WO2010074182A1 - Transdermal preparation - Google Patents

Transdermal preparation Download PDF

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Publication number
WO2010074182A1
WO2010074182A1 PCT/JP2009/071502 JP2009071502W WO2010074182A1 WO 2010074182 A1 WO2010074182 A1 WO 2010074182A1 JP 2009071502 W JP2009071502 W JP 2009071502W WO 2010074182 A1 WO2010074182 A1 WO 2010074182A1
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WO
WIPO (PCT)
Prior art keywords
sensitive adhesive
pressure
mass
support
acrylic
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PCT/JP2009/071502
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French (fr)
Japanese (ja)
Inventor
康慈 川原
徹 古賀
春奈 八巻
亨子 林
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ニチバン株式会社
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Priority to JP2010522120A priority Critical patent/JP4660858B2/en
Publication of WO2010074182A1 publication Critical patent/WO2010074182A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene

Definitions

  • the present invention relates to a novel percutaneous absorption-type preparation, and more particularly to a percutaneous absorption-type preparation excellent in both skin permeability and skin adhesion of a drug.
  • the percutaneous absorption type preparation is attracting attention as a dosage form that can eliminate problems inherent to the oral administration method, that is, a large dose due to the first-pass effect in the liver, and can maintain a stable blood concentration. Particularly in the present age of aging societies, it is attracting attention as a dosage form that facilitates administration of various drugs to patients who have difficulty swallowing.
  • the skin is the largest organ in the human body and is also an important tissue that protects the body from foreign substances such as chemical substances and bacteria from the outside world, drugs and the like are not easily passed through as foreign substances. There are a limited number of drugs that can be provided as absorption-type preparations.
  • the pressure-sensitive adhesive layer In order to improve the percutaneous absorption promotion effect of the drug, it is desirable to increase the content in the pressure-sensitive adhesive layer. However, if added in a large amount, the coagulation force of the pressure-sensitive adhesive is reduced. Occurs. If an acrylic pressure-sensitive adhesive using a cross-linking agent is used as the pressure-sensitive adhesive, the molecular weight can be controlled. Therefore, although a certain level of cohesion can be maintained even when a permeation accelerator is added, a cross-linking agent is generally used. In a rubber-based adhesive or a silicone-based adhesive that is not used, the amount of permeation accelerator used is limited. For this reason, in the case of using such an adhesive, conventionally, it has been necessary to examine the formulation of a reservoir type formulation, etc., rather than increasing the addition amount of the permeation enhancer.
  • the aforementioned acrylic pressure-sensitive adhesive that is, the acrylic copolymer used in the pressure-sensitive adhesive, can control the cohesive force by controlling the molecular weight using a crosslinking agent by using a monomer having a carboxyl group.
  • a product using an adhesive called an organogel to which a large amount of isopropyl myristate as an oil component is added has been put on the market (Flandre Tape S, Toei Aiyo Co., Ltd.).
  • acrylic pressure-sensitive adhesives using a monomer having a carboxyl group eg, acrylic acid
  • a copolymer react with (bond to) the carboxyl group when a basic drug is added. It is known to prevent drug release from.
  • the present invention makes it possible to add a large amount of permeation enhancer without reducing the above-mentioned problems, that is, the cohesive force of the adhesive, improve the bioavailability of the drug, and apply the adhesive to the skin. It is an object of the present invention to provide a percutaneous absorption preparation that satisfies the basic performance required as a percutaneous absorption preparation, such as improving the residue and stickiness of the skin.
  • the present inventors have heretofore been difficult by combining an acrylic pressure-sensitive adhesive obtained by using a monomer or a monomer mixture made of (meth) acrylic acid ester having no carboxyl group in the molecule and silica particles. It was found that a large amount of polyhydric alcohol fatty acid ester can be added to the pressure-sensitive adhesive layer. Based on these findings, the present invention has been completed that provides a percutaneously absorbable preparation that enables sustained drug release and is excellent in both skin permeability and skin adhesion of the drug.
  • the present invention relates to a transdermal preparation having a pressure-sensitive adhesive layer on a support, wherein the support has a moisture permeability of 300 g / m 2 ⁇ 24 hr or less, and forms a pressure-sensitive adhesive layer.
  • the polyhydric alcohol fatty acid ester is preferably composed mainly of propylene glycol monolaurate and contained in a proportion of 20 to 35% by mass with respect to the total mass of the adhesive component.
  • the acrylic pressure-sensitive adhesive is mainly a resin obtained by polymerizing a monomer or a monomer mixture comprising an acrylate ester and / or a methacrylic ester having no carboxyl group and hydroxy group in the molecule.
  • the acrylic pressure-sensitive adhesive is more preferably a copolymer of 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / dodecyl methacrylate.
  • the acrylic pressure-sensitive adhesive is desirably a pressure-sensitive adhesive having an intrinsic viscosity of 1.5 to 2.5, particularly preferably 1.9 to 2.1.
  • the support is preferably a support having a moisture permeability of 50 g / m 2 ⁇ 24 hr or less.
  • the said support body is a support body which has the bending resistance by the heart loop method of 80 mm or more.
  • the support is preferably made of a polyethylene film having a thickness of 10 to 70 ⁇ m.
  • the basic drug is preferably in the form of a salt of tamsulosin or in the form of a free base.
  • the pressure-sensitive adhesive is aggregated by combining a pressure-sensitive adhesive obtained by using an acrylate ester and / or a methacrylic acid ester having no carboxyl group in the molecule with silica particles having an average particle diameter of 5 ⁇ m or less.
  • a large amount of polyhydric alcohol fatty acid ester as a permeation accelerator can be added to the pressure-sensitive adhesive layer.
  • the adhesion to the skin can be improved, the adhesive residue on the skin and the stickiness of the skin can be improved, and the percutaneous absorption of the drug into the skin can be promoted.
  • the percutaneous absorption preparation of the present invention enables sustained drug release, is excellent in both skin permeability and skin adhesion of the drug, and has the basic performance required as a percutaneous absorption preparation. It is a satisfactory transdermal preparation.
  • FIG. 1 is a graph showing the results of cumulative permeation amounts of transdermal absorption preparations of Examples 1 to 3 and 7 and Comparative Examples 1, 2 and 4 to 6 containing tamsulosin (free base).
  • FIG. 2 is a graph showing the results of cumulative permeation amounts of the percutaneously absorbable preparations of Example 5 and Comparative Example 7 containing salmeterol (free base).
  • FIG. 3 is a graph showing the results of cumulative permeation amounts of the percutaneously absorbable preparations of Example 6 and Comparative Example 8 containing ketotifen fumarate.
  • FIG. 1 is a graph showing the results of cumulative permeation amounts of transdermal absorption preparations of Examples 1 to 3 and 7 and Comparative Examples 1, 2 and 4 to 6 containing tamsulosin (free base).
  • FIG. 2 is a graph showing the results of cumulative permeation amounts of the percutaneously absorbable preparations of Example 5 and Comparative Example 7 containing salmeterol (free base).
  • FIG. 3 is
  • Example 4 shows Example 1, Example 10 and Example 11 using a support having a moisture permeability of 50 g / m 2 ⁇ hr or less, and a support having a moisture permeability of 3,800 g / m 2 ⁇ hr. It is a graph which shows the result of the cumulative permeation
  • the percutaneous absorption type preparation of the present invention is a percutaneous absorption type preparation in which a pressure-sensitive adhesive layer is provided on the surface of a support, and a release liner is usually bonded to the pressure-sensitive adhesive layer so as to cover the entire surface thereof.
  • a pressure-sensitive adhesive layer is provided on the surface of a support, and a release liner is usually bonded to the pressure-sensitive adhesive layer so as to cover the entire surface thereof.
  • adhesive layer total mass standard means an adhesive, a basic drug, silica particles, and a polyhydric alcohol fatty acid ester, and other components (crosslinking agent, accelerator, antioxidant, filler, etc. )) Based on the total mass of the pressure-sensitive adhesive layer.
  • the total mass of the reference pressure-sensitive adhesive layer does not include the organic solvent used for dilution.
  • the pressure-sensitive adhesive layer which is a constituent element of the transdermally absorbable preparation of the present invention, contains a pressure-sensitive adhesive, a basic drug, silica particles, and a polyhydric alcohol fatty acid ester as essential components. Further, if desired, it may further contain other additives as described below which are generally used in the pressure-sensitive adhesive layer of the transdermal preparation.
  • the pressure-sensitive adhesive layer of the finally obtained transdermally absorbable preparation is preferably non-aqueous substantially free of water, and the effect of the present invention can be effectively obtained by using non-aqueous. .
  • Adhesive The adhesive contained in the adhesive layer of the transdermally absorbable preparation of the present invention is an acrylic monomer or monomer mixture comprising an acrylic ester and / or a methacrylic ester having no carboxyl group in the molecule.
  • the polymer is the main adhesive.
  • Examples of the (meth) acrylic acid ester having no carboxyl group in the molecule include n-butyl (meth) acrylate, n-hexyl (meth) acrylate, n-octyl (meth) acrylate, (meth) 2-ethylhexyl acrylate, isooctyl (meth) acrylate, isononyl (meth) acrylate, n-decyl (meth) acrylate, isodecyl (meth) acrylate, dodecyl (meth) acrylate, octadecyl (meth) acrylate Etc.
  • (meth) acrylic acid ester having no hydroxy group In addition to the carboxyl group, it is desirable to use (meth) acrylic acid ester having no hydroxy group as a monomer.
  • These (meth) acrylic acid esters can be used singly or in combination of two or more.
  • a copolymer obtained by using three kinds of esters of 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate and dodecyl methacrylate is preferably used as the acrylic pressure-sensitive adhesive.
  • the pressure-sensitive adhesive used in the present invention uses a monomer (or monomer mixture) mainly composed of (meth) acrylic acid ester having no carboxyl group in the molecule, and preferably has no hydroxy group in addition to the carboxyl group (meth).
  • a monomer (or monomer mixture) made of an acrylate ester is used, but if there is a reason, a monomer having a carboxyl group to such an extent that the effect of the present invention is not impaired is, for example, 5% or less based on the total mole number of the monomer It may be included in proportions.
  • the monomer having a carboxyl group include acrylic acid, methacrylic acid, maleic acid, maleic anhydride, itaconic acid and monobutyl maleate.
  • a monomer having a hydroxy group may be included to such an extent that the effects of the present invention are not impaired, and for example, it may be included in a proportion of 5% or less based on the total number of moles of monomers.
  • acrylic acid ester or methacrylic acid ester monomers containing a hydroxy group include: 2-hydroxyethyl acrylate, 3-hydroxypropyl acrylate, 4-hydroxybutyl acrylate, 2-hydroxyethyl methacrylate, methacrylic acid Examples thereof include acrylic acid esters or methacrylic acid esters such as 3-hydroxypropyl and 4-hydroxybutyl methacrylate.
  • the acrylate copolymer can be generally synthesized by radical polymerization.
  • the polymerization method include a solution polymerization method, an emulsion polymerization method, a bulk polymerization method, and the like, but a solution polymerization method is preferable because good adhesive properties can be obtained.
  • a radical polymerization initiator is added at a ratio of about 0.1 to 1% by mass with respect to the total monomer mass, and the mixture is stirred for several hours to several tens of hours at a temperature of about 40 to 90 ° C. in a nitrogen stream. And do it.
  • the polymerization initiator used here include organic peroxides such as benzoyl peroxide and lauroyl peroxide, and azo initiators such as azobisisobutyronitrile.
  • the polymerization degree is set so that the cohesive force is sufficient.
  • the amount of the intrinsic viscosity of the pressure-sensitive adhesive is adjusted according to conventional methods such as adjusting the amount of radical polymerization initiator added and optimizing the polymerization concentration and polymerization solvent. Specifically, the intrinsic viscosity of the pressure-sensitive adhesive is adjusted to be in the range of 1.2 to 2.5, preferably 1.5 to 2.5, particularly preferably 1.9 to 2.1. Adjust so that The intrinsic viscosity is measured according to the Japanese Pharmacopoeia Viscosity Measurement Method 1.
  • Basic drug The basic drug contained in the adhesive layer of the transdermal preparation of the present invention is not particularly limited.
  • antipyretic anti-inflammatory analgesics butorphanol tartrate, perisoxal citrate, etc.
  • Local anesthetics such as lidocaine, procaine, and their hydrochlorides
  • dysuria drugs such as tamsulosin
  • antiallergic drugs such as ketotifen fumarate
  • bronchodilators sacdilators (salmeterol)
  • narcotic analgesics fentanyl citrate, etc.
  • These drugs may be used alone or in combination of two or more.
  • Tamsulosin is present in the pressure-sensitive adhesive layer in the form of a free base or salt, and when present in the form of a salt, a basic additive is added to convert a part or all of the drug into the form of the free base. It is desirable to use it later.
  • Tamsulosin salts include pharmacologically acceptable salts such as inorganic acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, or organic acids such as acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid and lactic acid.
  • hydrochloride salt ie tamsulosin hydrochloride
  • acid addition salts can be used and in particular the hydrochloride salt, ie tamsulosin hydrochloride, is clinically useful.
  • basic additives used to convert a part or all of the drug into the free base form include potassium hydroxide, sodium hydroxide, acetate, monoethanolamine, diethanolamine, diisopropanolamine, And trishydroxymethylaminomethane.
  • the amount of the basic drug contained in the pressure-sensitive adhesive layer of the percutaneous absorption type preparation of the present invention can be appropriately changed depending on the kind of drug and the purpose of administration, but is usually 0 based on the total mass of the pressure-sensitive adhesive layer. It is desirable that the content be 1 to 20% by mass, preferably 1 to 10% by mass.
  • silica particles contained in the pressure-sensitive adhesive layer of the transdermal preparation of the present invention have an average particle size of 5 ⁇ m or less.
  • the content of the silica particles depends on the content of a later-described polyhydric alcohol fatty acid ester which is a liquid component, but is preferably 1 to 20% by mass, more preferably 1 to 10% by mass based on the total mass of the pressure-sensitive adhesive layer. It is desirable to be.
  • the adhesive layer of the transdermal preparation of the present invention contains a polyhydric alcohol fatty acid ester.
  • propylene glycol monolaurate is particularly desirable as the main component of the polyhydric alcohol fatty acid ester.
  • the main component is at least 50% or more, preferably 90% or more of the polyhydric alcohol fatty acid ester to be blended.
  • propylene glycol monolaurate in the pressure-sensitive adhesive layer, the transdermal absorbability of the drug can be improved and a pressure-sensitive adhesive with a soft feel can be obtained.
  • One or more polyhydric alcohol fatty acid esters other than propylene glycol monolaurate can be used in combination.
  • polyhydric alcohol fatty acid esters include propylene glycol fatty acid esters, glycerin fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, and the like, and it is desirable to use propylene glycol fatty acid esters.
  • Specific examples of the propylene glycol fatty acid ester include propylene glycol monopalmitate, propylene glycol monostearate, propylene glycol monooleate and the like, among which propylene glycol monolaurate is preferable.
  • the content of the polyhydric alcohol fatty acid ester is 15 to 40% by mass, preferably 20 to 35% by mass, based on the total mass of the pressure-sensitive adhesive layer.
  • propylene glycol monolaurate it is preferable to contain 20 to 35% by mass of propylene glycol monolaurate.
  • isopropyl myristate is used as the fatty acid ester instead of propylene glycol monolaurate, a result of low percutaneous absorption is obtained, which is not suitable as the configuration of the present invention, and has a special reason. It is desirable not to mix unless there is.
  • a solubilizer in addition to the above components, a solubilizer, a pharmaceutically acceptable permeation enhancer, a filler, an oxidation agent An inhibitor or the like can be further included.
  • various crosslinking agents are further added for the purpose of increasing the cohesive force of the adhesive. Can be added. Examples of the crosslinking agent include polyfunctional isocyanate compounds, polyfunctional epoxy compounds, and polyvalent metal salts.
  • the transdermal preparation of the present invention is a mixture (adhesive) obtained by blending an adhesive, a basic drug, silica particles, a polyhydric alcohol fatty acid ester, and other additives as required. Is coated on a suitable release liner, a suitable support is laminated thereon, and if necessary, it is cut into a suitable size to obtain a final product.
  • the support is appropriately selected according to the purpose in consideration of flexibility, stretchability, thickness, and the like in consideration of followability to the affected area and self-supporting property at the time of application.
  • the transdermal preparation of the present invention preferably uses a support having a moisture permeability in a specific numerical range in order to improve transdermal absorbability.
  • the moisture permeability (measured at JISZ0208, 40 ° C., 90% RH) of the support is preferably 300 g / m 2 ⁇ 24 hr or less, particularly preferably 50 g / m 2 ⁇ 24 hr or less.
  • the percutaneous absorption type preparation of the present invention is preferably adjusted so that the bending resistance of the support is a specific value in order to improve the followability to the skin and reduce the uncomfortable feeling.
  • the bending resistance (by the heart loop method) of the support is limited to 80 mm or more.
  • a support paper such as impregnated paper, coated paper, fine paper, craft paper, Japanese paper and glassine paper, polyester film, polyethylene film, polypropylene film, polyvinyl chloride film, polycarbonate film, polyurethane film, cellophane film, etc. And non-woven fabrics made of plastic films, foams, polyester fibers, polyethylene fibers and polypropylene fibers, fabric base materials such as woven fabrics and knitted fabrics, and laminates thereof.
  • the thickness of the support used is preferably 10 ⁇ m to 1000 ⁇ m, more preferably 10 ⁇ m to 700 ⁇ m for nonwoven fabrics, woven fabrics and knitted fabrics.
  • the thickness is preferably 5 ⁇ m to 200 ⁇ m, more preferably 5 ⁇ m to 100 ⁇ m.
  • the support is used alone or in the form of a laminate in which two or more of the nonwoven fabric, woven fabric, knitted fabric and plastic film are bonded.
