, an aliphatic dicarboxylic acid and the like can be selected. Examples include salt.
The aliphatic monocarboxylic acid is not particularly limited and may be appropriately selected depending on the intended purpose. For example, short-chain fatty acids having 2 or more and 7 or less carbon atoms such as acetic acid, butyric acid and hexanoic acid, octanoic acid, etc. Medium-chain fatty acids with 8 to 11 carbon atoms such as decanoic acid, long-chain fatty acids with 12 or more carbon atoms such as lauric acid, myristic acid, stearic acid, isostearic acid, and oleic acid, glycolic acid, lactic acid, 3-hydroxybutyric acid, Examples thereof include hydroxymonocarboxylic acids such as mandelic acid, monocarboxylic acids substituted with alkoxy groups such as methoxyacetic acid, and ketomonocarboxylic acids such as levulinic acid.
The alicyclic monocarboxylic acid is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include an alicyclic monocarboxylic acid having 6 or more and 8 or less carbon atoms such as cyclohexanecarboxylic acid. Be done.
The aliphatic dicarboxylic acid is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include sebacic acid, adipic acid, malic acid, maleic acid and fumaric acid.
　好ましいカルボン酸としては、炭素数１２以上の長鎖脂肪酸、ヒドロキシモノカルボン酸を挙げることができ、例えば、ミリスチン酸、ステアリン酸、イソステアリン酸、ラウリン酸、オレイン酸などが挙げられる。より好ましくはラウリン酸、又はオレイン酸である。
　前記カルボン酸の塩としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩、カルシウム塩などのアルカリ土類金属塩や、アミン塩が挙げられるが、入手のしやすさ、及び経皮吸収性の向上効果の観点から、ナトリウム塩が好ましい。 Preferred carboxylic acids include long-chain fatty acids having 12 or more carbon atoms and hydroxymonocarboxylic acids, and examples thereof include myristic acid, stearic acid, isostearic acid, lauric acid, and oleic acid. More preferably, it is lauric acid or oleic acid.
The salt of the carboxylic acid is not particularly limited and may be appropriately selected depending on the intended purpose. For example, an alkali metal salt such as a sodium salt or a potassium salt, an alkaline earth metal salt such as a calcium salt, or an amine salt. However, a sodium salt is preferable from the viewpoint of easy availability and an effect of improving transdermal absorbability.
　（ｈ７）ラクトン
　前記ラクトンとしては、特に制限はなく、目的に応じて適宜選択することができ、例えば、アスコルビン酸、イソアスコルビン酸等の５員環ラクトンなどが挙げられる。
　本発明の貼付剤においては、薬剤の安定性向上効果、又は経皮吸収性向上効果を考慮すると、カルボン酸塩又はラクトンとしては、オレイン酸ナトリウム、乳酸ナトリウム、アスコルビン酸、又はイソアスコルビン酸が好ましい。 (H7) Lactone The lactone is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include 5-membered ring lactones such as ascorbic acid and isoascorbic acid.
In the patch of the present invention, the carboxylate or lactone is preferably sodium oleate, sodium lactate, ascorbic acid, or isoascorbic acid in consideration of the effect of improving the stability of the drug or the effect of improving transdermal absorbability. ..
　本発明の貼付剤にカルボン酸塩又はラクトンを含有させる場合の粘着剤層における含有量としては、特に制限はなく、目的に応じて適宜選択することができるが、薬物１モルに対し、好ましくは０．１モル以上５モル以下、さらに好ましくは０．２モル以上３モル以下である。薬物１モルに対する添加量が０．１モルより少ない場合には、十分な経皮吸収性向上効果が得られないことがあり、薬物１モルに対する添加量が５モルより多い場合には、粘着特性等の製剤物性が悪化することがある。 When the patch of the present invention contains a carboxylate or a lactone, the content in the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably selected with respect to 1 mol of the drug. It is 0.1 mol or more and 5 mol or less, more preferably 0.2 mol or more and 3 mol or less. When the amount added to 1 mol of the drug is less than 0.1 mol, a sufficient effect of improving transdermal absorbability may not be obtained, and when the amount added to 1 mol of the drug is more than 5 mol, the adhesive property The physical characteristics of the drug may deteriorate.
　（ｈ８）界面活性剤
　前記界面活性剤としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、ポリオキシエチレンモノラウレート等のポリオキシエチレン脂肪酸エステル、ポリオキシエチレンソルビットテトラオレエート等のポリオキシエチレンソルビット脂肪酸エステル、ポリオキシエチレンソルビタンモノオレエート、ポリオキシエチレンソルビタンモノラウレート、ポリオキシエチレンソルビタンモノパルミテート等のポリオキシエチレンソルビタン脂肪酸エステル、ソルビタンモノラウレート、ソルビタンモノオレエート、ソルビタンセスキオレエート、ソルビタントリオレエート等のソルビタン脂肪酸エステル、グリセリンモノオレエート、ポリオキシエチレンヒマシ油誘導体、ポリオキシエチレン硬化ヒマシ油等のグリセリン脂肪酸エステル、ポリオキシエチレンラウリルエーテル、ポリオキシエチレンオレイルエーテル等のポリオキシエチレン高級脂肪族アルコールエーテル、ポリオキシエチレンノニルフェニルエーテル等のポリオキシエチレンアルキルフェニルエーテル、ポリオキシエチレンラウリルアミン、ポリオキシエチレンオレイルアミン等のポリオキシエチレンアルキルアミノエーテル、プルロニック（登録商標）Ｌ－３１、プルロニック（登録商標）Ｌ－４４等のポリオキシエチレンポリオキシプロピレン共重合体などの非イオン性界面活性剤、ラウリル硫酸ナトリウム等のアルキル硫酸ナトリウム類などの陰イオン性界面活性剤、アルキルトリメチルアンモニウム塩、アルキルジメチルアンモニウム塩等の陽イオン性界面活性剤、アルキルジメチルアミンオキシド、アルキルカルボキシベタイン等の両性界面活性剤などが挙げられ、これらより１種又は２種以上を選択して用いることができる。 (H8) Surfactant The surfactant is not particularly limited and may be appropriately selected depending on the intended purpose. For example, a polyoxyethylene fatty acid ester such as polyoxyethylene monolaurate, or a polyoxyethylene sorbit tetra. Polyoxyethylene sorbitan fatty acid ester such as oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan monopalmitate, sorbitan monolaurate, sorbitan mono Sorbitane fatty acid esters such as oleate, sorbitan sesquioleate, sorbitan trioleate, glycerin monooleate, polyoxyethylene castor oil derivatives, glycerin fatty acid esters such as polyoxyethylene hydrogenated castor oil, polyoxyethylene lauryl ether, polyoxyethylene Polyoxyethylene higher aliphatic alcohol ethers such as oleyl ether, polyoxyethylene alkylphenyl ethers such as polyoxyethylene nonylphenyl ether, polyoxyethylene alkylamino ethers such as polyoxyethylene laurylamine and polyoxyethylene oleylamine, and pururonic (registered). Nonionic surfactants such as polyoxyethylene polyoxypropylene copolymers such as L-31 and Pluronic® L-44, and anionic surfactants such as sodium alkyl sulfates such as sodium lauryl sulfate. Agents, cationic surfactants such as alkyltrimethylammonium salt and alkyldimethylammonium salt, amphoteric surfactants such as alkyldimethylamine oxide and alkylcarboxybetaine, etc., and one or more selected from these. Can be used.