  • the moisture permeability of the support is higher than the range shown above when used alone as a support, such as the urethane film, knitted fabric, non-woven fabric, woven fabric listed above, a polyethylene film, a polyester film, etc.
  • a laminated with a resin film are preferred.
  • a laminate obtained by bonding two or more types it is appropriately selected depending on the materials used, such as a pressure-sensitive adhesive, an adhesive, and a method of fusing with a hot roll.
  • a particularly preferable support is a polyolefin film, and polyethylene films such as LLDPE and LDPE are preferable.
  • the thickness of the support is preferably 5 to 120 ⁇ m, particularly preferably 10 to 70 ⁇ m, and further preferably 20 to 70 ⁇ m.
  • the polyolefin film preferably satisfies the above-mentioned moisture permeability and bending resistance.
  • the release liner used in the transdermal preparation of the present invention is appropriately selected according to the purpose in consideration of easy release from the pressure-sensitive adhesive layer, air permeability, water permeability and flexibility.
  • a film made of a polymer material such as polyethylene, polypropylene and polyester is used, and the film surface can be treated with silicon or fluorocarbon in order to enhance the peelability.
  • a solution to which an acrylic pressure-sensitive adhesive, a basic drug, silica particles, a polyhydric alcohol fatty acid ester, and other additives as necessary are added is prepared.
  • An organic solvent is added to this solution to adjust the concentration appropriately.
  • the organic solvent used here include n-hexane, toluene, ethyl acetate, acetone, and methyl ethyl ketone.
  • the concentration of the adhesive component in the diluted solution diluted with these organic solvents is preferably 10 to 50% by mass, More preferably, it is 20 to 40% by mass.
  • the solution (diluent) containing each component is stirred and dissolved and dispersed uniformly.
  • the solution thus obtained is uniformly applied on, for example, a release liner (silicone-treated polyester film) using a coating machine such as a knife coater, comma coater or reverse coater.
  • a coating machine such as a knife coater, comma coater or reverse coater.
  • the organic solvent is volatilized by holding for about 30 seconds to 10 minutes in a dry heat atmosphere maintained at a temperature of about 40 ° C to 130 ° C.
  • the drying conditions are appropriately selected depending on the type of organic solvent used and the thickness of the pressure-sensitive adhesive to be applied.
  • a transdermal absorption preparation can be obtained by laminating a support on the surface of the pressure-sensitive adhesive layer obtained by the above method and cutting the support into an appropriate size.
  • a release liner may be laminated on the surface of the pressure-sensitive adhesive layer. Thereafter, it may be desirable to store in an atmosphere of 40 to 60 ° C. for about one week and to undergo an aging step in which various components in the pressure-sensitive adhesive layer are adapted.
  • each component used such as an adhesive used in the Example and the comparative example
  • the detail of each component, such as an adhesive used in the Example and the comparative example, is as follows.
  • ⁇ Adhesive> ⁇ Acrylic adhesive (1) 100 parts by mass of 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate and dodecyl methacrylate mixed at a molar ratio of 1: 8: 1, and 0.5 parts by mass of lauroyl peroxide as a polymerization initiator were used.
  • Polymerization was performed by a conventional solution polymerization method at a concentration of 35% in ethyl acetate to obtain an acrylic pressure-sensitive adhesive (1).
  • the intrinsic viscosity of the obtained pressure-sensitive adhesive was 2.0.
  • Acrylic adhesive (2) “Nicazole TS-620” (methyl acrylate / acrylic acid-2-ethylhexyl copolymer resin emulsion) manufactured by Nippon Carbide Industries Co., Ltd. was used as the acrylic pressure-sensitive adhesive (2).
  • Acrylic adhesive (3) 100 parts by weight of 2-ethylhexyl acrylate and acrylic acid mixed at a molar ratio of 90.4%: 9.6%, 0.5 parts by weight of lauroyl peroxide as a polymerization initiator, and 33% in ethyl acetate
  • the acrylic pressure-sensitive adhesive (3) was obtained by polymerization using a conventional solution polymerization method.
  • Acrylic adhesive (4) “Duro-Tak 87-2287” (hydroxy group-containing acrylic polymer) manufactured by Henkel was used as the acrylic pressure-sensitive adhesive (4).
  • Example 1 The percutaneous absorption type preparation of Example 1 was obtained by the following composition and production method.
  • composition 1. Acrylic adhesive (1) 52.0 mass% 2. Light anhydrous silicic acid (1) 10.0% by mass 3. Propylene glycol monolaurate 30.0% by mass 4). Tamsulosin 8.0% by mass (Manufacturing method) After weighing the above components, the total solid content was adjusted to 20% by mass in the ethyl acetate solution and stirred until uniform. Coating on a single-sided siliconized PET (polyethylene terephthalate) film (film binder 75E-0010 No.
  • Example 2 The amount of propylene glycol monolaurate was 25% by mass, and each component was made the following composition accordingly, and the percutaneous absorption type preparation of Example 2 was obtained by the same production method as Example 1.
  • composition 1.
  • Acrylic adhesive (1) 65.0 mass% 2.
  • Light anhydrous silicic acid (1) 5.0% by mass 3.
  • Propylene glycol monolaurate 25.0% by mass 4).
  • Example 3 Propylene glycol monolaurate was used in an amount of 20% by mass, and as a result, each component had the following composition, and the percutaneous absorption type preparation of Example 3 was obtained by the same production method as Example 1.
  • composition 1.
  • Example 4 The transdermal absorption preparation of Example 4 was obtained in the same manner as in Example 1 except that the silica particles were changed to light anhydrous silicic acid (2) and the same composition as in Example 1 was used. It was. (composition) 1. Acrylic adhesive (1) 57.0% by mass 2. Light anhydrous silicic acid (2) 10.0% by mass 3. Propylene glycol monolaurate 25.0% by mass 4). Tamsulosin 8.0% by mass
  • Example 5 A percutaneously absorbable preparation of Example 5 was obtained in the same manner as in Example 1 using the same components as in Example 1 except that salmeterol was used as the basic drug.
  • composition 1. Acrylic adhesive (1) 55.0 mass% 2. Light anhydrous silicic acid (1) 10.0% by mass 3. Propylene glycol monolaurate 30.0% by mass 4). Salmeterol 5.0% by mass
  • Example 6 The basic ingredient was ketotifen fumarate, and the same ingredients as in Example 1 were used except that monoethanolamine was used as a basic additive used when converting part or all of the drug into the free base form.
  • the percutaneously absorbable preparation of Example 6 was obtained in the same manner as in Example 1, except that the coating amount of the pressure-sensitive adhesive layer after drying was 40 g / m 2. It was. (composition) 1. Acrylic adhesive (1) 47.5% by mass 2. Light anhydrous silicic acid (1) 10.0% by mass 3. Propylene glycol monolaurate 30.0% by mass 4). Monoethanolamine 2.5% by mass 5). Ketotifen fumarate 10.0% by mass
  • Example 7 Using the acrylic pressure-sensitive adhesive (2) as the pressure-sensitive adhesive, the transdermal preparation of Example 7 was obtained using the following composition and production method. (composition) 1. Acrylic adhesive (2) 57.0% by mass 2. Light anhydrous silicic acid (1) 5.0% by mass 3. Propylene glycol monolaurate 30.0% by mass 4). Tamsulosin 8.0% by mass (Manufacturing method) After weighing the above components, the total solid content was adjusted to 50% by mass in the emulsion and stirred until uniform. Coating on a single-sided siliconized PET (polyethylene terephthalate) film (film binder 75E-0010 No.
  • Example 8 The amount of each component used was set as follows, and the percutaneous absorption type preparation of Example 8 was obtained by the same production method as Example 1. (composition) 1. Acrylic adhesive (1) 54.0% by mass 2. Light anhydrous silicic acid (1) 10.0% by mass 3. Propylene glycol monolaurate 30.0% by mass 4). Tamsulosin 6.0% by mass
  • Example 9 The amount of each component used was set to the following composition, and the percutaneous absorption type preparation of Example 9 was obtained by the same production method as Example 1. (composition) 1. Acrylic adhesive (1) 57.0% by mass 2. Light anhydrous silicic acid (1) 10.0% by mass 3. Propylene glycol monolaurate 30.0% by mass 4). Tamsulosin 3.0% by mass
  • Example 10 The percutaneous absorption type of Example 10 with the same composition and production method as Example 1 except that a 25 ⁇ m-thick polyethylene film (Fujimori Kogyo Co., Ltd., moisture permeability 30 g / m 2 ⁇ 24 hr) was used as the support. A formulation was obtained.
  • Example 11 The percutaneously absorbable preparation of Example 11 has the same composition and production method as Example 1 except that a 40 ⁇ m-thick polyethylene film (Toray Industries, Inc., moisture permeability 25 g / m 2 ⁇ 24 hr) is used as the support. Got.
  • a 40 ⁇ m-thick polyethylene film Toray Industries, Inc., moisture permeability 25 g / m 2 ⁇ 24 hr
  • Example 12 A percutaneous absorption type preparation of Example 12 was obtained by the same composition and production method as Example 1 except that a 60 ⁇ m-thick polyethylene film (Toray Industries, Inc.) was used as the support.
  • a 60 ⁇ m-thick polyethylene film Toray Industries, Inc.
  • Comparative Example 1 A percutaneous absorption type preparation of Comparative Example 1 was obtained in the same manner as in Example 1 using the following composition.
  • composition 1.
  • Acrylic adhesive (1) 62.0 mass% 2.
  • composition A percutaneous absorption type preparation of Comparative Example 2 was obtained in the same manner as in Example 1 using the following composition.
  • composition 1. Acrylic adhesive (3) 59.5% by mass 2. Polyisocyanate 0.5% by mass 3. Propylene glycol monolaurate 30.0% by mass 4). Tamsulosin 10.0% by mass
  • Comparative Example 3 A percutaneous absorption type preparation of Comparative Example 3 was obtained in the same manner as in Example 1 using the following composition. (composition) 1. Acrylic adhesive (3) 54.5% by mass 2. Polyisocyanate 0.5% by mass 3. Propylene glycol monolaurate 30.0% by mass 4). Tamsulosin 15.0% by mass
  • composition A rubber-based adhesive was used as the adhesive, and the transdermal absorption preparation of Comparative Example 4 was obtained using the following composition and production method.
  • composition 1. Rubber adhesive 65.0% by mass 2. Propylene glycol monolaurate 30.0% by mass 3. Tamsulosin 5.0% by mass (Manufacturing method) After weighing the above components, the total solid content was adjusted to 50% by mass in the toluene solution and stirred until uniform. Coating on a single-sided siliconized PET (polyethylene terephthalate) film (film binder 75E-0010 No.
  • composition A percutaneous absorption type preparation of Comparative Example 5 was obtained in the same manner as in Example 1 using the following composition.
  • composition 1.
  • Acrylic adhesive (1) 85.0 mass% 2.
  • Light anhydrous silicic acid (1) 10.0% by mass 3.
  • composition A percutaneous absorption type preparation of Comparative Example 6 was obtained in the same manner as in Example 1 using the following composition.
  • composition 1.
  • Acrylic adhesive (1) 75.0 mass% 2.
  • Light anhydrous silicic acid (1) 10.0% by mass 3.
  • Propylene glycol monolaurate 10.0% by mass 4).
  • Tamsulosin 5.0% by mass
  • Comparative Example 7 Using the following composition, the percutaneous absorption preparation of Comparative Example 7 was obtained by the same production method as in Example 1. (composition) 1. Acrylic adhesive (3) 64.5% by mass 2. Polyisocyanate 0.5% by mass 3. Propylene glycol monolaurate 30.0% by mass 4). Salmeterol 5.0% by mass
  • Comparative Example 8 A percutaneous absorption type preparation of Comparative Example 8 was obtained in the same manner as in Example 1 except that the following composition was used and the coating amount of the pressure-sensitive adhesive layer after drying was 40 g / m 2 .
  • composition 1. Acrylic adhesive (3) 57.0% by mass 2. Polyisocyanate 0.5% by mass 3. Propylene glycol monolaurate 30.0% by mass 4). Monoethanolamine 2.5% by mass 5). Ketotifen fumarate 10.0% by mass
  • Comparative Example 9 A percutaneous absorption type preparation of Comparative Example 9 was obtained in the same manner as in Example 1 using the following composition.
  • composition 1. Acrylic adhesive (1) 57.0% by mass 2. Hydrous silicic acid 10.0% by mass 3. Propylene glycol monolaurate 25.0% by mass 4). Tamsulosin 8.0% by mass
  • composition (Manufacturing method) a) Boric acid was added to methanol to obtain a 10% by mass solution. b) 0.43 g of light anhydrous silicic acid and 2.25 ethyl acetate were added to 3.32 g of the solution a), and mixed in a mortar to obtain a dispersion. c) 9.7 g of acrylic pressure-sensitive adhesive (liquid) was added to the dispersion of b) and mixed for 1 hour in a mortar.
  • Comparative Example 18 Comparative Example 18 with the same composition and production method as Example 1 except that a 75 ⁇ m-thick calcium carbonate-containing polyethylene film (Mitsubishi Chemical Corporation, moisture permeability 3,800 g / m 2 ⁇ 24 hr) was used as the support. A percutaneous absorption type preparation was obtained.
  • a 75 ⁇ m-thick calcium carbonate-containing polyethylene film Mitsubishi Chemical Corporation, moisture permeability 3,800 g / m 2 ⁇ 24 hr
  • Comparative Example 19 A percutaneously absorbable preparation of Comparative Example 19 was obtained by the same composition and production method as Example 1 except that a calcium carbonate-containing polyethylene film (Mitsubishi Chemical Corporation) having a thickness of 80 ⁇ m was used as the support.
  • a calcium carbonate-containing polyethylene film Mitsubishi Chemical Corporation
  • Comparative Example 20 with the same composition and production method as Example 1 except that a 100 ⁇ m-thick calcium carbonate-containing polyethylene film (Mitsubishi Chemical Corporation, moisture permeability 2,850 g / m 2 ⁇ 24 hr) was used as the support. A percutaneous absorption type preparation was obtained.
  • a 100 ⁇ m-thick calcium carbonate-containing polyethylene film Mitsubishi Chemical Corporation, moisture permeability 2,850 g / m 2 ⁇ 24 hr
  • Comparative Examples 21 to 32 Using indomethacin or aspirin, which is an acidic drug, as a drug, percutaneous absorption preparations of Comparative Examples 21 to 32 were obtained by the same production method as in Example 1 with the following composition. In addition, each formulation was adjusted so that the application amount of the pressure-sensitive adhesive layer after drying was 30 g / m 2 . (composition)
  • the test temperature was set to 32 ° C., and 1 mL of the receiver liquid was collected every sampling time set in advance after the start of the test, and filled with the same amount of new receiver liquid.
  • the same amount of methanol was added to the collected receiver solution to remove impurities, and then the drug concentration was measured by HPLC to calculate the cumulative permeation amount. Each specimen was tested three times to obtain an average value. Table 9 shows the obtained results.
  • Adhesiveness of the preparation (normal / perspiration)
  • the adhesiveness of the obtained transdermally absorbable preparations of Examples and Comparative Examples was evaluated based on the following criteria using a finger tack method. Furthermore, after the percutaneous absorption preparation punched out to 10 cm 2 was applied to a healthy adult for 6 hours, the adhesive residue (adhesive residue) when the preparation was peeled was evaluated based on the following criteria. ⁇ Standard by finger tack method ⁇ : Very well attached ⁇ : Well attached: ⁇ : Not much sticky ⁇ Adhesive residue standard None: Adhesive residue (adhesive residue) is not visually observed. Slightly present: Some adhesive residue (adhesive residue) is visually observed.
  • Adhesive residue (adhesive residue) is clearly observed visually.
  • the percutaneous absorption type preparations of Examples and Comparative Examples were punched out to 10 cm 2 , and a healthy adult having this applied to the skin on the inner side of the forearm was allowed to sweat for 10 minutes in a room adjusted to room temperature 40 ° C.
  • the adhesion state was evaluated based on the following criteria.
  • the stickiness when the applied site was traced with a finger was evaluated based on the following criteria.
  • ⁇ Standard of adherence state ⁇ : The whole surface is attached.
  • ⁇ : Float is observed at the edge.
  • XX Criterion of skin stickiness that has fallen off. No: Slightly present: Part of the applied site is sticky Yes: The entire applied site is sticky The results obtained are shown in Table 10 and Table 11.
  • Example 3 the drug content was as low as 3%, and the cumulative permeation amount was lower than that in Example 1, Example 2, and Example 7, but Comparative Example 2 far exceeding the drug content in Example 3 And the skin permeability equivalent to or higher than that of Comparative Example 3 was shown, and the drug utilization rate was much higher.
  • Comparative Example 5 in which propylene glycol monolaurate was not blended and Comparative Example 6 in which the blending amount was as low as 10% showed extremely low skin permeability compared to Example 2 having the same amount of tamsulosin. Since Comparative Example 2 and Comparative Example 3 have almost the same amount of permeation, only Comparative Example 2 is shown in FIG.
  • Example 5 and Example 6 using the acrylic pressure-sensitive adhesive (1) showed a higher cumulative permeation amount than Comparative Examples 7 and 8 using the acrylic pressure-sensitive adhesive (3).
  • Comparative Examples 10 to 13 and Comparative Examples 14 to 17 using the acrylic pressure-sensitive adhesive (4) as the pressure-sensitive adhesive have a cumulative permeation amount and a drug utilization rate after 48 hours.
  • the result was very low compared to Example 8 and Example 9. That is, compared with the preparation using the hydroxy group-containing acrylic pressure-sensitive adhesive (4), the acrylic pressure-sensitive adhesive (1) containing no hydroxy group (2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, dodecyl methacrylate) As a result, it was found that the preparation using the polymer) had excellent drug skin permeability.
  • an acrylic pressure-sensitive adhesive (1) (acrylic acid-2-ethylhexyl / methacrylic acid-2-ethylhexyl / methacrylic acid dodecyl copolymer, ester-based), acrylic pressure-sensitive adhesive (3) (In various preparations using an acrylic pressure-sensitive adhesive (4) (hydroxy group-containing acrylic polymer) and a drug containing indomethacin (Table 6) as a drug and aspirin as a drug. When used (Table 7). As a result, when indomethacin is used, the formulation using the acrylic pressure-sensitive adhesive (3) (containing a carboxyl group) as the pressure-sensitive adhesive is slightly superior in both the accumulated permeation amount and the utilization rate after 24 hours.
  • Adhesiveness of the preparation As shown in Table 10 below, the preparations of Examples 1 to 4 showed no adhesive residue and showed sufficient adhesiveness and adhesiveness as a transdermal preparation. In addition, good adhesion was maintained even during sweating, and no skin stickiness after peeling was observed.
  • Comparative Example 1 On the other hand, as shown in Table 11, in the preparation of Comparative Example 1, although good results were obtained with respect to adhesiveness, adhesive residue and stickiness of the skin during sweating were recognized. This seems to be because propylene glycol monolaurate, which is a liquid component, could not be sufficiently retained, and the cohesive strength of the adhesive was reduced. Although the preparation of Comparative Example 2 gave good results with respect to adhesiveness, as described above, the cumulative permeation amount and the drug utilization rate showed low values, which were insufficient for exhibiting medicinal effects. In the preparation of Comparative Example 4 using a rubber-based adhesive, it was difficult to maintain adhesiveness by adding a large amount of propylene glycol monolaurate, finger tack was not suitable, and the preparation fell off due to sweating. Further, Comparative Example 9 using hydrous silicic acid having a large particle diameter as silica particles (filler) is insufficient in improving the cohesive force, and the adhesive remains slightly and the skin becomes sticky after peeling during sweating. Admitted.
  • Comparative Example 1 which does not contain silica particles obtained results excellent in drug skin permeability, but left a problem in skin adhesion.
  • an acrylic pressure-sensitive adhesive using a monomer having a carboxyl group was used (Comparative Example 2 and Comparative Example 3, Comparative Example 7 and Comparative Example 8)
  • the skin permeability and drug utilization rate of the drug were significantly reduced.
  • the result was that the adhesive force hardly developed (Comparative Example 4).
  • Examples 1 to 12 which are the percutaneous absorption preparations of the present invention all have excellent drug skin permeability and skin adhesion, and this preparation is a percutaneous absorption preparation. As a result, it was confirmed that they have excellent characteristics. Furthermore, it was confirmed that by using a support having a bending resistance of 80 mm or more, the flexibility is high, the followability to the skin is increased, and the adhesion is increased.

Abstract

Disclosed is a transdermal preparation which has the following basic properties required for a transdermal preparation: a permeation promoter can be added to the transdermal preparation in a large quantity without reducing the coagulation ability of an adhesive agent contained in the transdermal preparation; the bioavailability of a pharmaceutically active ingredient contained in the transdermal preparation can be improved; the amount of an adhesive agent remaining on the skin or the sticky feeling on the skin can be reduced; and others. Specifically disclosed is a transdermal preparation comprising a support and an adhesive layer comprising an adhesive composition and arranged on the support.  In the transdermal preparation, the adhesive composition comprises: an acrylic adhesive agent mainly composed of a resin that is produced by polymerizing a monomer comprising an acrylic acid ester and/or a methacrylic acid ester each having no carboxyl group in the molecule or a mixture of the monomer; a basic and pharmaceutically active ingredient; silica particles having an average particle diameter of 5 μm or less; and a polyhydric alcohol fatty acid ester, wherein the polyhydric alcohol fatty acid ester is contained in an amount of 15 to 40 mass% relative to the total mass of the adhesive composition.

Description

経皮吸収型製剤Transdermal preparation
　本発明は新規な経皮吸収型製剤、詳細には、薬物の皮膚透過性と皮膚付着性の双方に優れる経皮吸収型製剤に関する。 The present invention relates to a novel percutaneous absorption-type preparation, and more particularly to a percutaneous absorption-type preparation excellent in both skin permeability and skin adhesion of a drug.
　経皮吸収型製剤は、経口投与法に特有の問題点、すなわち肝臓における初回通過効果による大量投与を解消でき、また安定した血中濃度を維持できる剤形として注目されている。特に高齢化社会を迎える現代においては、嚥下が困難な患者への各種薬物の投与を容易にする剤形としても注目されている。
　一方、皮膚は人体最大の臓器であると共に、外界からの化学物質や細菌などの異物から体を守る重要な組織でもあることから、薬物なども異物として容易には通過させないため、現状では経皮吸収型製剤として提供できる薬物は限られている。
　そこで、薬物の皮膚透過を促進させる手段として、化学物質（低分子化合物など）を用いた透過促進剤の検討や、電気エネルギーによりイオン性薬物の経皮吸収を促進させるイオントフォレーシス、さらには超音波を用いたソノフォレーシス（超音波導入）等、様々な手法が検討されている。 The percutaneous absorption type preparation is attracting attention as a dosage form that can eliminate problems inherent to the oral administration method, that is, a large dose due to the first-pass effect in the liver, and can maintain a stable blood concentration. Particularly in the present age of aging societies, it is attracting attention as a dosage form that facilitates administration of various drugs to patients who have difficulty swallowing.
On the other hand, because the skin is the largest organ in the human body and is also an important tissue that protects the body from foreign substances such as chemical substances and bacteria from the outside world, drugs and the like are not easily passed through as foreign substances. There are a limited number of drugs that can be provided as absorption-type preparations.
Therefore, as a means to promote the skin permeation of drugs, study of permeation enhancers using chemical substances (such as low molecular weight compounds), iontophoresis to promote percutaneous absorption of ionic drugs by electric energy, Various methods such as sonophoresis using ultrasonic waves (introduction of ultrasonic waves) have been studied.
　上述の透過促進剤は、薬物の経皮吸収促進効果を向上させるには、粘着剤層中の含有量を増加させることが望ましいが、多量に添加すると粘着剤の凝集力が低下するなどの問題が生じる。
　粘着剤として架橋剤を用いたアクリル系粘着剤を使用するのであれば、分子量を制御できることから、透過促進剤を添加しても一定以上の凝集力を維持することができるものの、一般に架橋剤を使用しないゴム系粘着剤や、シリコーン系粘着剤では、透過促進剤の使用量が限定されることとなる。
　このため、こうした粘着剤を用いる場合、従来は透過促進剤の添加量を増やすのではなく、リザーバー型製剤などの製剤的な検討が必要とされていた。 In order to improve the percutaneous absorption promotion effect of the drug, it is desirable to increase the content in the pressure-sensitive adhesive layer. However, if added in a large amount, the coagulation force of the pressure-sensitive adhesive is reduced. Occurs.
If an acrylic pressure-sensitive adhesive using a cross-linking agent is used as the pressure-sensitive adhesive, the molecular weight can be controlled. Therefore, although a certain level of cohesion can be maintained even when a permeation accelerator is added, a cross-linking agent is generally used. In a rubber-based adhesive or a silicone-based adhesive that is not used, the amount of permeation accelerator used is limited.
For this reason, in the case of using such an adhesive, conventionally, it has been necessary to examine the formulation of a reservoir type formulation, etc., rather than increasing the addition amount of the permeation enhancer.
　前述のアクリル系粘着剤、すなわち該粘着剤に用いるアクリル系共重合体は、カルボキシル基を有するモノマーを使用することにより、架橋剤を用いた分子量制御による凝集力の制御が可能になる。このようにして、オイル成分であるミリスチン酸イソプロピルが多量添加されたオルガノゲルと呼ばれる粘着剤を使用した製品が上市されている（フランドルテープＳ、トーアエイヨー（株））。
　しかしながら、カルボキシル基を有するモノマー（例：アクリル酸）を共重合体に使用したアクリル系粘着剤は、塩基性薬物を添加した場合、カルボキシル基が塩基性薬物と反応（結合）するため、粘着剤からの薬物放出を妨げることが知られている。
　そのため、アクリル酸（カルボキシル基を有するモノマー）を有する粘着剤を使用する場合、多量の薬物を添加することが行なわれている（特許文献１参照）。
　また、透過促進剤として、多価アルコール脂肪酸エステルの使用が報告されている（特許文献２参照）。 The aforementioned acrylic pressure-sensitive adhesive, that is, the acrylic copolymer used in the pressure-sensitive adhesive, can control the cohesive force by controlling the molecular weight using a crosslinking agent by using a monomer having a carboxyl group. In this way, a product using an adhesive called an organogel to which a large amount of isopropyl myristate as an oil component is added has been put on the market (Flandre Tape S, Toei Aiyo Co., Ltd.).
However, acrylic pressure-sensitive adhesives using a monomer having a carboxyl group (eg, acrylic acid) as a copolymer react with (bond to) the carboxyl group when a basic drug is added. It is known to prevent drug release from.
Therefore, when using the adhesive which has acrylic acid (monomer which has a carboxyl group), adding a lot of drugs is performed (refer patent document 1).
Moreover, use of polyhydric alcohol fatty acid ester as a permeation accelerator has been reported (see Patent Document 2).
　上述したように、塩基性薬物を使用する場合、アクリル系粘着剤に含まれるカルボキシル基が塩基性薬物と反応するため、薬物の添加量を増やす必要があり、生物学的利用能（Ｂｉｏａｖａｉｌａｂｉｌｉｔｙ）が低下するという問題があった。
　従って、塩基性薬物を経皮吸収型製剤において効率よく利用するためには、カルボキシル基を含まないモノマーを用いて粘着剤を調製することが好ましいといえるが、前述の通り、このモノマーでは架橋剤が使用できないことから凝集力のコントロールが困難となり、ひいては、透過促進剤を多量に添加することを困難にするという問題があった。
　また、多価アルコール脂肪酸エステルも他の促進剤同様、凝集力の維持を難しくさせることから、粘着剤層への多量の添加は難しいという問題があった。 As described above, when a basic drug is used, since the carboxyl group contained in the acrylic adhesive reacts with the basic drug, it is necessary to increase the amount of the drug added, and the bioavailability is increased. There was a problem of lowering.
Therefore, in order to efficiently use a basic drug in a transdermal absorption-type preparation, it can be said that it is preferable to prepare a pressure-sensitive adhesive using a monomer that does not contain a carboxyl group. Since it cannot be used, it is difficult to control the cohesive force, and as a result, it is difficult to add a large amount of permeation accelerator.
In addition, polyhydric alcohol fatty acid esters, like other accelerators, make it difficult to maintain cohesive force, so that there is a problem that it is difficult to add a large amount to the pressure-sensitive adhesive layer.
　本発明は上述の問題点、すなわち、粘着剤の凝集力を低下させることなく透過促進剤の多量添加を可能にし、また、薬物の生物学的利用能を向上させ、且つ粘着剤の皮膚への残留や皮膚のべたつきを改善するなどの経皮吸収型製剤として求められる基本性能をも満足する経皮吸収型製剤を提供することを課題とする。 The present invention makes it possible to add a large amount of permeation enhancer without reducing the above-mentioned problems, that is, the cohesive force of the adhesive, improve the bioavailability of the drug, and apply the adhesive to the skin. It is an object of the present invention to provide a percutaneous absorption preparation that satisfies the basic performance required as a percutaneous absorption preparation, such as improving the residue and stickiness of the skin.
　そこで本発明者らは、分子内にカルボキシル基を持たない（メタ）アクリル酸エステルよりなるモノマー又はモノマー混合物を使用して得られるアクリル系粘着剤とシリカ粒子を組み合わせることにより、これまで困難であった多価アルコール脂肪酸エステルの粘着剤層への多量添加を可能にすることを見出した。そしてこれらの知見に基づいて持続的な薬物放出を可能にし、薬物の皮膚透過性と皮膚付着性の双方に優れた経皮吸収型製剤を提供する本発明を完成させた。 Therefore, the present inventors have heretofore been difficult by combining an acrylic pressure-sensitive adhesive obtained by using a monomer or a monomer mixture made of (meth) acrylic acid ester having no carboxyl group in the molecule and silica particles. It was found that a large amount of polyhydric alcohol fatty acid ester can be added to the pressure-sensitive adhesive layer. Based on these findings, the present invention has been completed that provides a percutaneously absorbable preparation that enables sustained drug release and is excellent in both skin permeability and skin adhesion of the drug.
　すなわち本発明は、支持体に粘着剤層を設けてなる経皮吸収型製剤において、該支持体は３００ｇ／ｍ2・２４ｈｒ以下の透湿度であり、該粘着剤層を形成する粘着剤組成物が、分子内にカルボキシル基を持たないアクリル酸エステル及び／またはメタクリル酸エステルよりなるモノマー又はモノマー混合物を重合してなる樹脂を主とするアクリル系粘着剤、塩基性薬物、平均粒子径が５μｍ以下のシリカ粒子、並びに多価アルコール脂肪酸エステルを含有し、前記多価アルコール脂肪酸エステルは粘着剤組成物の全質量に対して１５～４０質量％の割合で含まれてなる、経皮吸収型製剤に関する。 That is, the present invention relates to a transdermal preparation having a pressure-sensitive adhesive layer on a support, wherein the support has a moisture permeability of 300 g / m 2 · 24 hr or less, and forms a pressure-sensitive adhesive layer. Is an acrylic pressure-sensitive adhesive mainly composed of a resin obtained by polymerizing a monomer or a monomer mixture comprising an acrylate ester and / or a methacrylic ester having no carboxyl group in the molecule, a basic drug, and an average particle size of 5 μm or less And a polyhydric alcohol fatty acid ester, wherein the polyhydric alcohol fatty acid ester is contained at a ratio of 15 to 40% by mass with respect to the total mass of the pressure-sensitive adhesive composition. .
　前記経皮吸収型製剤において、前記多価アルコール脂肪酸エステルはプロピレングリコールモノラウレートを主成分とし、粘着剤成分の全質量に対して２０～３５質量％の割合で含まれてなることが望ましい。 In the percutaneous absorption preparation, the polyhydric alcohol fatty acid ester is preferably composed mainly of propylene glycol monolaurate and contained in a proportion of 20 to 35% by mass with respect to the total mass of the adhesive component.
　前記経皮吸収型製剤において、前記アクリル系粘着剤は分子内にカルボキシル基及びヒドロキシ基を持たないアクリル酸エステル及び／またはメタクリル酸エステルよりなるモノマー又はモノマー混合物を重合してなる樹脂を主とするものであることが望ましく、その場合、前記アクリル系粘着剤はアクリル酸－２－エチルヘキシル・メタクリル酸－２－エチルヘキシル・メタクリル酸ドデシル共重合体であることがより望ましい。
　また前記アクリル系粘着剤は１．５～２．５、特に好ましくは１．９～２．１の極限粘度を有する粘着剤であることが望ましい。 In the transdermal preparation, the acrylic pressure-sensitive adhesive is mainly a resin obtained by polymerizing a monomer or a monomer mixture comprising an acrylate ester and / or a methacrylic ester having no carboxyl group and hydroxy group in the molecule. In this case, the acrylic pressure-sensitive adhesive is more preferably a copolymer of 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / dodecyl methacrylate.
The acrylic pressure-sensitive adhesive is desirably a pressure-sensitive adhesive having an intrinsic viscosity of 1.5 to 2.5, particularly preferably 1.9 to 2.1.
　前記経皮吸収型製剤において、前記支持体は５０ｇ／ｍ2・２４ｈｒ以下の透湿度を有する支持体であることが望ましい。
　また前記支持体は８０ｍｍ以上のハートループ法による剛軟度を有する支持体であることが好ましい。
　さらに、前記支持体は厚さが１０～７０μｍであるポリエチレンフィルムよりなるものが好ましい。 In the transdermal preparation, the support is preferably a support having a moisture permeability of 50 g / m 2 · 24 hr or less.
Moreover, it is preferable that the said support body is a support body which has the bending resistance by the heart loop method of 80 mm or more.
Further, the support is preferably made of a polyethylene film having a thickness of 10 to 70 μm.
　そして前記塩基性薬物はタムスロシンの塩の形態であるか又は遊離塩基の形態であることが望ましい。 The basic drug is preferably in the form of a salt of tamsulosin or in the form of a free base.
　本発明によれば、分子内にカルボキシル基を持たないアクリル酸エステル及び／又はメタクリル酸エステルを使用して得られる粘着剤と平均粒子径が５μｍ以下のシリカ粒子を組み合わせることにより、粘着剤の凝集力を低下させることなく、粘着剤層に透過促進剤である多価アルコール脂肪酸エステルを多量に添加することができる。そしてそれにより、皮膚への付着性を改善し、また粘着剤の皮膚への残留や皮膚のべたつきを改善し、且つ薬物の皮膚への経皮吸収を促進させることができる。
　そしてこうした構成により、本発明の経皮吸収型製剤は、持続的な薬物放出を可能にし、薬物の皮膚透過性と皮膚付着性の双方に優れ、経皮吸収型製剤として求められる基本性能をも満足する経皮吸収型製剤となる。 According to the present invention, the pressure-sensitive adhesive is aggregated by combining a pressure-sensitive adhesive obtained by using an acrylate ester and / or a methacrylic acid ester having no carboxyl group in the molecule with silica particles having an average particle diameter of 5 μm or less. Without reducing the force, a large amount of polyhydric alcohol fatty acid ester as a permeation accelerator can be added to the pressure-sensitive adhesive layer. And thereby, the adhesion to the skin can be improved, the adhesive residue on the skin and the stickiness of the skin can be improved, and the percutaneous absorption of the drug into the skin can be promoted.