　前記界面活性剤のうち、経皮吸収性を高める上で、常温で液状の非イオン性界面活性剤が好ましく、常温で液状のポリオキシエチレン高級脂肪族アルコールエーテルやソルビタン脂肪酸エステルがより好ましく、ポリオキシエチレンラウリルエーテルやソルビタンモノラウレートが特に好ましい。
　本発明の貼付剤において、界面活性剤を含有させる場合の粘着剤層中における含有量としては、特に制限はなく、目的に応じて適宜選択することができるが、好ましくは０．０１質量％以上１０質量％以下、より好ましくは０．１質量％以上５質量％以下である。 Among the above-mentioned surfactants, nonionic surfactants that are liquid at room temperature are preferable, and polyoxyethylene higher aliphatic alcohol ethers and sorbitan fatty acid esters that are liquid at room temperature are more preferable, and poly Oxyethylene lauryl ether and sorbitan monolaurate are particularly preferred.
In the patch of the present invention, the content in the pressure-sensitive adhesive layer when the surfactant is contained is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 0.01% by mass or more. It is 10% by mass or less, more preferably 0.1% by mass or more and 5% by mass or less.
　（ｈ９）充填剤
　前記粘着剤層の柔軟性を制御するために充填剤を含有させることができる。
　前記充填剤としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、無水ケイ酸、軽質無水ケイ酸、含水ケイ酸等のケイ素化合物、エチルセルロース、メチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース等のセルロース誘導体、ポリビニルアルコール等の水溶性高分子、乾燥水酸化アルミニウムゲル、含水ケイ酸アルミニウム等のアルミニウム化合物、カオリン、酸化チタンなどが挙げられる。前記充填剤は、単独でも２種以上混合して使用してもよい。
　前記充填剤の含有量としては、特に制限はなく、目的に応じて適宜選択することができ、高い皮膚透過性及び貼付剤として十分な凝集力、粘着力が維持できる範囲で含有させることができる。中でも好ましくは、粘着剤成分全量に対して１０質量％以下であり、さらに好ましくは５質量％以下であり、最も好ましくは２質量％以下である。 (H9) Filler A filler can be contained to control the flexibility of the pressure-sensitive adhesive layer.
The filler is not particularly limited and may be appropriately selected depending on the intended purpose. For example, silicon compounds such as silicic acid anhydride, light silicic acid anhydride and hydrous silicic acid, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose and hydroxy Examples thereof include cellulose derivatives such as propylmethyl cellulose, water-soluble polymers such as polyvinyl alcohol, dry aluminum hydroxide gel, aluminum compounds such as hydrous aluminum silicate, kaolin and titanium oxide. The filler may be used alone or in combination of two or more.
The content of the filler is not particularly limited and can be appropriately selected depending on the intended purpose, and can be contained within a range in which high skin permeability and sufficient cohesive force and adhesive force can be maintained as a patch. .. Above all, it is preferably 10% by mass or less, more preferably 5% by mass or less, and most preferably 2% by mass or less with respect to the total amount of the pressure-sensitive adhesive component.
　（ｈ１０）結晶析出抑制剤
　前記粘着剤層中で薬物の結晶析出を抑制するために結晶析出抑制剤を含有させることができる。
　前記結晶析出抑制剤としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、ポリビニルピロリドン、酢酸ビニル－ビニルピロリドン共重合体、ポリビニルカプロラクタム－ポリビニル酢酸－ポリエチレングルコールグラフトコポリマー、アミノアルキルメタクリレートコポリマー、メタクリル酸コポリマー、アンモニオアルキルメタクリレートコポリマーなどが挙げられる。前記結晶析出抑制剤は、単独でも２種以上混合して使用してもよい。 (H10) Crystal Deposition Inhibitor An agent for suppressing crystal precipitation can be contained in the pressure-sensitive adhesive layer in order to suppress crystal precipitation of a drug.
The crystal precipitation inhibitor is not particularly limited and may be appropriately selected depending on the intended purpose. For example, polyvinylpyrrolidone, vinyl acetate-vinylpyrrolidone copolymer, polyvinylcaprolactam-polyvinylacetic acid-polyethylene glucol graft copolymer, etc. Aminoalkyl methacrylate copolymers, methacrylic acid copolymers, ammonioalkyl methacrylate copolymers and the like can be mentioned. The crystal precipitation inhibitor may be used alone or in combination of two or more.