With such a configuration, the percutaneous absorption preparation of the present invention enables sustained drug release, is excellent in both skin permeability and skin adhesion of the drug, and has the basic performance required as a percutaneous absorption preparation. It is a satisfactory transdermal preparation.
図１は、タムスロシン（遊離塩基）を含有する実施例１乃至３及び７並びに比較例１、２及び４乃至６の経皮吸収型製剤の累積透過量の結果を示すグラフである。FIG. 1 is a graph showing the results of cumulative permeation amounts of transdermal absorption preparations of Examples 1 to 3 and 7 and Comparative Examples 1, 2 and 4 to 6 containing tamsulosin (free base). 図２は、サルメテロール（遊離塩基）を含有する実施例５並びに比較例７の経皮吸収型製剤の累積透過量の結果を示すグラフである。FIG. 2 is a graph showing the results of cumulative permeation amounts of the percutaneously absorbable preparations of Example 5 and Comparative Example 7 containing salmeterol (free base). 図３は、ケトチフェンフマル酸塩を含有する実施例６並びに比較例８の経皮吸収型製剤の累積透過量の結果を示すグラフである。FIG. 3 is a graph showing the results of cumulative permeation amounts of the percutaneously absorbable preparations of Example 6 and Comparative Example 8 containing ketotifen fumarate. 図４は、５０ｇ／ｍ2・ｈｒ以下の透湿度を有する支持体を用いた実施例１、実施例１０及び実施例１１、並びに３，８００ｇ／ｍ2・ｈｒの透湿度を有する支持体を用いた比較例１８の経皮吸収型製剤の累積透過量の結果を示すグラフである。FIG. 4 shows Example 1, Example 10 and Example 11 using a support having a moisture permeability of 50 g / m 2 · hr or less, and a support having a moisture permeability of 3,800 g / m 2 · hr. It is a graph which shows the result of the cumulative permeation | transmission amount of the transdermal absorption type preparation of the comparative example 18 used.
　本発明の経皮吸収型製剤は支持体の表面に粘着剤層を設け、該粘着剤層の上に通常その全面を覆うように剥離ライナーを貼り合わせてなる経皮吸収型製剤であり、以下に本発明の各構成要素及びその機能に関してさらに説明する。
　なお本発明において「粘着剤層全質量基準」とは、粘着剤、塩基性薬物、シリカ粒子、及び多価アルコール脂肪酸エステル、及びその他の成分（架橋剤、促進剤、酸化防止剤、充填剤など）からなる粘着剤層の全質量を基準とすることを意味するものとする。但し、基準となる粘着剤層の全質量に、希釈のためなどに用いた有機溶媒は含まれない。 The percutaneous absorption type preparation of the present invention is a percutaneous absorption type preparation in which a pressure-sensitive adhesive layer is provided on the surface of a support, and a release liner is usually bonded to the pressure-sensitive adhesive layer so as to cover the entire surface thereof. Next, each component of the present invention and its function will be further described.
In the present invention, “adhesive layer total mass standard” means an adhesive, a basic drug, silica particles, and a polyhydric alcohol fatty acid ester, and other components (crosslinking agent, accelerator, antioxidant, filler, etc. )) Based on the total mass of the pressure-sensitive adhesive layer. However, the total mass of the reference pressure-sensitive adhesive layer does not include the organic solvent used for dilution.
１）粘着剤層
　本発明の経皮吸収型製剤の構成要素である粘着剤層は、粘着剤、塩基性薬物、シリカ粒子及び多価アルコール脂肪酸エステルを必須の成分として含む。
　また所望により、経皮吸収型製剤の粘着剤層に一般に用いられる以下に述べるようなその他添加剤をさらに含むことができる。
なお、最終的に得られる経皮吸収型製剤の粘着剤層は、実質的に水を含まない非水系であることが好ましく、非水系とすることにより本発明の効果を有効に得ることができる。 1) Pressure-sensitive adhesive layer The pressure-sensitive adhesive layer, which is a constituent element of the transdermally absorbable preparation of the present invention, contains a pressure-sensitive adhesive, a basic drug, silica particles, and a polyhydric alcohol fatty acid ester as essential components.
Further, if desired, it may further contain other additives as described below which are generally used in the pressure-sensitive adhesive layer of the transdermal preparation.
The pressure-sensitive adhesive layer of the finally obtained transdermally absorbable preparation is preferably non-aqueous substantially free of water, and the effect of the present invention can be effectively obtained by using non-aqueous. .
（１）粘着剤
　本発明の経皮吸収型製剤の粘着剤層に含まれる粘着剤は、分子内にカルボキシル基を持たないアクリル酸エステル及び／又はメタクリル酸エステルよりなるモノマー又はモノマー混合物のアクリル系重合体を主要な粘着剤とする。 (1) Adhesive The adhesive contained in the adhesive layer of the transdermally absorbable preparation of the present invention is an acrylic monomer or monomer mixture comprising an acrylic ester and / or a methacrylic ester having no carboxyl group in the molecule. The polymer is the main adhesive.
　上記分子内にカルボキシル基を持たない（メタ）アクリル酸エステルとしては、例えば、（メタ）アクリル酸ｎ－ブチル、（メタ）アクリル酸ｎ－ヘキシル、（メタ）アクリル酸ｎ－オクチル、（メタ）アクリル酸－２－エチルヘキシル、（メタ）アクリル酸イソオクチル、（メタ）アクリル酸イソノニル、（メタ）アクリル酸ｎ－デシル、（メタ）アクリル酸イソデシル、（メタ）アクリル酸ドデシル、（メタ）アクリル酸オクタデシル等が挙げられる。
　なお、カルボキシル基に加え、ヒドロキシ基を持たない（メタ）アクリル酸エステルをモノマーとして使用することが望ましい。
　これら（メタ）アクリル酸エステルは、一種を単独で、或いは二種以上を組合せて使用することができる。
　中でも、アクリル酸－２－エチルヘキシル、メタクリル酸－２－エチルヘキシル及びメタクリル酸ドデシルの３種のエステルを用いて得られる共重合体を、アクリル系粘着剤として使用することが好ましい。 Examples of the (meth) acrylic acid ester having no carboxyl group in the molecule include n-butyl (meth) acrylate, n-hexyl (meth) acrylate, n-octyl (meth) acrylate, (meth) 2-ethylhexyl acrylate, isooctyl (meth) acrylate, isononyl (meth) acrylate, n-decyl (meth) acrylate, isodecyl (meth) acrylate, dodecyl (meth) acrylate, octadecyl (meth) acrylate Etc.
In addition to the carboxyl group, it is desirable to use (meth) acrylic acid ester having no hydroxy group as a monomer.
These (meth) acrylic acid esters can be used singly or in combination of two or more.
Among them, a copolymer obtained by using three kinds of esters of 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate and dodecyl methacrylate is preferably used as the acrylic pressure-sensitive adhesive.
　なお、本発明で用いる粘着剤は、主として分子内にカルボキシル基を持たない（メタ）アクリル酸エステルよりなるモノマー（又はモノマー混合物）を用い、好ましくはカルボキシル基に加えヒドロキシ基を持たない（メタ）アクリル酸エステルよりなるモノマー（又はモノマー混合物）を用いるが、理由がある場合には本発明の効果を阻害しない程度にカルボキシル基を持つモノマーを、例えばモノマーの総モル数に基づいて５％以下の割合で含んでいてもよい。
　カルボキシル基を持つモノマーとしては、アクリル酸、メタクリル酸、マレイン酸、無水マレイン酸、イタコン酸及びマレイン酸モノブチルなどが挙げられる。
　また理由がある場合には、本発明の効果を阻害しない程度にヒドロキシ基を持つモノマーを含んでいても良く、例えば、モノマーの総モル数に基づいて５％以下の割合で含んでいてもよい。
　ヒドロキシ基を含むアクリル酸エステルまたはメタクリル酸エステルモノマーとしては、アクリル酸－２－ヒドロキシエチル、アクリル酸－３－ヒドロキシプロピル、アクリル酸－４－ヒドロキシブチル、メタクリル酸－２－ヒドロキシエチル、メタクリル酸－３－ヒドロキシプロピル、メタクリル酸－４－ヒドロキシブチルなどのアクリル酸エステルまたはメタクリル酸エステルなどが挙げられる。 The pressure-sensitive adhesive used in the present invention uses a monomer (or monomer mixture) mainly composed of (meth) acrylic acid ester having no carboxyl group in the molecule, and preferably has no hydroxy group in addition to the carboxyl group (meth). A monomer (or monomer mixture) made of an acrylate ester is used, but if there is a reason, a monomer having a carboxyl group to such an extent that the effect of the present invention is not impaired is, for example, 5% or less based on the total mole number of the monomer It may be included in proportions.
Examples of the monomer having a carboxyl group include acrylic acid, methacrylic acid, maleic acid, maleic anhydride, itaconic acid and monobutyl maleate.
If there is a reason, a monomer having a hydroxy group may be included to such an extent that the effects of the present invention are not impaired, and for example, it may be included in a proportion of 5% or less based on the total number of moles of monomers. .
Examples of acrylic acid ester or methacrylic acid ester monomers containing a hydroxy group include: 2-hydroxyethyl acrylate, 3-hydroxypropyl acrylate, 4-hydroxybutyl acrylate, 2-hydroxyethyl methacrylate, methacrylic acid Examples thereof include acrylic acid esters or methacrylic acid esters such as 3-hydroxypropyl and 4-hydroxybutyl methacrylate.
　アクリル酸エステル共重合体は、一般にラジカル重合により合成することができる。重合法としては、溶液重合法、乳化重合法又は塊状重合法などが挙げられるが、良好な粘着特性を得られることから溶液重合法が好ましい。
　重合反応は、全モノマー質量に対して０．１乃至１質量％程度の割合でラジカル重合開始剤を加え、窒素気流下、４０乃至９０℃程度の温度下にて、数時間乃至数十時間撹拌して行う。なおここで用いる重合開始剤としては、ベンゾイルパーオキサイド及びラウロイルパーオキサイドなどの有機過酸化物、アゾビスイソブチロニトリルなどのアゾ系開始剤などが挙げられる。 The acrylate copolymer can be generally synthesized by radical polymerization. Examples of the polymerization method include a solution polymerization method, an emulsion polymerization method, a bulk polymerization method, and the like, but a solution polymerization method is preferable because good adhesive properties can be obtained.
In the polymerization reaction, a radical polymerization initiator is added at a ratio of about 0.1 to 1% by mass with respect to the total monomer mass, and the mixture is stirred for several hours to several tens of hours at a temperature of about 40 to 90 ° C. in a nitrogen stream. And do it. Examples of the polymerization initiator used here include organic peroxides such as benzoyl peroxide and lauroyl peroxide, and azo initiators such as azobisisobutyronitrile.
　特にアクリル系粘着剤としてアクリル酸－２－エチルヘキシル、メタクリル酸－２－エチルヘキシル及びメタクリル酸ドデシルの３種のエステルを用いて得られる共重合体を用いる場合、凝集力が十分になるように重合度を高める必要があり、ラジカル重合開始剤の添加量を調整したり、重合時の濃度や重合溶媒を最適化するなどの常法に従い、粘着剤の極限粘度の数値範囲を調整する。具体的には、粘着剤の極限粘度が１．２～２．５の範囲となるように調整し、好ましくは１．５～２．５、特に好ましくは１．９～２．１の範囲となるように調整する。極限粘度の測定方法は、日本薬局方粘度測定法第１法に従って実施する。 In particular, when a copolymer obtained using three types of esters of 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate and dodecyl methacrylate is used as the acrylic pressure-sensitive adhesive, the polymerization degree is set so that the cohesive force is sufficient. The amount of the intrinsic viscosity of the pressure-sensitive adhesive is adjusted according to conventional methods such as adjusting the amount of radical polymerization initiator added and optimizing the polymerization concentration and polymerization solvent. Specifically, the intrinsic viscosity of the pressure-sensitive adhesive is adjusted to be in the range of 1.2 to 2.5, preferably 1.5 to 2.5, particularly preferably 1.9 to 2.1. Adjust so that The intrinsic viscosity is measured according to the Japanese Pharmacopoeia Viscosity Measurement Method Method 1.
（２）塩基性薬物
　本発明の経皮吸収型製剤の粘着剤層に含まれる塩基性薬物としては特に限定されず、例えば、解熱消炎鎮痛薬（ブトルファノール酒石酸塩、ペリソキサールクエン酸塩等）、局所麻酔薬（リドカイン、プロカイン等やこれらの塩酸塩等）、排尿障害治療薬（タムスロシン等）、抗アレルギー薬（ケトチフェンフマル酸塩等）、気管支拡張薬（サルメテロール）、セロトニン受容体拮抗制吐薬、麻薬系の鎮痛薬（フェンタニルクエン酸塩等）などが挙げられる。
　これらの薬物は一種を単独使用してもよいし、或いは二種以上を併用してもよい。 (2) Basic drug The basic drug contained in the adhesive layer of the transdermal preparation of the present invention is not particularly limited. For example, antipyretic anti-inflammatory analgesics (butorphanol tartrate, perisoxal citrate, etc.) Local anesthetics (such as lidocaine, procaine, and their hydrochlorides), dysuria drugs (such as tamsulosin), antiallergic drugs (such as ketotifen fumarate), bronchodilators (salmeterol), serotonin receptor antagonist antiemetics And narcotic analgesics (fentanyl citrate, etc.).
These drugs may be used alone or in combination of two or more.
　上記塩基性薬物の中でも、タムスロシンを使用することが望ましい。タムスロシンは遊離塩基の形態又は塩の形態で粘着剤層中に存在し、塩の形態で存在する場合には塩基性の添加物を加えて薬物の一部又は全部を遊離塩基の形態に変換した後、使用することが望ましい。
　タムスロシンの塩には、薬理学的に許容される塩、例えば塩酸、硫酸、臭化水素酸等の無機酸、又は酢酸、シュウ酸、マレイン酸、フマル酸、クエン酸、乳酸等の有機酸との酸付加塩があり、これらを使用することができ、特に、塩酸塩、すなわちタムスロシン塩酸塩は臨床的に有用である。
　また薬物の一部又は全部を遊離塩基の形態に変換する際に使用する塩基性の添加物の例としては、水酸化カリウム、水酸化ナトリウム、酢酸塩、モノエタノールアミン、ジエタノールアミン、ジイソプロパノールアミン、トリスヒドロキシメチルアミノメタン等が挙げられる。 Among the above basic drugs, it is desirable to use tamsulosin. Tamsulosin is present in the pressure-sensitive adhesive layer in the form of a free base or salt, and when present in the form of a salt, a basic additive is added to convert a part or all of the drug into the form of the free base. It is desirable to use it later.
Tamsulosin salts include pharmacologically acceptable salts such as inorganic acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, or organic acids such as acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid and lactic acid. These acid addition salts can be used and in particular the hydrochloride salt, ie tamsulosin hydrochloride, is clinically useful.
Examples of basic additives used to convert a part or all of the drug into the free base form include potassium hydroxide, sodium hydroxide, acetate, monoethanolamine, diethanolamine, diisopropanolamine, And trishydroxymethylaminomethane.
　本発明の経皮吸収型製剤の粘着剤層に含まれる上記塩基性薬物の量は、薬物の種類や投与目的に応じて適宜変更可能であるが、通常、粘着剤層の全質量基準で０．１乃至２０質量％、好ましくは１乃至１０質量％であることが望ましい。 The amount of the basic drug contained in the pressure-sensitive adhesive layer of the percutaneous absorption type preparation of the present invention can be appropriately changed depending on the kind of drug and the purpose of administration, but is usually 0 based on the total mass of the pressure-sensitive adhesive layer. It is desirable that the content be 1 to 20% by mass, preferably 1 to 10% by mass.
（３）シリカ粒子
　本発明の経皮吸収型製剤の粘着剤層に含まれるシリカ粒子は、平均粒子径が５μｍ以下のものを使用する。
　上記シリカ粒子の含有量は、液状成分である後述する多価アルコール脂肪酸エステルの含有量によるが、好ましくは粘着剤層の全質量基準で１乃至２０質量％、より好ましくは１乃至１０質量％であることが望ましい。 (3) Silica particles The silica particles contained in the pressure-sensitive adhesive layer of the transdermal preparation of the present invention have an average particle size of 5 μm or less.
The content of the silica particles depends on the content of a later-described polyhydric alcohol fatty acid ester which is a liquid component, but is preferably 1 to 20% by mass, more preferably 1 to 10% by mass based on the total mass of the pressure-sensitive adhesive layer. It is desirable to be.
（４）多価アルコール脂肪酸エステル
　本発明の経皮吸収型製剤の粘着剤層には、多価アルコール脂肪酸エステルを含有する。特に、多価アルコール脂肪酸エステルの主成分としては、プロピレングリコールモノラウレートが特に望ましい。主成分とは、配合する多価アルコール脂肪酸エステルの少なくとも５０％以上、好ましくは９０％以上を占める場合とする。プロピレングリコールモノラウレートを粘着剤層に含有させることで、薬物の経皮吸収性を向上させ、ソフトな感触のある粘着剤とすることができる。プロピレングリコールモノラウレート以外の多価アルコール脂肪酸エステルを１種類以上併用させることもできる。
　その他の多価アルコール脂肪酸エステルとしては、プロピレングリコール脂肪酸エステル、グリセリン脂肪酸エステル、ソルビタン脂肪酸エステル、ショ糖脂肪酸エステル等が挙げられ、好ましくはプロピレングリコール脂肪酸エステルを用いることが望ましい。
　プロピレングリコール脂肪酸エステルの具体例としては、プロピレングリコールモノパルミテート、プロピレングリコールモノステアレート、プロピレングリコールモノオレエート等が挙げられ、中でも、プロピレングリコールモノラウレートが好ましい。
　上記多価アルコール脂肪酸エステルの含有量は、粘着剤層の全質量基準で１５乃至４０質量％、好ましくは２０乃至３５質量％である。特にプロピレングリコールモノラウレートを２０乃至３５質量％含有することが好ましい。
　なお、プロピレングリコールモノラウレートの代わりに、脂肪酸エステルとしてミリスチン酸イソプロピルを用いた場合は、経皮吸収性が低い結果が得られており、本発明の構成としては不適であり、特段の理由が無いかぎり配合しない方が望ましい。 (4) Polyhydric alcohol fatty acid ester The adhesive layer of the transdermal preparation of the present invention contains a polyhydric alcohol fatty acid ester. In particular, propylene glycol monolaurate is particularly desirable as the main component of the polyhydric alcohol fatty acid ester. The main component is at least 50% or more, preferably 90% or more of the polyhydric alcohol fatty acid ester to be blended. By containing propylene glycol monolaurate in the pressure-sensitive adhesive layer, the transdermal absorbability of the drug can be improved and a pressure-sensitive adhesive with a soft feel can be obtained. One or more polyhydric alcohol fatty acid esters other than propylene glycol monolaurate can be used in combination.
Other polyhydric alcohol fatty acid esters include propylene glycol fatty acid esters, glycerin fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, and the like, and it is desirable to use propylene glycol fatty acid esters.
Specific examples of the propylene glycol fatty acid ester include propylene glycol monopalmitate, propylene glycol monostearate, propylene glycol monooleate and the like, among which propylene glycol monolaurate is preferable.
The content of the polyhydric alcohol fatty acid ester is 15 to 40% by mass, preferably 20 to 35% by mass, based on the total mass of the pressure-sensitive adhesive layer. In particular, it is preferable to contain 20 to 35% by mass of propylene glycol monolaurate.
In addition, when isopropyl myristate is used as the fatty acid ester instead of propylene glycol monolaurate, a result of low percutaneous absorption is obtained, which is not suitable as the configuration of the present invention, and has a special reason. It is desirable not to mix unless there is.
（５）その他添加剤
　本発明の経皮吸収型製剤の粘着剤層には、上記成分の他に、溶解剤、薬学的に許容され通常貼付剤等に用いられる透過促進剤、充填剤、酸化防止剤などを更に含むことができる。
　また、本発明の経皮吸収型製剤の粘着剤層に用いるアクリル系粘着剤において、カルボキシル基を持つモノマーを使用する場合には、粘着剤の凝集力を増大させる目的で、各種架橋剤を更に添加することができる。
　架橋剤としては、多官能イソシアネート化合物、多官能エポキシ化合物及び多価金属塩などが挙げられる。 (5) Other additives In the adhesive layer of the transdermal preparation of the present invention, in addition to the above components, a solubilizer, a pharmaceutically acceptable permeation enhancer, a filler, an oxidation agent An inhibitor or the like can be further included.
Moreover, in the acrylic adhesive used for the adhesive layer of the transdermal preparation of the present invention, when a monomer having a carboxyl group is used, various crosslinking agents are further added for the purpose of increasing the cohesive force of the adhesive. Can be added.
Examples of the crosslinking agent include polyfunctional isocyanate compounds, polyfunctional epoxy compounds, and polyvalent metal salts.
２）支持体
　本発明の経皮吸収型製剤は、粘着剤、塩基性薬物、シリカ粒子、多価アルコール脂肪酸エステル及び必要に応じてその他添加剤等を配合して得られた混合物（粘着剤）を、適当な剥離ライナー上に塗布し、その上に適当な支持体を貼り合わせ、必要により適当な大きさに切断して、最終的な製品とすることができる。
　上記支持体は患部への追従性ならびに貼付時の自己支持性などを加味して、柔軟性、伸縮性ならびに厚さなどを考慮し、目的に応じて適宜選択する。
　また、本発明の経皮吸収型製剤は、経皮吸収性向上のために、特定の数値範囲の透湿度を有する支持体を使用することが好ましい。具体的には、支持体の透湿度（ＪＩＳＺ０２０８、４０℃、９０％ＲＨにおいて測定される）は３００ｇ／ｍ2・２４ｈｒ以下、特に５０ｇ／ｍ2・２４ｈｒ以下のものが好ましい。支持体の透湿度を上記範囲内とすることにより、多価アルコール脂肪酸エステルの促進効果が増し、塩基性薬物の皮膚透過性が増大する。
　また、本発明の経皮吸収型製剤は、皮膚への追従性向上、違和感の低減のために、支持体の剛軟度を特定の値とするように調整することが好ましい。具体的には、支持体の剛軟度（ハートループ法による）を８０ｍｍ以上に制限する。支持体の剛軟度を上記範囲とすることにより、経皮吸収型製剤の柔軟性が向上し、皮膚への追従性が向上し、貼付時の違和感が減少する。
　このような支持体として、含浸紙、コート紙、上質紙、クラフト紙、和紙及びグラシン紙などの紙、ポリエステルフィルム、ポリエチレンフィルム、ポリプロピレンフィルム、ポリ塩化ビニルフィルム、ポリカーボネートフィルム、ポリウレタンフィルム及びセロハンフィルムなどのプラスチックフィルム、発泡体、ポリエステル繊維、ポリエチレン繊維及びポリプロピレン繊維などからなる不織布、織布及び編布などの布基材、これらの積層体などが挙げられる。これらの中でも伸縮性の点では不織布、織布及び編布が、使用性の面では透明性を有するプラスチックフィルムが好ましい。
　用いる支持体の厚さは、不織布、織布及び編布では好ましくは１０μｍ乃至１０００μｍ、より好ましくは１０μｍ乃至７００μｍである。また、プラスチックフィルムであれば好ましくは５μｍ乃至２００μｍ、より好ましくは５μｍ乃至１００μｍである。
　また支持体は、上記不織布、織布、編布及びプラスチックフィルムのうち、一種を単独で用いるか、あるいは二種以上を貼り合わせた積層体を用いることが望ましい。
　特に、上記で列挙したウレタンフィルム、編布、不織布、織布など、単独で支持体として用いた場合に支持体の透湿度が上記で示した範囲より高くなる場合は、ポリエチレンフィルムやポリエステルフィルムなどの樹脂フィルムとラミネートしたものが好ましい。特に、二種以上を貼り合わせた積層体とする場合は、粘着剤、接着剤、熱ロールにより融着する方法等、用いられる素材によって適宜選択される。
　本発明において特に好ましい支持体は、ポリオレフィンフィルムで、ＬＬＤＰＥ、ＬＤＰＥ等のポリエチレンフィルムが好ましい。この場合、支持体の厚さとしては５～１２０μｍが好ましく、特に好ましくは１０～７０μｍ、さらに好ましくは２０～７０μｍである。前記ポリオレフィンフィルムは、前述の透湿度及び剛軟度を満たすものが好ましい。 2) Support The transdermal preparation of the present invention is a mixture (adhesive) obtained by blending an adhesive, a basic drug, silica particles, a polyhydric alcohol fatty acid ester, and other additives as required. Is coated on a suitable release liner, a suitable support is laminated thereon, and if necessary, it is cut into a suitable size to obtain a final product.
The support is appropriately selected according to the purpose in consideration of flexibility, stretchability, thickness, and the like in consideration of followability to the affected area and self-supporting property at the time of application.
In addition, the transdermal preparation of the present invention preferably uses a support having a moisture permeability in a specific numerical range in order to improve transdermal absorbability. Specifically, the moisture permeability (measured at JISZ0208, 40 ° C., 90% RH) of the support is preferably 300 g / m 2 · 24 hr or less, particularly preferably 50 g / m 2 · 24 hr or less. By setting the moisture permeability of the support within the above range, the promoting effect of the polyhydric alcohol fatty acid ester is increased, and the skin permeability of the basic drug is increased.
Further, the percutaneous absorption type preparation of the present invention is preferably adjusted so that the bending resistance of the support is a specific value in order to improve the followability to the skin and reduce the uncomfortable feeling. Specifically, the bending resistance (by the heart loop method) of the support is limited to 80 mm or more. By setting the bending resistance of the support within the above range, the flexibility of the transdermal preparation is improved, the followability to the skin is improved, and the uncomfortable feeling at the time of application is reduced.
As such a support, paper such as impregnated paper, coated paper, fine paper, craft paper, Japanese paper and glassine paper, polyester film, polyethylene film, polypropylene film, polyvinyl chloride film, polycarbonate film, polyurethane film, cellophane film, etc. And non-woven fabrics made of plastic films, foams, polyester fibers, polyethylene fibers and polypropylene fibers, fabric base materials such as woven fabrics and knitted fabrics, and laminates thereof. Among these, nonwoven fabrics, woven fabrics, and knitted fabrics are preferable in terms of stretchability, and plastic films having transparency in terms of usability are preferable.
The thickness of the support used is preferably 10 μm to 1000 μm, more preferably 10 μm to 700 μm for nonwoven fabrics, woven fabrics and knitted fabrics. In the case of a plastic film, the thickness is preferably 5 μm to 200 μm, more preferably 5 μm to 100 μm.
In addition, it is desirable that the support is used alone or in the form of a laminate in which two or more of the nonwoven fabric, woven fabric, knitted fabric and plastic film are bonded.
In particular, when the moisture permeability of the support is higher than the range shown above when used alone as a support, such as the urethane film, knitted fabric, non-woven fabric, woven fabric listed above, a polyethylene film, a polyester film, etc. Those laminated with a resin film are preferred. In particular, when a laminate obtained by bonding two or more types is selected, it is appropriately selected depending on the materials used, such as a pressure-sensitive adhesive, an adhesive, and a method of fusing with a hot roll.
In the present invention, a particularly preferable support is a polyolefin film, and polyethylene films such as LLDPE and LDPE are preferable. In this case, the thickness of the support is preferably 5 to 120 μm, particularly preferably 10 to 70 μm, and further preferably 20 to 70 μm. The polyolefin film preferably satisfies the above-mentioned moisture permeability and bending resistance.
３）剥離ライナー
　本発明の経皮吸収型製剤に用いられる剥離ライナーは、粘着剤層からの容易な剥離性、通気性、通水性ならびに柔軟性などを考慮して、目的に応じて適宜選択する。好ましくはポリエチレン、ポリプロピレン及びポリエステル等の高分子材料からなるフィルムが使用され、剥離性を高めるためにフィルム表面をシリコン処理、又はフルオロカーボン処理して用いることもできる。 3) Release liner The release liner used in the transdermal preparation of the present invention is appropriately selected according to the purpose in consideration of easy release from the pressure-sensitive adhesive layer, air permeability, water permeability and flexibility. . Preferably, a film made of a polymer material such as polyethylene, polypropylene and polyester is used, and the film surface can be treated with silicon or fluorocarbon in order to enhance the peelability.
４）経皮吸収型製剤の製法
　本発明の経皮吸収型製剤の粘着剤層に用いる粘着剤、すなわち前記アクリル酸エステル共重合体を前述の溶液重合法で合成した場合、重合後にはアクリル酸エステル共重合体を含有する溶液として得られることになる。この溶液をそのまま、あるいは適当な有機溶媒で希釈し、「アクリル系粘着剤溶液」として本発明の経皮吸収型製剤の製造に用いることができることから、溶液塗工法を用いることが好ましい。
　溶液塗工法では、まずはじめに、アクリル系粘着剤、塩基性薬物、シリカ粒子、多価アルコール脂肪酸エステル及び必要に応じてその他添加剤などを添加した溶液を調製する。この溶液に有機溶媒を添加して適宜濃度を調整する。
　ここで用いられる有機溶媒としては、ｎ－ヘキサン、トルエン、酢酸エチル、アセトン、メチルエチルケトンなどがあり、これら有機溶媒にて希釈した希釈液中の粘着剤成分の濃度は好ましくは１０乃至５０質量％、より好ましくは２０乃至４０質量％である。
　次に、各成分を含有する溶液（希釈液）を撹拌して均一に溶解、分散させる。このようにして得られた溶液をナイフコーター、コンマコーター又はリバースコーターなどの塗工機を用いて、たとえば剥離ライナー（シリコーン処理したポリエステルフィルム）上に均一に塗布する。
　塗布後、約４０℃乃至１３０℃の温度に保持した乾熱雰囲気下に約３０秒乃至１０分間保持して有機溶媒を揮発させる。使用する有機溶媒の種類及び塗布する粘着剤の厚みにより、乾燥条件を適宜選択する。
　前記の方法にて得られた粘着剤層の表面に支持体をラミネートし、適切な大きさに裁断することにより、経皮吸収型製剤（貼付剤）を得ることができる。支持体の種類によっては、支持体上に粘着剤層を形成した後、粘着剤層の表面に剥離ライナーをラミネートしても良い。その後、４０～６０℃の雰囲気下で１週間程度保存し、粘着剤層中の各種成分をなじませる熟成工程を経ることが場合によっては望ましい。 4) Production method of percutaneous absorption type preparation When the pressure-sensitive adhesive used in the pressure-sensitive adhesive layer of the percutaneous absorption type preparation of the present invention, that is, the acrylate copolymer is synthesized by the aforementioned solution polymerization method, acrylic acid is polymerized after the polymerization. It will be obtained as a solution containing an ester copolymer. Since this solution can be used as it is or diluted with a suitable organic solvent and used as the “acrylic adhesive solution” for the production of the transdermal preparation of the present invention, it is preferable to use the solution coating method.
In the solution coating method, first, a solution to which an acrylic pressure-sensitive adhesive, a basic drug, silica particles, a polyhydric alcohol fatty acid ester, and other additives as necessary are added is prepared. An organic solvent is added to this solution to adjust the concentration appropriately.
Examples of the organic solvent used here include n-hexane, toluene, ethyl acetate, acetone, and methyl ethyl ketone. The concentration of the adhesive component in the diluted solution diluted with these organic solvents is preferably 10 to 50% by mass, More preferably, it is 20 to 40% by mass.
Next, the solution (diluent) containing each component is stirred and dissolved and dispersed uniformly. The solution thus obtained is uniformly applied on, for example, a release liner (silicone-treated polyester film) using a coating machine such as a knife coater, comma coater or reverse coater.
After the application, the organic solvent is volatilized by holding for about 30 seconds to 10 minutes in a dry heat atmosphere maintained at a temperature of about 40 ° C to 130 ° C. The drying conditions are appropriately selected depending on the type of organic solvent used and the thickness of the pressure-sensitive adhesive to be applied.
A transdermal absorption preparation (patch) can be obtained by laminating a support on the surface of the pressure-sensitive adhesive layer obtained by the above method and cutting the support into an appropriate size. Depending on the type of the support, after the pressure-sensitive adhesive layer is formed on the support, a release liner may be laminated on the surface of the pressure-sensitive adhesive layer. Thereafter, it may be desirable to store in an atmosphere of 40 to 60 ° C. for about one week and to undergo an aging step in which various components in the pressure-sensitive adhesive layer are adapted.
　以下、実施例を挙げて、本発明を更に詳しく説明するが、本発明は、これら実施例に限定されるものでない。 Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.
［使用した各成分］
　実施例及び比較例で使用した粘着剤等の各成分の詳細は以下の通りである。
＜粘着剤＞
・アクリル系粘着剤（１）
　アクリル酸－２－エチルヘキシル、メタクリル酸－２－エチルヘキシル、メタクリル酸ドデシルを１：８：１のモル比にて混合したもの１００質量部、重合開始剤としてラウロイルパーオキサイド０．５質量部を用い、酢酸エチル中３５％の濃度にて、常法の溶液重合法により重合し、アクリル系粘着剤（１）を得た。得られた粘着剤の極限粘度は２．０であった。
・アクリル系粘着剤（２）
　日本カーバイド工業（株）製「ニカゾール　ＴＳ－６２０」（アクリル酸メチル・アクリル酸－２－エチルヘキシル共重合樹脂エマルジョン）をアクリル系粘着剤（２）として用いた。
・アクリル系粘着剤（３）
　アクリル酸－２－エチルヘキシルとアクリル酸を９０．４％：９．６％のモル比で混合したもの１００質量部、重合開始剤としてラウロイルパーオキサイド０．５質量部を用い、酢酸エチル中３３％の濃度にて、常法の溶液重合法により重合し、アクリル系粘着剤（３）を得た。
・アクリル系粘着剤（４）
　ヘンケル社の「Ｄｕｒｏ－Ｔａｋ　８７－２２８７」（ヒドロキシ基含有アクリル系重合体）をアクリル系粘着剤（４）として用いた。
・ゴム系粘着剤
　スチレン・イソプレン・スチレンブロック共重合体（ＳＩＳ５００２、ＪＳＲ（株））４９．５質量％、水添ロジンエステル（パインクリスタルＫＥ－３１１、荒川化学工業（株））４９．５質量％、ジブチルヒドロキシトルエン（ＢＨＴ－Ｆ、キリンフードテック（株））１．０質量％を用いてゴム系粘着剤を得た。
＜塩基性薬物＞
・タムスロシン：タムスロシン遊離塩基
・タムスロシン塩酸塩：タムスロシンの塩酸塩
・サルメテロール：サルメテロール遊離塩基
・ケトチフェンフマル酸塩：ケトチフェンのフマル酸塩
＜酸性薬物＞
・インドメタシン
・アスピリン
＜シリカ粒子＞
・軽質無水ケイ酸（１）：アエロジル２００（平均粒子径：約０．０１２μｍ、日本アエロジル（株））
・軽質無水ケイ酸（２）：サイリシア３５０（平均粒子径：３．９μｍ、富士シリシア化学（株））
・含水ケイ酸：サイロスフェアＣ１５１０（平均粒子径：１０μｍ、富士シリシア化学（株））
＜多価アルコール脂肪酸エステル＞
・プロピレングリコールモノラウレート：リケマールＰＬ－１００（理研ビタミン（株））
＜その他＞
・モノエタノールアミン：試薬特級（関東化学（株））
・ポリイソシアネート：コロネートＨＬ（日本ポリウレタン工業（株））
・ミリスチン酸イソプロピル：ＩＰＭ－Ｒ（高級アルコール工業（株））
・ソルビタンモノラウレート：試薬（関東化学（株））
・ソルビタンモノオレエート：試薬（関東化学（株））
・ラウリン酸ジエタノールアミド：試薬（和光純薬工業（株）） [Each component used]
The detail of each component, such as an adhesive used in the Example and the comparative example, is as follows.