　前記結晶析出抑制の含有量としては、特に制限はなく、目的に応じて適宜選択することができ、貼付剤として粘着力が維持される範囲で含有させることができる。中でも好ましくは粘着剤成分全量に対して０．０１質量％以上１０質量％以下であり、より好ましくは０．１質量％以上５質量％以下である。 The content of the crystal precipitation suppression is not particularly limited and can be appropriately selected depending on the purpose, and can be contained as a patch within a range in which the adhesive strength is maintained. Above all, it is preferably 0.01% by mass or more and 10% by mass or less, and more preferably 0.1% by mass or more and 5% by mass or less with respect to the total amount of the pressure-sensitive adhesive component.
　（ｉ）粘着付与剤
　前記貼付剤は、前記粘着剤層の粘着力を高める観点から、粘着付与剤を含んでいてもよい。
　本発明において、「粘着付与剤」とは、通常貼付剤の分野で汎用される粘着付与剤であり、特に制限はなく、目的に応じて適宜選択することができ、例えば、ロジン系樹脂、ポリテルペン系樹脂、クマロン－インデン樹脂、石油系樹脂、テルペン樹脂、テルペン－フェノール樹脂、脂環族飽和炭化水素樹脂などが挙げられる。 (I) Adhesive-imparting agent The patch may contain a tackifier from the viewpoint of enhancing the adhesive strength of the pressure-sensitive adhesive layer.
In the present invention, the "tackiness-imparting agent" is a tackifier that is generally used in the field of patches, and is not particularly limited and may be appropriately selected depending on the intended purpose. For example, a rosin-based resin or a polyterpene. Examples thereof include based resins, kumaron-inden resins, petroleum resins, terpene resins, terpene-phenol resins, and alicyclic saturated hydrocarbon resins.
　十分な薬効を得るために必要な粘着力を実現するために、前記粘着付与剤を添加してもよいが、粘着付与剤を大量に添加すると薬物の放出性が低下したり、皮膚刺激性が増大することから、粘着付与剤の含量は粘着剤成分全量に対して５０質量％以下であることが好ましく、より好ましくは３０質量％以下、さらに好ましくは２０質量％以下、よりさらに好ましくは１０質量％以下であり、特に好ましくは５重量％以下であり、粘着付与剤を含まないのが最も好ましい。 The tackifier may be added in order to achieve the adhesive strength required to obtain a sufficient medicinal effect, but if a large amount of the tackifier is added, the release property of the drug is lowered or the skin is irritating. Since it increases, the content of the tackifier is preferably 50% by mass or less, more preferably 30% by mass or less, still more preferably 20% by mass or less, still more preferably 10% by mass, based on the total amount of the pressure-sensitive adhesive component. % Or less, particularly preferably 5% by mass or less, and most preferably no tackifier.
　＜その他の要素＞
　前記貼付剤は、当該分野において一般的な剥離ライナーを備えることもできる。つまり、本発明の貼付剤は、支持体、粘着剤層、及び剥離ライナーがこの順で積層されたものであってもよい。
　前記剥離ライナーとしては、特に制限はなく、目的に応じて適宜選択することができ、例えば、グラシン紙、ポリエチレン、ポリプロピレン等のポリオレフィン、ポリエチレンテレフタレート等のポリエステル、ポリスチレンなどの樹脂フィルム；アルミフィルム；発泡ポリエチレンフィルム又は発泡ポリプロピレンフィルム；前記のうち２種以上の積層物などを用いることができる。また、前記剥離ライナーは、シリコーン加工、フッ素樹脂加工、エンボス加工、親水性加工、疎水性加工などを施したものなどを用いることもできる。 <Other factors>
The patch may also include a release liner that is common in the art. That is, the patch of the present invention may be one in which a support, an adhesive layer, and a release liner are laminated in this order.
The release liner is not particularly limited and may be appropriately selected depending on the intended purpose. For example, glassin paper, polyolefin such as polyethylene and polypropylene, polyester such as polyethylene terephthalate, resin film such as polystyrene; aluminum film; foaming. Polystyrene film or expanded polypropylene film; two or more kinds of laminates among the above can be used. Further, as the release liner, one that has been subjected to silicone processing, fluororesin processing, embossing processing, hydrophilic processing, hydrophobic processing, or the like can also be used.
　前記剥離ライナーの厚さとしては、特に制限はなく、目的に応じて適宜選択することができるが、１０μｍ以上２００μｍ以下が好ましく、１５μｍ以上１５０μｍ以下がより好ましい。 The thickness of the release liner is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 10 μm or more and 200 μm or less, and more preferably 15 μm or more and 150 μm or less.
　（貼付剤の製造方法）
　前記貼付剤の製造方法は、前記貼付剤を製造する方法であって、前記支持体と前記粘着剤層を積層する工程を含み、さらにその他の工程を有することができる。
　前記粘着剤層、及び支持体は、上述のとおりである。 (Manufacturing method of patch)
The method for producing the patch is a method for producing the patch, which may include a step of laminating the support and the pressure-sensitive adhesive layer, and may further include other steps.
The pressure-sensitive adhesive layer and the support are as described above.
　＜支持体と粘着剤層の積層工程＞
　前記支持体と粘着剤層の積層工程としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、前記粘着剤層に前記支持体を圧着して、積層する方法などが挙げられる。 <Laminating process of support and adhesive layer>
The step of laminating the support and the pressure-sensitive adhesive layer is not particularly limited and may be appropriately selected depending on the intended purpose. For example, a method of crimping the support to the pressure-sensitive adhesive layer and laminating the support can be mentioned. Be done.
　＜その他の工程＞
　前記その他の工程としては、特に制限はなく、目的に応じて適宜選択することができるが、例えば、剥離ライナーの積層工程などが挙げられる。
　前記剥離ライナーは、上述のとおりである。 <Other processes>
The other steps are not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a step of laminating a release liner.
The release liner is as described above.