<Adhesive>
・ Acrylic adhesive (1)
100 parts by mass of 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate and dodecyl methacrylate mixed at a molar ratio of 1: 8: 1, and 0.5 parts by mass of lauroyl peroxide as a polymerization initiator were used. Polymerization was performed by a conventional solution polymerization method at a concentration of 35% in ethyl acetate to obtain an acrylic pressure-sensitive adhesive (1). The intrinsic viscosity of the obtained pressure-sensitive adhesive was 2.0.
・ Acrylic adhesive (2)
“Nicazole TS-620” (methyl acrylate / acrylic acid-2-ethylhexyl copolymer resin emulsion) manufactured by Nippon Carbide Industries Co., Ltd. was used as the acrylic pressure-sensitive adhesive (2).
・ Acrylic adhesive (3)
100 parts by weight of 2-ethylhexyl acrylate and acrylic acid mixed at a molar ratio of 90.4%: 9.6%, 0.5 parts by weight of lauroyl peroxide as a polymerization initiator, and 33% in ethyl acetate The acrylic pressure-sensitive adhesive (3) was obtained by polymerization using a conventional solution polymerization method.
・ Acrylic adhesive (4)
“Duro-Tak 87-2287” (hydroxy group-containing acrylic polymer) manufactured by Henkel was used as the acrylic pressure-sensitive adhesive (4).
Rubber adhesive Styrene / isoprene / styrene block copolymer (SIS5002, JSR Corp.) 49.5% by mass, hydrogenated rosin ester (Pine Crystal KE-311, Arakawa Chemical Industries Ltd.) 49.5% by mass %, Dibutylhydroxytoluene (BHT-F, Kirin Foodtech Co., Ltd.) 1.0 mass% was used to obtain a rubber-based pressure-sensitive adhesive.
<Basic drug>
• Tamsulosin: Tamsulosin free base • Tamsulosin hydrochloride: Tamsulosin hydrochloride • Salmeterol: salmeterol free base • Ketotifen fumarate: Ketotifen fumarate <acidic drug>
・ Indomethacin / aspirin <silica particles>
-Light silicic acid anhydride (1): Aerosil 200 (average particle size: about 0.012 μm, Nippon Aerosil Co., Ltd.)
-Light anhydrous silicic acid (2): Silicia 350 (average particle size: 3.9 μm, Fuji Silysia Chemical Ltd.)
Hydrous silicic acid: Cyrossphere C1510 (average particle size: 10 μm, Fuji Silysia Chemical Ltd.)
<Polyhydric alcohol fatty acid ester>
・ Propylene glycol monolaurate: Riquemar PL-100 (RIKEN Vitamin Co., Ltd.)
<Others>
・ Monoethanolamine: Special reagent grade (Kanto Chemical Co., Inc.)
・ Polyisocyanate: Coronate HL (Nippon Polyurethane Industry Co., Ltd.)
・ Isopropyl myristate: IPM-R (Higher Alcohol Industry Co., Ltd.)
・ Sorbitan monolaurate: Reagent (Kanto Chemical Co., Inc.)
・ Sorbitan monooleate: Reagent (Kanto Chemical Co., Inc.)
・ Lauric acid diethanolamide: Reagent (Wako Pure Chemical Industries, Ltd.)
＜実施例１＞
　以下の組成及び製法により、実施例１の経皮吸収型製剤を得た。
（組成）
１．アクリル系粘着剤（１）　　　　　　　　　　５２．０質量％
２．軽質無水ケイ酸（１）　　　　　　　　　　　１０．０質量％
３．プロピレングリコールモノラウレート　　　　３０．０質量％
４．タムスロシン　　　　　　　　　　　　　　　　８．０質量％
（製法）
　上記成分を秤量後、全体の固形分が酢酸エチル溶液中２０質量％となるように調製し、均一になるまで撹拌した。
　乾燥後の粘着剤層の塗布量が２５ｇ／ｍ2となるように、７５μｍ厚の片面シリコン処理ＰＥＴ（ポリエチレンテレフタレート）フィルム（フィルムバイナ７５Ｅ－００１０　Ｎｏ．２３、藤森工業（株））上に塗布し、１１０℃で３分間乾燥させた。
　次いで、粘着剤層の片面に２５μｍ厚ののＰＥＴフィルム（ルミラーＳ１０、東レ（株）、透湿度３８ｇ／ｍ2・２４ｈｒ）を貼り合わせて裁断し、経皮吸収型製剤を得た。 <Example 1>
The percutaneous absorption type preparation of Example 1 was obtained by the following composition and production method.
(composition)
1. Acrylic adhesive (1) 52.0 mass%
2. Light anhydrous silicic acid (1) 10.0% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Tamsulosin 8.0% by mass
(Manufacturing method)
After weighing the above components, the total solid content was adjusted to 20% by mass in the ethyl acetate solution and stirred until uniform.
Coating on a single-sided siliconized PET (polyethylene terephthalate) film (film binder 75E-0010 No. 23, Fujimori Kogyo Co., Ltd.) having a thickness of 75 μm so that the coating amount of the pressure-sensitive adhesive layer after drying is 25 g / m 2. And dried at 110 ° C. for 3 minutes.
Next, a 25 μm thick PET film (Lumirror S10, Toray Industries, Inc., moisture permeability 38 g / m 2 · 24 hr) was bonded to one side of the pressure-sensitive adhesive layer and cut to obtain a transdermally absorbable preparation.
＜実施例２＞
　プロピレングリコールモノラウレートの使用量を２５質量％とし、それに伴い各成分を以下の組成とし、実施例１と同様の製法にて、実施例２の経皮吸収型製剤を得た。
（組成）
１．アクリル系粘着剤（１）　　　　　　　　　　６５．０質量％
２．軽質無水ケイ酸（１）　　　　　　　　　　　　５．０質量％
３．プロピレングリコールモノラウレート　　　　２５．０質量％
４．タムスロシン　　　　　　　　　　　　　　　　５．０質量％ <Example 2>
The amount of propylene glycol monolaurate was 25% by mass, and each component was made the following composition accordingly, and the percutaneous absorption type preparation of Example 2 was obtained by the same production method as Example 1.
(composition)
1. Acrylic adhesive (1) 65.0 mass%
2. Light anhydrous silicic acid (1) 5.0% by mass
3. Propylene glycol monolaurate 25.0% by mass
4). Tamsulosin 5.0% by mass
＜実施例３＞
　プロピレングリコールモノラウレートの使用量を２０質量％とし、それに伴い各成分を以下の組成とし、実施例１と同様の製法にて、実施例３の経皮吸収型製剤を得た。
（組成）
１．アクリル系粘着剤（１）　　　　　　　　　　７２．０質量％
２．軽質無水ケイ酸（１）　　　　　　　　　　　　５．０質量％
３．プロピレングリコールモノラウレート　　　　２０．０質量％
４．タムスロシン　　　　　　　　　　　　　　　　３．０質量％ <Example 3>
Propylene glycol monolaurate was used in an amount of 20% by mass, and as a result, each component had the following composition, and the percutaneous absorption type preparation of Example 3 was obtained by the same production method as Example 1.
(composition)
1. Acrylic adhesive (1) 72.0 mass%
2. Light anhydrous silicic acid (1) 5.0% by mass
3. Propylene glycol monolaurate 20.0% by mass
4). Tamsulosin 3.0% by mass
＜実施例４＞
　シリカ粒子を軽質無水ケイ酸（２）とした以外は実施例１と同じ成分を用い、以下の組成を用いて実施例１と同様の製法にて、実施例４の経皮吸収型製剤を得た。
（組成）
１．アクリル系粘着剤（１）　　　　　　　　　　５７．０質量％
２．軽質無水ケイ酸（２）　　　　　　　　　　　１０．０質量％
３．プロピレングリコールモノラウレート　　　　２５．０質量％
４．タムスロシン　　　　　　　　　　　　　　　　８．０質量％ <Example 4>
The transdermal absorption preparation of Example 4 was obtained in the same manner as in Example 1 except that the silica particles were changed to light anhydrous silicic acid (2) and the same composition as in Example 1 was used. It was.
(composition)
1. Acrylic adhesive (1) 57.0% by mass
2. Light anhydrous silicic acid (2) 10.0% by mass
3. Propylene glycol monolaurate 25.0% by mass
4). Tamsulosin 8.0% by mass
＜実施例５＞
　塩基性薬物をサルメテロールとした以外は実施例１と同じ成分を用い、以下の組成を用いて実施例１と同様の製法にて、実施例５の経皮吸収型製剤を得た。
（組成）
１．アクリル系粘着剤（１）　　　　　　　　　　５５．０質量％
２．軽質無水ケイ酸（１）　　　　　　　　　　　１０．０質量％
３．プロピレングリコールモノラウレート　　　　３０．０質量％
４．サルメテロール　　　　　　　　　　　　　　　５．０質量％ <Example 5>
A percutaneously absorbable preparation of Example 5 was obtained in the same manner as in Example 1 using the same components as in Example 1 except that salmeterol was used as the basic drug.
(composition)
1. Acrylic adhesive (1) 55.0 mass%
2. Light anhydrous silicic acid (1) 10.0% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Salmeterol 5.0% by mass
＜実施例６＞
　塩基性薬物をケトチフェンフマル酸塩とし、さらに薬物の一部又は全部を遊離塩基の形態に変換する際に使用する塩基性の添加物としてモノエタノールアミンを使用した以外は実施例１と同じ成分を用い、以下の組成を用いて、乾燥後の粘着剤層の塗布量を４０ｇ／ｍ2とすること以外は、実施例１と同様の製法にて、実施例６の経皮吸収型製剤を得た。
（組成）
１．アクリル系粘着剤（１）　　　　　　　　　　４７．５質量％
２．軽質無水ケイ酸（１）　　　　　　　　　　　１０．０質量％
３．プロピレングリコールモノラウレート　　　　３０．０質量％
４．モノエタノールアミン　　　　　　　　　　　　２．５質量％
５．ケトチフェンフマル酸塩　　　　　　　　　　　１０．０質量％ <Example 6>
The basic ingredient was ketotifen fumarate, and the same ingredients as in Example 1 were used except that monoethanolamine was used as a basic additive used when converting part or all of the drug into the free base form. Using the following composition, the percutaneously absorbable preparation of Example 6 was obtained in the same manner as in Example 1, except that the coating amount of the pressure-sensitive adhesive layer after drying was 40 g / m 2. It was.
(composition)
1. Acrylic adhesive (1) 47.5% by mass
2. Light anhydrous silicic acid (1) 10.0% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Monoethanolamine 2.5% by mass
5). Ketotifen fumarate 10.0% by mass
＜実施例７＞
　粘着剤としてアクリル系粘着剤（２）を使用し、以下の組成及び製法を用いて、実施例７の経皮吸収型製剤を得た。
（組成）
１．アクリル系粘着剤（２）　　　　　　　　　　５７．０質量％
２．軽質無水ケイ酸（１）　　　　　　　　　　　　５．０質量％
３．プロピレングリコールモノラウレート　　　　３０．０質量％
４．タムスロシン　　　　　　　　　　　　　　　　８．０質量％
（製法）
　上記成分を秤量後、全体の固形分がエマルジョン中５０質量％となるように調製し、均一になるまで撹拌した。
　乾燥後の粘着剤層の塗布量が２５ｇ／ｍ2となるように、７５μｍ厚の片面シリコン処理ＰＥＴ（ポリエチレンテレフタレート）フィルム（フィルムバイナ７５Ｅ－００１０　Ｎｏ．２３、藤森工業（株））上に塗布し、１１０℃で３分間乾燥させた。
　次いで、粘着剤層の片面に２５μｍのＰＥＴフィルム（ルミラーＳ１０、東レ（株）、透湿度３８ｇ／ｍ2・２４ｈｒ）を貼り合わせて裁断し、経皮吸収型製剤を得た。 <Example 7>
Using the acrylic pressure-sensitive adhesive (2) as the pressure-sensitive adhesive, the transdermal preparation of Example 7 was obtained using the following composition and production method.
(composition)
1. Acrylic adhesive (2) 57.0% by mass
2. Light anhydrous silicic acid (1) 5.0% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Tamsulosin 8.0% by mass
(Manufacturing method)
After weighing the above components, the total solid content was adjusted to 50% by mass in the emulsion and stirred until uniform.
Coating on a single-sided siliconized PET (polyethylene terephthalate) film (film binder 75E-0010 No. 23, Fujimori Kogyo Co., Ltd.) having a thickness of 75 μm so that the coating amount of the pressure-sensitive adhesive layer after drying is 25 g / m 2. And dried at 110 ° C. for 3 minutes.
Next, a 25 μm PET film (Lumirror S10, Toray Industries, Inc., moisture permeability 38 g / m 2 · 24 hr) was bonded to one side of the pressure-sensitive adhesive layer and cut to obtain a percutaneous absorption type preparation.
＜実施例８＞
　各成分の使用量を以下の組成とし、実施例１と同様の製法にて、実施例８の経皮吸収型製剤を得た。
（組成）
１．アクリル系粘着剤（１）　　　　　　　　　　５４．０質量％
２．軽質無水ケイ酸（１）　　　　　　　　　　　１０．０質量％
３．プロピレングリコールモノラウレート　　　　３０．０質量％
４．タムスロシン　　　　　　　　　　　　　　　　６．０質量％ <Example 8>
The amount of each component used was set as follows, and the percutaneous absorption type preparation of Example 8 was obtained by the same production method as Example 1.
(composition)
1. Acrylic adhesive (1) 54.0% by mass
2. Light anhydrous silicic acid (1) 10.0% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Tamsulosin 6.0% by mass
＜実施例９＞
　各成分の使用量を以下の組成とし、実施例１と同様の製法にて、実施例９の経皮吸収型製剤を得た。
（組成）
１．アクリル系粘着剤（１）　　　　　　　　　　５７．０質量％
２．軽質無水ケイ酸（１）　　　　　　　　　　　１０．０質量％
３．プロピレングリコールモノラウレート　　　　３０．０質量％
４．タムスロシン　　　　　　　　　　　　　　　　３．０質量％ <Example 9>
The amount of each component used was set to the following composition, and the percutaneous absorption type preparation of Example 9 was obtained by the same production method as Example 1.
(composition)
1. Acrylic adhesive (1) 57.0% by mass
2. Light anhydrous silicic acid (1) 10.0% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Tamsulosin 3.0% by mass
＜実施例１０＞
　支持体として、２５μｍ厚のポリエチレンフィルム（藤森工業（株）、透湿度３０ｇ／ｍ2・２４ｈｒ）とすること以外は実施例１と同様の組成及び製法にて、実施例１０の経皮吸収型製剤を得た。 <Example 10>
The percutaneous absorption type of Example 10 with the same composition and production method as Example 1 except that a 25 μm-thick polyethylene film (Fujimori Kogyo Co., Ltd., moisture permeability 30 g / m 2 · 24 hr) was used as the support. A formulation was obtained.
＜実施例１１＞
　支持体として、４０μｍ厚のポリエチレンフィルム（東レ（株）、透湿度２５ｇ／ｍ2・２４ｈｒ）とすること以外は実施例１と同様の組成及び製法にて、実施例１１の経皮吸収型製剤を得た。 <Example 11>
The percutaneously absorbable preparation of Example 11 has the same composition and production method as Example 1 except that a 40 μm-thick polyethylene film (Toray Industries, Inc., moisture permeability 25 g / m 2 · 24 hr) is used as the support. Got.
＜実施例１２＞
　支持体として、６０μｍ厚のポリエチレンフィルム（東レ（株））とすること以外は実施例１と同様の組成及び製法にて、実施例１２の経皮吸収型製剤を得た。 <Example 12>
A percutaneous absorption type preparation of Example 12 was obtained by the same composition and production method as Example 1 except that a 60 μm-thick polyethylene film (Toray Industries, Inc.) was used as the support.
＜比較例１＞
　以下の組成を用い、実施例１と同様の製法にて、比較例１の経皮吸収型製剤を得た。
（組成）
１．アクリル系粘着剤（１）　　　　　　　　　　６２．０質量％
２．プロピレングリコールモノラウレート　　　　３０．０質量％
３．タムスロシン　　　　　　　　　　　　　　　　８．０質量％ <Comparative Example 1>
A percutaneous absorption type preparation of Comparative Example 1 was obtained in the same manner as in Example 1 using the following composition.
(composition)
1. Acrylic adhesive (1) 62.0 mass%
2. Propylene glycol monolaurate 30.0% by mass
3. Tamsulosin 8.0% by mass
＜比較例２＞
　以下の組成を用い、実施例１と同様の製法にて、比較例２の経皮吸収型製剤を得た。
（組成）
１．アクリル系粘着剤（３）　　　　　　　　　　５９．５質量％
２．ポリイソシアネート　　　　　　　　　　　　　０．５質量％
３．プロピレングリコールモノラウレート　　　　３０．０質量％
４．タムスロシン　　　　　　　　　　　　　　　１０．０質量％ <Comparative example 2>
A percutaneous absorption type preparation of Comparative Example 2 was obtained in the same manner as in Example 1 using the following composition.
(composition)
1. Acrylic adhesive (3) 59.5% by mass
2. Polyisocyanate 0.5% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Tamsulosin 10.0% by mass
＜比較例３＞
　以下の組成を用い、実施例１と同様の製法にて、比較例３の経皮吸収型製剤を得た。
（組成）
１．アクリル系粘着剤（３）　　　　　　　　　　５４．５質量％
２．ポリイソシアネート　　　　　　　　　　　　　０．５質量％
３．プロピレングリコールモノラウレート　　　　３０．０質量％
４．タムスロシン　　　　　　　　　　　　　　　１５．０質量％ <Comparative Example 3>
A percutaneous absorption type preparation of Comparative Example 3 was obtained in the same manner as in Example 1 using the following composition.
(composition)
1. Acrylic adhesive (3) 54.5% by mass
2. Polyisocyanate 0.5% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Tamsulosin 15.0% by mass
＜比較例４＞
　粘着剤としてゴム系粘着剤を使用し、以下の組成及び製法を用いて、比較例４の経皮吸収型製剤を得た。
（組成）
１．ゴム系粘着剤　　　　　　　　　　　　　　　６５．０質量％
２．プロピレングリコールモノラウレート　　　　３０．０質量％
３．タムスロシン　　　　　　　　　　　　　　　　５．０質量％
（製法）
　上記成分を秤量後、全体の固形分がトルエン溶液中５０質量％となるように調製し、均一になるまで撹拌した。
　乾燥後の粘着剤層の塗布量が２５ｇ／ｍ2となるように、７５μｍ厚の片面シリコン処理ＰＥＴ（ポリエチレンテレフタレート）フィルム（フィルムバイナ７５Ｅ－００１０　Ｎｏ．２３、藤森工業（株））上に塗布し、１１０℃で３分間乾燥させた。
　次いで、粘着剤層の片面に２５μｍ厚のＰＥＴフィルム（ルミラーＳ１０、東レ（株））を貼り合わせて裁断し経皮吸収型製剤を得た。 <Comparative example 4>
A rubber-based adhesive was used as the adhesive, and the transdermal absorption preparation of Comparative Example 4 was obtained using the following composition and production method.
(composition)
1. Rubber adhesive 65.0% by mass
2. Propylene glycol monolaurate 30.0% by mass
3. Tamsulosin 5.0% by mass
(Manufacturing method)
After weighing the above components, the total solid content was adjusted to 50% by mass in the toluene solution and stirred until uniform.
Coating on a single-sided siliconized PET (polyethylene terephthalate) film (film binder 75E-0010 No. 23, Fujimori Kogyo Co., Ltd.) having a thickness of 75 μm so that the coating amount of the pressure-sensitive adhesive layer after drying is 25 g / m 2. And dried at 110 ° C. for 3 minutes.
Next, a 25 μm-thick PET film (Lumirror S10, Toray Industries, Inc.) was bonded to one side of the pressure-sensitive adhesive layer and cut to obtain a transdermal preparation.
＜比較例５＞
　以下の組成を用い、実施例１と同様の製法にて、比較例５の経皮吸収型製剤を得た。
（組成）
１．アクリル系粘着剤（１）　　　　　　　　　　８５．０質量％
２．軽質無水ケイ酸（１）　　　　　　　　　　　１０．０質量％
３．タムスロシン　　　　　　　　　　　　　　　　５．０質量％ <Comparative Example 5>
A percutaneous absorption type preparation of Comparative Example 5 was obtained in the same manner as in Example 1 using the following composition.
(composition)
1. Acrylic adhesive (1) 85.0 mass%
2. Light anhydrous silicic acid (1) 10.0% by mass
3. Tamsulosin 5.0% by mass
＜比較例６＞
　以下の組成を用い、実施例１と同様の製法にて、比較例６の経皮吸収型製剤を得た。
（組成）
１．アクリル系粘着剤（１）　　　　　　　　　　７５．０質量％
２．軽質無水ケイ酸（１）　　　　　　　　　　　１０．０質量％
３．プロピレングリコールモノラウレート　　　　１０．０質量％
４．タムスロシン　　　　　　　　　　　　　　　　５．０質量％ <Comparative Example 6>
A percutaneous absorption type preparation of Comparative Example 6 was obtained in the same manner as in Example 1 using the following composition.
(composition)
1. Acrylic adhesive (1) 75.0 mass%
2. Light anhydrous silicic acid (1) 10.0% by mass
3. Propylene glycol monolaurate 10.0% by mass
4). Tamsulosin 5.0% by mass
＜比較例７＞
　以下の組成を用い、実施例１と同様の製法にて、比較例７の経皮吸収型製剤を得た。
（組成）
１．アクリル系粘着剤（３）　　　　　　　　　　６４．５質量％
２．ポリイソシアネート　　　　　　　　　　　　　０．５質量％
３．プロピレングリコールモノラウレート　　　　３０．０質量％
４．サルメテロール　　　　　　　　　　　　　　　５．０質量％ <Comparative Example 7>
Using the following composition, the percutaneous absorption preparation of Comparative Example 7 was obtained by the same production method as in Example 1.
(composition)
1. Acrylic adhesive (3) 64.5% by mass
2. Polyisocyanate 0.5% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Salmeterol 5.0% by mass
＜比較例８＞
　以下の組成を用い、乾燥後の粘着剤層の塗布量を４０ｇ／ｍ2とすること以外は、実施例１と同様の製法にて、比較例８の経皮吸収型製剤を得た。
（組成）
１．アクリル系粘着剤（３）　　　　　　　　　　５７．０質量％
２．ポリイソシアネート　　　　　　　　　　　　　０．５質量％
３．プロピレングリコールモノラウレート　　　　３０．０質量％
４．モノエタノールアミン　　　　　　　　　　　　２．５質量％
５．ケトチフェンフマル酸塩　　　　　　　　　　１０．０質量％ <Comparative Example 8>
A percutaneous absorption type preparation of Comparative Example 8 was obtained in the same manner as in Example 1 except that the following composition was used and the coating amount of the pressure-sensitive adhesive layer after drying was 40 g / m 2 .
(composition)
1. Acrylic adhesive (3) 57.0% by mass
2. Polyisocyanate 0.5% by mass
3. Propylene glycol monolaurate 30.0% by mass
4). Monoethanolamine 2.5% by mass
5). Ketotifen fumarate 10.0% by mass
＜比較例９＞
　以下の組成を用い、実施例１と同様の製法にて、比較例９の経皮吸収型製剤を得た。
（組成）
１．アクリル系粘着剤（１）　　　　　　　　　　５７．０質量％
２．含水ケイ酸　　　　　　　　　　　　　　　　１０．０質量％
３．プロピレングリコールモノラウレート　　　　２５．０質量％
４．タムスロシン　　　　　　　　　　　　　　　　８．０質量％ <Comparative Example 9>
A percutaneous absorption type preparation of Comparative Example 9 was obtained in the same manner as in Example 1 using the following composition.
(composition)
1. Acrylic adhesive (1) 57.0% by mass
2. Hydrous silicic acid 10.0% by mass
3. Propylene glycol monolaurate 25.0% by mass
4). Tamsulosin 8.0% by mass
＜比較例１０～１３＞
　粘着剤としてアクリル系粘着剤（４）を使用し、以下の組成及び製法を用いて、比較例１０～１３の経皮吸収型製剤を得た。
（組成）
Figure JPOXMLDOC01-appb-T000001
 （製法）
ａ）メタノールにホウ酸を加え、１０質量％の溶液を得た。
ｂ）ａ）の溶液３．３２ｇに軽質無水ケイ酸０．４０ｇ及び酢酸エチル２．２５を加え、乳鉢で混合して分散液を得た。
ｃ）ｂ）の分散液にアクリル系粘着剤（液体）９．７ｇを加え、乳鉢で１時間混合した。
ｄ）タムスロシン塩酸塩０．２５ｇ、酢酸ナトリウム０．０７ｇ、ミリスチン酸イソプロピル０．２５ｇ、ソルビタンモノラウレート０．１５ｇを約１５時間混合し、さらにｃ）の液１１．７８ｇを加え、乳鉢で１時間混合し、一晩放置（１６時間）し、さらに３時間混合した。
ｅ）ｄ）の液を７５μｍ厚の片面シリコン処理ＰＥＴ（ポリエチレンテレフタレート）フィルム（フィルムバイナ７５Ｅ－００１０　Ｎｏ．２３、藤森工業（株））のシリコン処理面に展延し、室温で１０分放置後、８０℃で１０分間乾燥した。その後支持体（ポリエチレンテレフタレートフィルム、２５μｍ）を積層して裁断し、比較例１０の経皮吸収型製剤を得た。
　同様に、比較例１１～１３の経皮吸収型製剤を製造した。
　なお、乾燥後の粘着剤層の塗布量はそれぞれ、７８ｇ／ｍ2（比較例１０）、６８ｇ／ｍ2（比較例１１）、７０ｇ／ｍ2（比較例１２）、７５ｇ／ｍ2（比較例１３）である。
　なおこの比較例１０～１３の経皮吸収型製剤は、国際公開第２００７／０２３７９１号パンフレットに記載の実施例４に準ずる例である。 <Comparative Examples 10 to 13>
Acrylic pressure-sensitive adhesive (4) was used as the pressure-sensitive adhesive, and the percutaneously absorbable preparations of Comparative Examples 10 to 13 were obtained using the following composition and production method.
(composition)
Figure JPOXMLDOC01-appb-T000001
 (Manufacturing method)
a) Boric acid was added to methanol to obtain a 10% by mass solution.
b) 0.43 g of light anhydrous silicic acid and 2.25 ethyl acetate were added to 3.32 g of the solution a), and mixed in a mortar to obtain a dispersion.
c) 9.7 g of acrylic pressure-sensitive adhesive (liquid) was added to the dispersion of b) and mixed for 1 hour in a mortar.
d) 0.25 g of tamsulosin hydrochloride, 0.07 g of sodium acetate, 0.25 g of isopropyl myristate and 0.15 g of sorbitan monolaurate were mixed for about 15 hours, and 11.78 g of the liquid c) was further added. Mix for hours, leave overnight (16 hours) and mix for an additional 3 hours.
e) The liquid of d) was spread on a silicon-treated surface of a 75 μm-thick single-sided silicon-treated PET (polyethylene terephthalate) film (film binder 75E-0010 No. 23, Fujimori Kogyo Co., Ltd.) and left at room temperature for 10 minutes. And dried at 80 ° C. for 10 minutes. Thereafter, a support (polyethylene terephthalate film, 25 μm) was laminated and cut to obtain a transdermal absorption preparation of Comparative Example 10.
Similarly, the percutaneous absorption preparations of Comparative Examples 11 to 13 were produced.
Incidentally, each of the coating amount of the adhesive layer after drying, 78 g / m 2 (Comparative Example 10), 68g / m 2 (Comparative Example 11), 70g / m 2 (Comparative Example 12), 75g / m 2 (comparative Example 13).
The percutaneous absorption type preparations of Comparative Examples 10 to 13 are examples according to Example 4 described in International Publication No. 2007/023791 pamphlet.
＜比較例１４～１７＞
　粘着剤としてアクリル系粘着剤（４）を使用し、以下の組成にて、実施例１と同様の製法にて、比較例１４～１７の経皮吸収型製剤を得た。なお、乾燥後の粘着剤層の塗布量はそれぞれ、２５ｇ／ｍ2（比較例１４）、２５ｇ／ｍ2（比較例１５）、２４ｇ／ｍ2（比較例１６）、３０ｇ／ｍ2（比較例１７）である。
（組成）
Figure JPOXMLDOC01-appb-T000002
 <Comparative Examples 14 to 17>
Using the acrylic pressure-sensitive adhesive (4) as the pressure-sensitive adhesive, percutaneously absorbable preparations of Comparative Examples 14 to 17 were obtained by the same production method as in Example 1 with the following composition. The coating amount of the pressure-sensitive adhesive layer after drying was 25 g / m 2 (Comparative Example 14), 25 g / m 2 (Comparative Example 15), 24 g / m 2 (Comparative Example 16), and 30 g / m 2 (Comparative), respectively. Example 17).
(composition)
Figure JPOXMLDOC01-appb-T000002
＜比較例１８＞
　支持体として、７５μｍ厚の炭酸カルシウム含有ポリエチレンフィルム（三菱化学（株）、透湿度３，８００ｇ／ｍ2・２４ｈｒ）とすること以外は実施例１と同様の組成及び製法にて、比較例１８の経皮吸収型製剤を得た。 <Comparative Example 18>
Comparative Example 18 with the same composition and production method as Example 1 except that a 75 μm-thick calcium carbonate-containing polyethylene film (Mitsubishi Chemical Corporation, moisture permeability 3,800 g / m 2 · 24 hr) was used as the support. A percutaneous absorption type preparation was obtained.
＜比較例１９＞
　支持体として、８０μｍ厚の炭酸カルシウム含有ポリエチレンフィルム（三菱化学（株））とすること以外は実施例１と同様の組成及び製法にて、比較例１９の経皮吸収型製剤を得た。 <Comparative Example 19>
A percutaneously absorbable preparation of Comparative Example 19 was obtained by the same composition and production method as Example 1 except that a calcium carbonate-containing polyethylene film (Mitsubishi Chemical Corporation) having a thickness of 80 μm was used as the support.
＜比較例２０＞
　支持体として、１００μｍ厚の炭酸カルシウム含有ポリエチレンフィルム（三菱化学（株）、透湿度２，８５０ｇ／ｍ2・２４ｈｒ）とすること以外は実施例１と同様の組成及び製法にて、比較例２０の経皮吸収型製剤を得た。 <Comparative Example 20>
Comparative Example 20 with the same composition and production method as Example 1 except that a 100 μm-thick calcium carbonate-containing polyethylene film (Mitsubishi Chemical Corporation, moisture permeability 2,850 g / m 2 · 24 hr) was used as the support. A percutaneous absorption type preparation was obtained.
＜比較例２１～３２＞
　薬物として酸性薬物であるインドメタシン又はアスピリンを使用し、以下の組成にて、実施例１と同様の製法にて、比較例２１～３２の経皮吸収型製剤を得た。なお、何れの製剤も乾燥後の粘着剤層の塗布量が３０ｇ／ｍ2となるように調整した。
（組成）
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
 <Comparative Examples 21 to 32>
Using indomethacin or aspirin, which is an acidic drug, as a drug, percutaneous absorption preparations of Comparative Examples 21 to 32 were obtained by the same production method as in Example 1 with the following composition. In addition, each formulation was adjusted so that the application amount of the pressure-sensitive adhesive layer after drying was 30 g / m 2 .
(composition)
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
［評価試験法］
　上記実施例及び比較例の経皮吸収型製剤を下記の評価試験法に従って試験し、薬物の皮膚透過性、経皮吸収型製剤の付着性及び発汗時の付着性を評価した。
（１）皮膚透過性試験法
　得られた実施例及び比較例の経皮吸収型製剤を１．７７ｃｍ2に打ち抜き、Ｆｒａｎｚ（フランツ）型拡散セル及びヘアレスマウス（７週齢、雄性）腹部摘出皮膚を使用して、以下の手順にて皮膚透過試験を行った。
　レシーバー液として生理食塩水或いはｐＨ７．４リン酸塩緩衝液（３２℃）を使用し、試験開始後から予め設定したサンプリング時間（２、３、４時間）ごとにレシーバー液の１ｍＬを採取し、同量の新しいレシーバー液を充填した。
　採取したレシーバー液に同量のメタノールを加えて不純物を除去した後、ＨＰＬＣにより薬物濃度を測定し、累積透過量を算出した。各検体について３回試験し平均値を得た。
　なお、実施例１乃至実施例３及び実施例７乃至実施例９、比較例１乃至比較例６及び比較例１０乃至比較例１７については、４８時間後の薬物利用率を［（４８時間目の累積透過量）／（単位面積当たりの薬物含量）×１００］として算出し、比較例２１乃至比較例２６については、２４時間後の薬物利用率を［（２４時間目の累積透過量）／（単位面積当たりの薬物含量）×１００］として、比較例２７乃至比較例３２については１２時間後の薬物利用率を［（１２時間目の累積透過量）／（単位面積当たりの薬物含量）×１００］として、夫々算出した。
なお、単位面積当たりの薬物含量は（塗布量）×（薬物濃度）より算出した。
　得られた結果を表１乃至表８並びに図１乃至図４に示す。 [Evaluation test method]
The percutaneous absorption preparations of the above Examples and Comparative Examples were tested according to the following evaluation test methods, and the skin permeability of the drug, the adhesion of the percutaneous absorption preparation and the adhesion during perspiration were evaluated.
(1) Skin Permeability Test Method The percutaneous absorption preparations obtained in Examples and Comparative Examples were punched out to 1.77 cm 2 , and a Franz-type diffusion cell and a hairless mouse (7 weeks old, male) abdominal excised skin The skin permeation test was conducted according to the following procedure.
Saline or pH 7.4 phosphate buffer solution (32 ° C.) is used as the receiver solution, and 1 mL of the receiver solution is collected at every preset sampling time (2, 3, 4 hours) after the start of the test. The same amount of new receiver solution was filled.
The same amount of methanol was added to the collected receiver solution to remove impurities, and then the drug concentration was measured by HPLC to calculate the cumulative permeation amount. Each specimen was tested three times to obtain an average value.
For Examples 1 to 3 and 7 to 9, Comparative Examples 1 to 6, and Comparative Examples 10 to 17, the drug utilization rate after 48 hours was set to [(48th hour Cumulative permeation amount) / (Drug content per unit area) × 100], and for Comparative Examples 21 to 26, the drug utilization rate after 24 hours was calculated as [(cumulative permeation amount at 24 hours) / ( (Drug content per unit area) × 100], for Comparative Examples 27 to 32, the drug utilization rate after 12 hours is [(cumulative permeation amount at 12 hours) / (drug content per unit area) × 100]. ] Were calculated respectively.
The drug content per unit area was calculated from (application amount) × (drug concentration).
The obtained results are shown in Tables 1 to 8 and FIGS.