　－剥離ライナーの積層工程－
　前記剥離ライナーの積層工程としては、特に制限はなく、目的に応じて適宜選択することができるが、例えば、前記支持体と粘着剤層の積層工程前に、前記粘着剤層形成用の塗工液を剥離ライナー上に展延し、塗工液中の溶媒を乾燥して剥離ライナーの表面に粘着剤層を積層する工程（展延・乾燥工程）、又は、前記支持体と粘着剤層の積層工程後に、前記粘着剤層に前記剥離ライナーを圧着して、積層する工程などが挙げられる。 -Laminating process of release liner-
The laminating step of the release liner is not particularly limited and may be appropriately selected depending on the intended purpose. For example, before the laminating step of the support and the pressure-sensitive adhesive layer, the coating for forming the pressure-sensitive adhesive layer is performed. A step of spreading the liquid on a release liner, drying the solvent in the coating liquid, and laminating an adhesive layer on the surface of the release liner (spreading / drying step), or a step of spreading and drying the support and the pressure-sensitive adhesive layer. After the laminating step, a step of crimping the release liner to the pressure-sensitive adhesive layer and laminating can be mentioned.
　－－展延・乾燥工程－－
　前記展延・乾燥工程としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、（ａ）ブロナンセリン又はその塩、（ｂ）熱可塑性エラストマー、（ｃ）不揮発性炭化水素油、をそれぞれ、トルエン等の溶媒に溶解又は分散させて、粘着剤層形成用の塗工液を調製し、得られた塗工液を剥離ライナーに塗布し、次いで乾燥させる方法などが挙げられる。 －－Expanding / drying process －－
The spreading / drying step is not particularly limited and may be appropriately selected depending on the intended purpose. For example, (a) bronanceline or a salt thereof, (b) a thermoplastic elastomer, and (c) a non-volatile hydrocarbon oil. , Each of the above is dissolved or dispersed in a solvent such as toluene to prepare a coating liquid for forming an adhesive layer, and the obtained coating liquid is applied to a release liner and then dried.
　前記塗布としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、ロールコーター、ダイコーター、グラビアロールコーター、リバースロールコーター、キスロールコーター、ディップロールコーター、バーコーター、ナイフコーター、スプレーコーター等の慣用のコーターなどを用いて行うことができる。 The coating is not particularly limited and may be appropriately selected depending on the intended purpose. For example, roll coater, die coater, gravure roll coater, reverse roll coater, kiss roll coater, dip roll coater, bar coater, knife coater. , A conventional coater such as a spray coater can be used.
　前記塗工液に使用する溶媒としては、特に制限はなく、目的に応じて適宜選択することができるが、前記（ａ）、前記（ｂ）、前記（ｃ）成分、を、均一に溶解又は分散できるものが好ましく、例えば、トルエン等の芳香族系炭化水素、シクロヘキサン、メチルシクロヘキサン等の脂環族系炭化水素、ヘキサン、ヘプタン等の脂肪族系炭化水素、テトラヒドロフラン、ジエチルエーテル、ｔ－ブチルメチルエーテル等のエーテル類、アセトン、メチルエチルケトン、メチルイソブチルケトン等のケトン類、エタノール、プロパノール、ブタノール等のアルコール類、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチル、酢酸イソブチル等の酢酸エステル類などが挙げられる。
　これらの溶媒は、単独、もしくは２種以上を組み合わせて使用することができる。粘着剤層を構成する各成分の溶解性が良好なことから、トルエン等の芳香族系炭化水素、シクロヘキサン、メチルシクロヘキサン等の脂環族系炭化水素、ヘキサン、ヘプタン等の脂肪族系炭化水素を単独もしくは混合して使用すること、もしくは、トルエン等の芳香族系炭化水素、ヘキサン、ヘプタン等の脂肪族系炭化水素と、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチル、酢酸イソブチル等の酢酸エステル類を組み合わせて使用することが好ましい。 The solvent used in the coating liquid is not particularly limited and may be appropriately selected depending on the intended purpose. However, the components (a), (b) and (c) may be uniformly dissolved or dissolved. Those that can be dispersed are preferable, for example, aromatic hydrocarbons such as toluene, alicyclic hydrocarbons such as cyclohexane and methylcyclohexane, aliphatic hydrocarbons such as hexane and heptane, tetrahydrofuran, diethyl ether and t-butyl methyl. Examples include ethers such as ethers, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, alcohols such as ethanol, propanol and butanol, and acetate esters such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate. Be done.
These solvents can be used alone or in combination of two or more. Since each component constituting the pressure-sensitive adhesive layer has good solubility, aromatic hydrocarbons such as toluene, alicyclic hydrocarbons such as cyclohexane and methylcyclohexane, and aliphatic hydrocarbons such as hexane and heptane can be used. It can be used alone or in combination, or it can be used alone or in combination with aromatic hydrocarbons such as toluene, aliphatic hydrocarbons such as hexane and heptane, and acetates such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate. It is preferable to use them in combination.
　前記乾燥としては、特に制限はなく、目的に応じて適宜選択することができるが、加熱下、例えば、４０℃以上１５０℃以下程度の温度で行うことが好ましく、使用する溶媒や使用量によって、乾燥温度や乾燥時間、乾燥方式を調整すればよい。
　乾燥後の粘着剤層は、必要とする皮膚粘着性や、経皮吸収性能により単位面積当たりの重量を調整すればよい。皮膚粘着性を得つつ、製造可能な範囲としては、特に制限はなく、目的に応じて適宜選択することができるが、乾燥後の粘着剤層が、好ましくは１０ｇ／ｍ２以上１，０００ｇ／ｍ２以下であり、より好ましくは２０ｇ／ｍ２以上８００ｇ／ｍ２以下、さらに好ましくは３０ｇ／ｍ２以上６００ｇ／ｍ２以下である。 The drying is not particularly limited and may be appropriately selected depending on the intended purpose, but it is preferably carried out under heating, for example, at a temperature of about 40 ° C. or higher and 150 ° C. or lower, depending on the solvent used and the amount used. The drying temperature, drying time, and drying method may be adjusted.
The weight per unit area of the adhesive layer after drying may be adjusted according to the required skin adhesiveness and transdermal absorption performance. The range that can be produced while obtaining skin adhesiveness is not particularly limited and may be appropriately selected depending on the intended purpose, but the pressure-sensitive adhesive layer after drying is preferably 10 g / m 2 or more and 1,000 g / g. It is m 2 or less, more preferably 20 g / m 2 or more and 800 g / m 2 or less, and further preferably 30 g / m 2 or more and 600 g / m 2 or less.
　以下、本発明の実施例を説明するが、本発明は、これらの実施例に何ら限定されるものではない。 Hereinafter, examples of the present invention will be described, but the present invention is not limited to these examples.
＜実施例１：貼付剤の製造＞
　表１に示す処方に従って、粘着剤層を構成する各成分を秤取した。なお、表１の各成分の数値は、質量％である。先ず、スチレン系ブロック共重合体をトルエンに溶解した後、ブロナンセリン、流動パラフィンを加えて混合撹拌し、粘着剤層形成用の塗工液を調製した。
　上記塗工液を、剥離ライナーであるシリコーン処理したポリエチレンテレフタレート（ＰＥＴ）製フィルムに塗布した。５０℃のオーブンにて６０分間乾燥後、該粘着剤層の表面にＰＥＴ製フィルム（支持体）をラミネートし、１５ｃｍ×３０ｃｍの大きさに裁断して貼付剤を得た。 <Example 1: Production of patch>
Each component constituting the pressure-sensitive adhesive layer was weighed according to the formulation shown in Table 1. The numerical value of each component in Table 1 is mass%. First, a styrene-based block copolymer was dissolved in toluene, bronancerin and liquid paraffin were added, and the mixture was mixed and stirred to prepare a coating liquid for forming an adhesive layer.
The above coating liquid was applied to a silicone-treated polyethylene terephthalate (PET) film which is a release liner. After drying in an oven at 50 ° C. for 60 minutes, a PET film (support) was laminated on the surface of the pressure-sensitive adhesive layer and cut into a size of 15 cm × 30 cm to obtain a patch.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
＜試験例１：皮膚透過性の評価＞
　除毛した雄性ヘアレスラット（ＨＷＹ／Ｓｌｃ、ＳＰＦ、５週齢）の腹部摘出皮膚を直径２．５ｃｍの円形に打ち抜いた。実施例で作製した貼付剤を直径１．３ｃｍの円形に打ち抜き、ラット皮膚上に貼付した後、垂直型拡散セルにセットし、経皮吸収試験自動サンプリング装置（コスメディ社製）にて試験を開始した。レセプター液として緩衝液を用い、液温３２℃で試験を行った。試験開始から２４時間後にレセプター液の一部をサンプリングし、レセプター液中のラット皮膚を透過してきた薬物量をＨＰＬＣにより定量した。ブロナンセリン含有の対照製剤としては、ロナセン（登録商標）テープ（既存製剤）を使用した。測定は各貼付剤につき３～６例ずつ行い、測定値の平均値を算出し、ロナセン（登録商標）テープの値に対して何倍になるか、で薬物皮膚透過性を評価した。結果を表１に示す。 <Test Example 1: Evaluation of skin permeability>
The abdominal excised skin of a depilated male hairless rat (HWY / Slc, SPF, 5 weeks old) was punched into a circle with a diameter of 2.5 cm. The patch prepared in the example was punched into a circle with a diameter of 1.3 cm, attached onto rat skin, set in a vertical diffusion cell, and tested with a percutaneous absorption test automatic sampling device (manufactured by Cosmedy). It started. A buffer solution was used as the receptor solution, and the test was conducted at a solution temperature of 32 ° C. Twenty-four hours after the start of the test, a part of the receptor solution was sampled, and the amount of drug that had permeated the rat skin in the receptor solution was quantified by HPLC. As the control preparation containing blonanserin, Lonasen® tape (existing preparation) was used. The measurement was performed in 3 to 6 cases for each patch, the average value of the measured values was calculated, and the drug skin permeability was evaluated by how many times the value of the Lonasen® tape was used. The results are shown in Table 1.
＜試験例２：凝集力の評価＞
　以下の基準で、貼付剤の粘着剤層の凝集力をフィンガータック（指触試験）にて４段階で評価した。結果を表１に示す。
　３：　糊残りは全く認められなかった。
　２：　糊残りはほぼ認められず、問題のない範囲であった。
　１：　やや凝集力が不足しているが、問題のない範囲であった。
　０：　糊残り、型崩れ等が認められ、凝集力不足が顕著であった。 <Test Example 2: Evaluation of cohesive force>
Based on the following criteria, the cohesive force of the pressure-sensitive adhesive layer of the patch was evaluated on a 4-point scale by finger tack (touch test). The results are shown in Table 1.
3: No adhesive residue was observed.
2: Almost no adhesive residue was observed, and there was no problem.
1: The cohesive force was slightly insufficient, but it was within the range where there was no problem.
0: Glue residue, shape loss, etc. were observed, and insufficient cohesive force was remarkable.
＜試験例３：粘着性の評価＞
　以下の基準で、貼付剤の粘着剤層の粘着性をフィンガータック（指触試験）にて４段階で評価した。結果を表１に示す。
　３：　ロナセン（登録商標）テープと同程度の粘着性を示した。
　２：　ロナセン（登録商標）テープよりもやや低い粘着性であった。
　１：　粘着性が弱く、指が容易に剥がれる程度であった。
　０：　全く付着せず、剥がれが顕著であった。 <Test Example 3: Evaluation of Adhesiveness>
Based on the following criteria, the adhesiveness of the adhesive layer of the patch was evaluated on a 4-point scale by finger tack (touch test). The results are shown in Table 1.
3: The adhesiveness was similar to that of Blonanserin (registered trademark) tape.
2: The adhesiveness was slightly lower than that of Blonanserin (registered trademark) tape.
1: The adhesiveness was weak, and the finger was easily peeled off.
0: No adhesion at all, and peeling was remarkable.
＜実施例２：貼付剤の製造＞
　粘着剤層を構成する各成分を表１に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表１に示す。 <Example 2: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 1.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.
＜実施例３：貼付剤の製造＞
　粘着剤層を構成する各成分を表１に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表１に示す。 <Example 3: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 1.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.
＜実施例４：貼付剤の製造＞
　粘着剤層を構成する各成分を表１に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表１に示す。 <Example 4: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 1.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.
＜実施例５：貼付剤の製造＞
　粘着剤層を構成する各成分を表１に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表１に示す。 <Example 5: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 1.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.
＜実施例６：貼付剤の製造＞
　粘着剤層を構成する各成分を表１に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表１に示す。 <Example 6: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 1.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.
＜実施例７：貼付剤の製造＞
　粘着剤層を構成する各成分を表１に示す処方に代えた以外は、比較例２と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表１に示す。 <Example 7: Production of patch>
A patch was produced in the same manner as in Comparative Example 2 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 1.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.
＜実施例８：貼付剤の製造＞
　粘着剤層を構成する各成分を表１に示す処方に代え、スチレン系ブロック共重合体及びポリイソブチレンをトルエンに溶解した後、ブロナンセリン、流動パラフィン及び各添加剤を加えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表１に示す。 <Example 8: Production of patch>
Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 1, a styrene-based block copolymer and polyisobutylene were dissolved in toluene, and then bronanceline, liquid paraffin and each additive were added. The patch was manufactured in the same manner as in the above.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.
＜比較例１：貼付剤の製造＞
　粘着剤層を構成する各成分を表１に示す処方に代え、アクリル系粘着剤及び酢酸エチルを混合した後、ブロナンセリンを加えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表１に示す。 <Comparative Example 1: Manufacture of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 1, an acrylic pressure-sensitive adhesive and ethyl acetate were mixed, and then blonanserin was added.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.
＜比較例２：貼付剤の製造＞
　粘着剤層を構成する各成分を表１に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表１に示す。 <Comparative Example 2: Manufacture of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 1.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.
＜比較例３：貼付剤の製造＞
　粘着剤層を構成する各成分を表１に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表１に示す。 <Comparative Example 3: Manufacture of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 1.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.
＜比較例４：貼付剤の製造＞
　粘着剤層を構成する各成分を表１に示す処方に代え、乾燥後の粘着剤層の厚さが約６０μｍとなるように塗布した以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表１に示す。 <Comparative Example 4: Manufacture of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was applied in place of the formulation shown in Table 1 so that the thickness of the pressure-sensitive adhesive layer after drying was about 60 μm. ..
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 1.
　表１に示す結果の通り、スチレン・イソプレン・スチレンブロック共重合体を粘着基剤ポリマーとして用いた実施例１は、特許文献１の製剤技術を用いた、アクリル系粘着基剤の比較例１よりも高い透過性を示すことが判明した。また、特許文献２の製剤技術を用いた比較例４と比較して、乳酸を除いた実施例７は高い透過性を示し、乳酸を多量添加することで、皮膚透過性が低下する傾向が見られた。
　実施例１に添加剤を加えた実施例２及び８の貼付剤は既存製剤よりも３倍以上高い皮膚透過性を示した。一方、比較例２から４は、１．５モル当量より多い乳酸を添加しているため、実施例２の貼付剤よりも皮膚透過性が低くなり、さらに乳酸添加量に依存して皮膚透過性が低下する傾向がみられたと共に、製造後保存している製剤の粘着剤層中に結晶が析出してしまう現象が見られた。 As shown in the results shown in Table 1, Example 1 using the styrene / isoprene / styrene block copolymer as the pressure-sensitive adhesive base polymer is based on Comparative Example 1 of an acrylic pressure-sensitive adhesive base using the formulation technology of Patent Document 1. Was also found to show high permeability. Further, as compared with Comparative Example 4 using the formulation technique of Patent Document 2, Example 7 excluding lactic acid showed high permeability, and the addition of a large amount of lactic acid tended to reduce the skin permeability. Was done.
The patches of Examples 2 and 8 to which the additive was added to Example 1 showed skin permeability that was more than 3 times higher than that of the existing preparation. On the other hand, in Comparative Examples 2 to 4, since more than 1.5 molar equivalents of lactic acid were added, the skin permeability was lower than that of the patch of Example 2, and the skin permeability was further dependent on the amount of lactic acid added. There was a tendency for lactic acid to decrease, and a phenomenon was observed in which crystals were precipitated in the pressure-sensitive adhesive layer of the formulation stored after production.
＜実施例９：貼付剤の製造＞
　粘着剤層を構成する各成分を表２に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表２に示す。 <Example 9: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 2.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
＜実施例１０：貼付剤の製造＞
　粘着剤層を構成する各成分を表２に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表２に示す。 <Example 10: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 2.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.
＜実施例１１：貼付剤の製造＞
　粘着剤層を構成する各成分を表２に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表２に示す。 <Example 11: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 2.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.
＜実施例１２：貼付剤の製造＞
　粘着剤層を構成する各成分を表２に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表２に示す。 <Example 12: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 2.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.
＜実施例１３：貼付剤の製造＞
　粘着剤層を構成する各成分を表２に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表２に示す。 <Example 13: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 2.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.
＜実施例１４：貼付剤の製造＞
　粘着剤層を構成する各成分を表２に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表２に示す。 <Example 14: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 2.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.
＜実施例１５：貼付剤の製造＞
　粘着剤層を構成する各成分を表２に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表２に示す。 <Example 15: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 2.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.
＜実施例１６：貼付剤の製造＞
　粘着剤層を構成する各成分を表２に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表２に示す。 <Example 16: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 2.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 2.
　表２の結果に示す通り、実施例１と実施例９から１２よりアジピン酸ジイソプロピルが高い吸収促進効果を示すことがわかった。また、実施例１３から１６の貼付剤は既存製剤よりも６倍以上高い皮膚透過性を示し、α－モノイソステアリルグリセリルエーテルが高い吸収促進効果を示すことがわかった。 As shown in the results of Table 2, it was found that diisopropyl adipate showed a higher absorption promoting effect than Examples 1 and 9 to 12. It was also found that the patches of Examples 13 to 16 showed skin permeability 6 times or more higher than those of the existing preparations, and that α-monoisostearyl glyceryl ether showed a high absorption promoting effect.
＜実施例１７：貼付剤の製造＞
　粘着剤層を構成する各成分を表３に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表３に示す。 <Example 17: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 3.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 3.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
＜実施例１８：貼付剤の製造＞
　粘着剤層を構成する各成分を表３に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表３に示す。 <Example 18: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 3.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 3.
＜実施例１９：貼付剤の製造＞
　粘着剤層を構成する各成分を表３に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表３に示す。 <Example 19: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 3.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 3.
　表３に示す結果の通り、各種脂肪族ジカルボン酸エステルを含む実施例１７から１９の貼付剤は、いずれも既存製剤よりも４倍以上高い皮膚透過性を示した。 As shown in the results shown in Table 3, the patches of Examples 17 to 19 containing various aliphatic dicarboxylic acid esters all showed skin permeability that was four times or more higher than that of the existing preparations.
＜実施例２０：貼付剤の製造＞
　粘着剤層を構成する各成分を表４に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表４に示す。 <Example 20: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 4.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 4.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
＜実施例２１：貼付剤の製造＞
　粘着剤層を構成する各成分を表４に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表４に示す。 <Example 21: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 4.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 4.
＜実施例２２：貼付剤の製造＞
　粘着剤層を構成する各成分を表４に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表４に示す。 <Example 22: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 4.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 4.
　表４に示す結果の通り、乳酸を除く液状の有機酸を添加した実施例２０から２２は、乳酸を添加した実施例５と同等の透過性を示したと共に、ブロナンセリンの結晶析出を抑制する現象が見られた。 As shown in the results shown in Table 4, Examples 20 to 22 to which a liquid organic acid excluding lactic acid was added showed the same permeability as Example 5 to which lactic acid was added, and a phenomenon of suppressing crystal precipitation of blonanserin. It was observed.
＜実施例２３：貼付剤の製造＞
　粘着剤層を構成する各成分を表５に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表５に示す。 <Example 23: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 5.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
＜実施例２４：貼付剤の製造＞
　粘着剤層を構成する各成分を表５に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表５に示す。 <Example 24: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 5.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.
＜実施例２５：貼付剤の製造＞
　粘着剤層を構成する各成分を表５に示す処方に代えた以外は、実施例１と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表５に示す。 <Example 25: Production of patch>
A patch was produced in the same manner as in Example 1 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 5.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.
＜実施例２６：貼付剤の製造＞
　粘着剤層を構成する各成分を表５に示す処方に代えた以外は、実施例８と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表５に示す。 <Example 26: Production of patch>
A patch was produced in the same manner as in Example 8 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 5.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.
＜実施例２７：貼付剤の製造＞
　粘着剤層を構成する各成分を表５に示す処方に代えた以外は、実施例８と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表５に示す。 <Example 27: Production of patch>
A patch was produced in the same manner as in Example 8 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 5.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.
＜実施例２８：貼付剤の製造＞
　粘着剤層を構成する各成分を表５に示す処方に代えた以外は、実施例８と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表５に示す。 <Example 28: Production of patch>
A patch was produced in the same manner as in Example 8 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 5.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.
＜実施例２９：貼付剤の製造＞
　粘着剤層を構成する各成分を表５に示す処方に代えた以外は、実施例８と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表５に示す。 <Example 29: Production of patch>
A patch was produced in the same manner as in Example 8 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 5.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.
＜実施例３０：貼付剤の製造＞
　粘着剤層を構成する各成分を表５に示す処方に代えた以外は、実施例８と同様にして貼付剤を製造した。
　実施例１と同様にして皮膚透過性、凝集力、及び粘着性を評価した。結果を表５に示す。 <Example 30: Production of patch>
A patch was produced in the same manner as in Example 8 except that each component constituting the pressure-sensitive adhesive layer was replaced with the formulation shown in Table 5.
Skin permeability, cohesive force, and adhesiveness were evaluated in the same manner as in Example 1. The results are shown in Table 5.
　表５に示す結果の通り、脂肪族ジカルボン酸エステル、グリセリンモノエーテル、及び、ポリオキシエチレンラウリルエーテルもしくは乳酸を除く液状の有機酸を含む実施例２４から３０の貼付剤は、いずれも既存製剤よりも４倍以上の高い皮膚透過性を示した。 As shown in the results shown in Table 5, the patches of Examples 24 to 30 containing an aliphatic dicarboxylic acid ester, a glycerin monoether, and a liquid organic acid other than polyoxyethylene lauryl ether or lactic acid were all compared with existing preparations. Also showed 4 times higher skin permeability.
　本発明の態様としては、例えば、以下のものなどが挙げられる。
　＜１＞　支持体と、前記支持体上の粘着剤層と、を有し、前記粘着剤層が、ブロナンセリン又はその塩、熱可塑性エラストマー、乳酸、及び不揮発性炭化水素油を含み、前記粘着剤層における乳酸の量が前記粘着剤層に含まれるブロナンセリンに対し０モル当量超１．５モル当量以下であることを特徴とする、貼付剤である。
　＜２＞　支持体と、前記支持体上の粘着剤層と、を有し、前記粘着剤層が、ブロナンセリン又はその塩、熱可塑性エラストマー、及び不揮発性炭化水素油を含み、乳酸を含まないことを特徴とする、貼付剤である。
　＜３＞　前記熱可塑性エラストマーが、スチレン系ブロック共重合体を含む、前記＜１＞又は＜２＞に記載の貼付剤である。
　＜４＞　前記スチレン系ブロック共重合体が、スチレン・イソプレン・スチレンブロック共重合体とスチレン・イソプレンブロック共重合体との混合物である、前記＜３＞に記載の貼付剤である。
　＜５＞　前記粘着剤層が、ポリイソブチレンを含む、前記＜１＞から＜４＞のいずれかに記載の貼付剤である。
　＜６＞　前記粘着剤層が、脂肪族ジカルボン酸エステルを含む、前記＜１＞から＜５＞のいずれかに記載の貼付剤である。
　＜７＞前記粘着剤層が、グリセリンモノエーテルを含む、前記＜１＞から＜６＞のいずれかに記載の貼付剤である。
　＜８＞前期粘着剤層が、乳酸を除く液状の有機酸を含む、前記＜１＞から＜７＞のいずれかに記載の貼付剤である。
　＜９＞　前記＜１＞から＜８＞のいずれかに記載の貼付剤を製造する方法であって、前記支持体と前記粘着剤層を積層する工程を含む貼付剤の製造方法である。 Examples of aspects of the present invention include the following.
<1> The pressure-sensitive adhesive comprises a support and a pressure-sensitive adhesive layer on the support, wherein the pressure-sensitive adhesive layer contains bronanceline or a salt thereof, a thermoplastic elastomer, lactic acid, and a non-volatile hydrocarbon oil. The patch is characterized in that the amount of lactic acid in the layer is more than 0 molar equivalent and 1.5 molar equivalent or less with respect to the bronanceline contained in the pressure-sensitive adhesive layer.
<2> It has a support and a pressure-sensitive adhesive layer on the support, and the pressure-sensitive adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, and a non-volatile hydrocarbon oil, and does not contain lactic acid. It is a patch characterized by.
<3> The patch according to <1> or <2>, wherein the thermoplastic elastomer contains a styrene-based block copolymer.
<4> The patch according to <3>, wherein the styrene-based block copolymer is a mixture of a styrene / isoprene / styrene block copolymer and a styrene / isoprene block copolymer.
<5> The patch according to any one of <1> to <4>, wherein the pressure-sensitive adhesive layer contains polyisobutylene.
<6> The patch according to any one of <1> to <5>, wherein the pressure-sensitive adhesive layer contains an aliphatic dicarboxylic acid ester.
<7> The patch according to any one of <1> to <6>, wherein the pressure-sensitive adhesive layer contains glycerin monoether.
<8> The patch according to any one of <1> to <7> above, wherein the initial pressure-sensitive adhesive layer contains a liquid organic acid other than lactic acid.
<9> The method for producing a patch according to any one of <1> to <8>, which comprises a step of laminating the support and the pressure-sensitive adhesive layer.

Claims (9)

  1. 　支持体と、
    　前記支持体上の粘着剤層と、を有し、
    　前記粘着剤層が、ブロナンセリン又はその塩、熱可塑性エラストマー、乳酸、及び不揮発性炭化水素油を含み、前記粘着剤層における乳酸の量が前記粘着剤層に含まれるブロナンセリンに対し０モル当量超１．５モル当量以下であることを特徴とする、貼付剤。     With the support
    With an adhesive layer on the support,
    The pressure-sensitive adhesive layer contains bronanserin or a salt thereof, a thermoplastic elastomer, lactic acid, and a non-volatile hydrocarbon oil, and the amount of lactic acid in the pressure-sensitive adhesive layer is more than 0 molar equivalent to bronanceline contained in the pressure-sensitive adhesive layer. A patch characterized by being less than or equal to 5.5 molar equivalents.
  2. 　支持体と、
    　前記支持体上の粘着剤層と、を有し、
    　前記粘着剤層が、ブロナンセリン又はその塩、熱可塑性エラストマー、及び不揮発性炭化水素油を含み、乳酸を含まないことを特徴とする、貼付剤。     With the support
    With an adhesive layer on the support,
    A patching agent, wherein the pressure-sensitive adhesive layer contains blonanserin or a salt thereof, a thermoplastic elastomer, and a non-volatile hydrocarbon oil, and does not contain lactic acid.
  3. 　前記熱可塑性エラストマーが、スチレン系ブロック共重合体を含む、請求項１又は２に記載の貼付剤。 The patch according to claim 1 or 2, wherein the thermoplastic elastomer contains a styrene-based block copolymer.
  4. 　前記スチレン系ブロック共重合体が、スチレン・イソプレン・スチレンブロック共重合体とスチレン・イソプレンブロック共重合体との混合物である、請求項３に記載の貼付剤。 The patch according to claim 3, wherein the styrene-based block copolymer is a mixture of a styrene / isoprene / styrene block copolymer and a styrene / isoprene block copolymer.
  5. 　前記粘着剤層が、ポリイソブチレンを含む、請求項１から４のいずれかに記載の貼付剤。 The patch according to any one of claims 1 to 4, wherein the pressure-sensitive adhesive layer contains polyisobutylene.
  6. 　前記粘着剤層が、脂肪族ジカルボン酸エステルを含む、請求項１から５のいずれかに記載の貼付剤。 The patch according to any one of claims 1 to 5, wherein the pressure-sensitive adhesive layer contains an aliphatic dicarboxylic acid ester.
  7. 　前記粘着剤層が、グリセリンモノエーテルを含む、請求項１から６のいずれかに記載の貼付剤。 The patch according to any one of claims 1 to 6, wherein the pressure-sensitive adhesive layer contains glycerin monoether.
  8. 　前記粘着剤層が、乳酸を除く液状の有機酸を含む、請求項１から７のいずれかに記載の貼付剤。 The patch according to any one of claims 1 to 7, wherein the pressure-sensitive adhesive layer contains a liquid organic acid other than lactic acid.
  9. 　請求項１から８のいずれかに記載の貼付剤を製造する方法であって、
    　前記支持体と前記粘着剤層を積層する工程を含む貼付剤の製造方法。     A method for producing a patch according to any one of claims 1 to 8.
    A method for producing a patch, which comprises a step of laminating the support and the pressure-sensitive adhesive layer.
PCT/JP2021/002958 2020-02-05 2021-01-28 Blonanserin-containing patch and method for manufacturing same WO2021157457A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007142295A1 (en) * 2006-06-09 2007-12-13 Dainippon Sumitomo Pharma Co., Ltd. Novel tape preparation
JP5837518B2 (en) * 2011-02-02 2015-12-24 大日本住友製薬株式会社 Patch preparation for transdermal absorption

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007142295A1 (en) * 2006-06-09 2007-12-13 Dainippon Sumitomo Pharma Co., Ltd. Novel tape preparation
JP5837518B2 (en) * 2011-02-02 2015-12-24 大日本住友製薬株式会社 Patch preparation for transdermal absorption

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