（２）透過促進剤の促進効果比較
　プロピレングリコールモノラウレート及びミリスチン酸イソプロピルをそれぞれ３０及び４５質量％となるように流動パラフィンと混合した溶液、または流動パラフィンにタムスロシンを過飽和になるまで加え、３２℃で一晩攪拌した懸濁液をドナー溶液として、以下の手順で皮膚透過試験を実施した。
　水平型拡散セルにヘアレスマウス（７週齢、雄性）腹部摘出皮膚を装着し、レシーバーセルに生理食塩水、ドナーセルに上記懸濁液を満たした。試験温度を３２℃とし、試験開始後から予め設定したサンプリング時間ごとにレシーバー液の１ｍＬを採取し、同量の新しいレシーバー液を充填した。
　採取したレシーバー液に同量のメタノールを加えて不純物を除去した後、ＨＰＬＣにより薬物濃度を測定し、累積透過量を算出した。各検体について３回試験し平均値を得た。
　得られた結果を表９に示す。 (2) Comparison of accelerating effect of permeation enhancer A solution in which propylene glycol monolaurate and isopropyl myristate were mixed with liquid paraffin so as to be 30% by mass and 45% by mass respectively, or tamsulosin was added to liquid paraffin until supersaturated, and 32 The skin permeation test was carried out by the following procedure using the suspension stirred overnight at 0 ° C. as a donor solution.
A hairless mouse (7-week-old, male) abdominal excised skin was attached to the horizontal diffusion cell, the receiver cell was filled with physiological saline, and the donor cell was filled with the suspension. The test temperature was set to 32 ° C., and 1 mL of the receiver liquid was collected every sampling time set in advance after the start of the test, and filled with the same amount of new receiver liquid.
The same amount of methanol was added to the collected receiver solution to remove impurities, and then the drug concentration was measured by HPLC to calculate the cumulative permeation amount. Each specimen was tested three times to obtain an average value.
Table 9 shows the obtained results.
（３）製剤の付着性（通常時／発汗時）
　得られた実施例及び比較例の経皮吸収型製剤の付着性を、フィンガータック法を用いて以下の基準に基づいて評価した。さらに、１０ｃｍ２に打抜いた経皮吸収型製剤を健常成人に６時間貼付後、製剤を剥離した時の粘着剤の残留（糊残り）を下記の基準に基づいて評価した。
・フィンガータック法による基準
　　○：極めてよく付く　　　　△：よく付く　　　：×：あまり付かない
・粘着剤の残留の基準
　　無　　　　：目視で粘着剤の残留（糊残り）は認められない。
　　わずかに有：目視で粘着剤の残留（糊残り）が一部認められる。
　　有　　　　：目視で粘着剤の残留（糊残り）が明らかに認められる。
　また実施例及び比較例の経皮吸収型製剤を１０ｃｍ２に打ち抜き、これを前腕内側の皮膚に貼付した健常成人を室温４０℃に調整した部屋に１０分間滞在させて発汗させた後、製剤の付着状態を以下の基準に基づいて評価した。さらに、経皮吸収型製剤を皮膚から剥離した後、貼付部位を指でなぞった時のべたつきについて、下記の基準に基づいて評価した。
・付着状態の基準
　　○　　　　：全面が付着している
　　△　　　　：エッジ部に浮きがみられる
　　×　　　　：面の半分以上に浮きが見られる
　　××　　　：脱落した
・皮膚のべたつきの基準
　　無　　　　：貼付部位のべたつきがない
　　わずかに有：貼付部位の一部がべたつく
　　有　　　　：貼付部位の全面がべたつく
　得られた結果を表１０及び表１１に示す。 (3) Adhesiveness of the preparation (normal / perspiration)
The adhesiveness of the obtained transdermally absorbable preparations of Examples and Comparative Examples was evaluated based on the following criteria using a finger tack method. Furthermore, after the percutaneous absorption preparation punched out to 10 cm 2 was applied to a healthy adult for 6 hours, the adhesive residue (adhesive residue) when the preparation was peeled was evaluated based on the following criteria.
・ Standard by finger tack method ○: Very well attached △: Well attached: ×: Not much sticky ・ Adhesive residue standard None: Adhesive residue (adhesive residue) is not visually observed.
Slightly present: Some adhesive residue (adhesive residue) is visually observed.
Existence: Adhesive residue (adhesive residue) is clearly observed visually.
In addition, the percutaneous absorption type preparations of Examples and Comparative Examples were punched out to 10 cm 2 , and a healthy adult having this applied to the skin on the inner side of the forearm was allowed to sweat for 10 minutes in a room adjusted to room temperature 40 ° C. The adhesion state was evaluated based on the following criteria. Furthermore, after peeling the transdermally absorbable preparation from the skin, the stickiness when the applied site was traced with a finger was evaluated based on the following criteria.
・ Standard of adherence state ○: The whole surface is attached. △: Float is observed at the edge. ×: Float is seen in more than half of the surface. XX: Criterion of skin stickiness that has fallen off. No: Slightly present: Part of the applied site is sticky Yes: The entire applied site is sticky The results obtained are shown in Table 10 and Table 11.
（４）柔軟性の評価
　実施例及び比較例に使用する支持体について、２ｃｍ×２５ｃｍの試験片を採取し、試験片の有効長が２０ｃｍとなるように、水平棒にハートループ状に取り付けた。１分間経過後に、水平棒頂部とループ最下点との距離Ｌ（ｍｍ）を測定した。各検体について５回測定した平均値を剛軟度（ｍｍ）とした。
　実施例及び比較例の経皮吸収型製剤を３０ｃｍ2に打ち抜き、これを健常成人の肘内側に貼付し、約９０度の角度に腕を曲げた時の付着状態を以下の基準に基づいて評価した。
　○：全面が付着している
　△：わずかに浮きが見られる
　×：シワ状に浮きが見られる
　得られた結果を表１２に示す。 (4) Evaluation of flexibility About the support used in Examples and Comparative Examples, a 2 cm × 25 cm test piece was sampled and attached to a horizontal bar in a heart loop shape so that the effective length of the test piece was 20 cm. . After 1 minute, the distance L (mm) between the top of the horizontal bar and the lowest point of the loop was measured. The average value measured five times for each specimen was defined as the bending resistance (mm).
The percutaneous absorption type preparations of Examples and Comparative Examples were punched out to 30 cm 2, applied to the inner side of the elbow of a healthy adult, and the adhesion state when the arm was bent at an angle of about 90 degrees was evaluated based on the following criteria. did.
○: The entire surface is attached. Δ: Slightly floating is observed. X: Wrinkled is observed. Table 12 shows the obtained results.
［評価試験結果］
（１）皮膚透過性
　タムスロシン（遊離塩基）の皮膚透過性の評価結果を表１並びに図１に示す。
　表１及び図１に示す結果より判るように、アクリル系粘着剤（１）を用いた実施例１及び実施例２並びにアクリル系粘着剤（２）を用いた実施例７は、カルボキシル基を持つモノマーを用いて重合した樹脂からなるアクリル系粘着剤（３）を用いた比較例２及び比較例３、ゴム系粘着剤を用いた比較例４と比較して、持続的に高い累積透過量を示すとともに高い薬物利用率を示し、薬効を発揮するのに十分であると認められる値を示した。
　また、実施例３は薬物含量が３％と低く、累積透過量は実施例１、実施例２及び実施例７を下回る結果となったが、実施例３の薬物含量を遥かに上回る比較例２及び比較例３と同等以上の皮膚透過性を示し、薬物利用率は、遥かに高い値を示した。
　一方、プロピレングリコールモノラウレートを配合しなかった比較例５、配合量が１０％と少なかった比較例６は、タムスロシン濃度が同量の実施例２に比べ極めて低い皮膚透過性しか示さなかった。
　なお比較例２と比較例３はほぼ同じような透過量の推移であるため図１には比較例２のみ示した。 [Evaluation test results]
(1) Skin permeability Table 1 and FIG. 1 show the evaluation results of tamsulosin (free base) skin permeability.
As can be seen from the results shown in Table 1 and FIG. 1, Examples 1 and 2 using the acrylic pressure-sensitive adhesive (1) and Example 7 using the acrylic pressure-sensitive adhesive (2) have a carboxyl group. Compared with Comparative Example 2 and Comparative Example 3 using an acrylic pressure-sensitive adhesive (3) composed of a resin polymerized using a monomer, and Comparative Example 4 using a rubber-based pressure-sensitive adhesive, a continuously high permeation amount is obtained. In addition to the above, the drug utilization rate was high, and the value was considered to be sufficient to exert the drug effect.
In Example 3, the drug content was as low as 3%, and the cumulative permeation amount was lower than that in Example 1, Example 2, and Example 7, but Comparative Example 2 far exceeding the drug content in Example 3 And the skin permeability equivalent to or higher than that of Comparative Example 3 was shown, and the drug utilization rate was much higher.
On the other hand, Comparative Example 5 in which propylene glycol monolaurate was not blended and Comparative Example 6 in which the blending amount was as low as 10% showed extremely low skin permeability compared to Example 2 having the same amount of tamsulosin.
Since Comparative Example 2 and Comparative Example 3 have almost the same amount of permeation, only Comparative Example 2 is shown in FIG.
　同様に、表２及び図２（塩基性薬物としてサルメテロールを使用した場合）、表３及び図３（同ケトチフェンフマル酸塩を使用した場合）に示すように、タムスロシン以外の塩基性薬物を使用した場合においても、アクリル系粘着剤（１）を使用した実施例５及び実施例６は、アクリル系粘着剤（３）を用いた比較例７及び比較例８よりも高い累積透過量を示した。 Similarly, as shown in Table 2 and FIG. 2 (when salmeterol is used as a basic drug) and Table 3 and FIG. 3 (when the same ketotifen fumarate is used), a basic drug other than tamsulosin was used. Even in the case, Example 5 and Example 6 using the acrylic pressure-sensitive adhesive (1) showed a higher cumulative permeation amount than Comparative Examples 7 and 8 using the acrylic pressure-sensitive adhesive (3).
　また、表４及び表５に示すように、粘着剤としてアクリル系粘着剤（４）を用いた比較例１０～１３及び比較例１４～１７は、４８時間後の累積透過量、薬物利用率が実施例８及び実施例９と比べて非常に低いという結果となった。
　すなわち、ヒドロキシ基含有アクリル系粘着剤（４）を用いた製剤に比べ、ヒドロキシ基を含まないアクリル系粘着剤（１）（アクリル酸－２－エチルヘキシル・メタクリル酸－２－エチルヘキシル・メタクリル酸ドデシル共重合体）を用いた製剤は薬物の皮膚透過性に優れる製剤であるとする結果となった。 As shown in Tables 4 and 5, Comparative Examples 10 to 13 and Comparative Examples 14 to 17 using the acrylic pressure-sensitive adhesive (4) as the pressure-sensitive adhesive have a cumulative permeation amount and a drug utilization rate after 48 hours. The result was very low compared to Example 8 and Example 9.
That is, compared with the preparation using the hydroxy group-containing acrylic pressure-sensitive adhesive (4), the acrylic pressure-sensitive adhesive (1) containing no hydroxy group (2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, dodecyl methacrylate) As a result, it was found that the preparation using the polymer) had excellent drug skin permeability.
　なお、粘着剤としてアクリル系粘着剤（１）（アクリル酸－２－エチルヘキシル・メタクリル酸－２－エチルヘキシル・メタクリル酸ドデシル共重合体、エステル系）を用いたもの、アクリル系粘着剤（３）（カルボキシル基を含むもの）及びアクリル系粘着剤（４）（ヒドロキシ基含有アクリル系重合体）を用いた各種製剤において、薬物として酸性薬物であるインドメタシンを使用した場合（表６）及び薬物としてアスピリンを使用した場合（表７）を示す。
　これをみると、インドメタシンを用いた場合には、粘着剤としてアクリル系粘着剤（３）（カルボキシル基を含むもの）を用いた製剤が累積透過量、２４時間後の利用率ともに若干優れるという結果となり、アクリル系粘着剤（１）（エステル系）を用いたものとアクリル系粘着剤（４）（ヒドロキシ基含有）を用いた製剤はほぼ同じとする結果となった。また、アスピリンを用いた場合には、何れの粘着剤を用いても累積透過量、１２時間後の利用率ともにほぼ同じとする結果となった。
　これは、塩基性薬物（タムスロシン、サルメテロール、ケトチフェンフマル酸塩）を用いて実施した前出の実施例・比較例とは異なる挙動を示すものである。 In addition, an acrylic pressure-sensitive adhesive (1) (acrylic acid-2-ethylhexyl / methacrylic acid-2-ethylhexyl / methacrylic acid dodecyl copolymer, ester-based), acrylic pressure-sensitive adhesive (3) ( In various preparations using an acrylic pressure-sensitive adhesive (4) (hydroxy group-containing acrylic polymer) and a drug containing indomethacin (Table 6) as a drug and aspirin as a drug. When used (Table 7).
As a result, when indomethacin is used, the formulation using the acrylic pressure-sensitive adhesive (3) (containing a carboxyl group) as the pressure-sensitive adhesive is slightly superior in both the accumulated permeation amount and the utilization rate after 24 hours. As a result, the preparation using the acrylic pressure-sensitive adhesive (1) (ester) and the preparation using the acrylic pressure-sensitive adhesive (4) (containing a hydroxy group) were almost the same. Further, when aspirin was used, the cumulative permeation amount and the utilization rate after 12 hours were almost the same regardless of which adhesive was used.
This shows a behavior different from the previous examples and comparative examples carried out using basic drugs (tamsulosin, salmeterol, ketotifen fumarate).
　また、表８、図４に示す結果より分かるように、５０ｇ／ｍ2・ｈｒ以下の透湿度を有する支持体を用いた実施例１、実施例１０及び実施例１１は、高い透湿性を有する支持体を用いた比較例１８に比べて皮膚透過性が非常に高い結果となった。 Further, as can be seen from the results shown in Table 8 and FIG. 4, Examples 1, 10 and 11 using a support having a moisture permeability of 50 g / m 2 · hr or less have high moisture permeability. As a result, the skin permeability was very high as compared with Comparative Example 18 using the support.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000012
（２）透過促進剤の促進効果
　下記表９に示すように、促進剤としてプロピレングリコールモノラウレートまたはミリスチン酸イソプロピルを使用した際の促進効果を比較したところ、ミリスチン酸イソプロピルを促進剤として使用した場合、プロピレングリコールモノラウレートに比べて４８時間の累積透過量が極めて低く、促進効果が低いことが確認された。 (2) Accelerating effect of permeation accelerator As shown in Table 9 below, when the accelerating effect when propylene glycol monolaurate or isopropyl myristate was used as the accelerator was compared, isopropyl myristate was used as the accelerator. In this case, it was confirmed that the cumulative permeation amount for 48 hours was very low compared with propylene glycol monolaurate, and the acceleration effect was low.
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013
（３）製剤の付着性（通常時／発汗時）
　下記表１０に示すように、実施例１乃至実施例４の製剤は、粘着剤の残留が認められず、経皮吸収型製剤として十分な粘着性及び付着性を示した。
　また発汗時においても良好な付着性を維持しており、剥離後の皮膚のべたつきも認められなかった。 (3) Adhesiveness of the preparation (Normal / Sweating)
As shown in Table 10 below, the preparations of Examples 1 to 4 showed no adhesive residue and showed sufficient adhesiveness and adhesiveness as a transdermal preparation.
In addition, good adhesion was maintained even during sweating, and no skin stickiness after peeling was observed.
　一方、表１１に示すように、比較例１の製剤においては、付着性については良好な結果が得られたものの、糊残り並びに発汗時の皮膚のべたつきが認められた。これは、液状成分であるプロピレングリコールモノラウレートを十分に保持できず、粘着剤の凝集力が低下したためとみられる。
　比較例２の製剤は付着性については良好な結果が得られているものの、前述したとおり、累積透過量及び薬物利用率は低い値を示し、薬効を発揮するには不十分であった。
　ゴム系粘着剤を用いた比較例４の製剤は、多量のプロピレングリコールモノラウレートを添加することにより、粘着性の維持が困難となり、フィンガータックは不適を示し、発汗により製剤が脱落した。
　また、シリカ粒子（充填剤）として粒子径の大きい含水ケイ酸を用いた比較例９は、凝集力の改善効果が不足し、わずかに粘着剤の残留と発汗時における剥離後の皮膚のべたつきが認められた。 On the other hand, as shown in Table 11, in the preparation of Comparative Example 1, although good results were obtained with respect to adhesiveness, adhesive residue and stickiness of the skin during sweating were recognized. This seems to be because propylene glycol monolaurate, which is a liquid component, could not be sufficiently retained, and the cohesive strength of the adhesive was reduced.
Although the preparation of Comparative Example 2 gave good results with respect to adhesiveness, as described above, the cumulative permeation amount and the drug utilization rate showed low values, which were insufficient for exhibiting medicinal effects.
In the preparation of Comparative Example 4 using a rubber-based adhesive, it was difficult to maintain adhesiveness by adding a large amount of propylene glycol monolaurate, finger tack was not suitable, and the preparation fell off due to sweating.
Further, Comparative Example 9 using hydrous silicic acid having a large particle diameter as silica particles (filler) is insufficient in improving the cohesive force, and the adhesive remains slightly and the skin becomes sticky after peeling during sweating. Admitted.
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
（４）柔軟性の評価
　表１２に示すように、支持体の剛軟度が８０ｍｍ以上の実施例１０乃至実施例１２は、柔軟性が高く屈曲部への付着性が良好であり、浮きが見られなかった。
　一方、支持体の剛軟度が８０ｍｍ未満である比較例１９及び比較例２０に関しては、柔軟性が低く屈曲した際に浮きが見られた。 (4) Evaluation of flexibility As shown in Table 12, Examples 10 to 12 in which the flexural softness of the support is 80 mm or more have high flexibility and good adhesion to the bent portion, and the float is not lifted. I couldn't see it.
On the other hand, regarding Comparative Example 19 and Comparative Example 20 in which the bending resistance of the support was less than 80 mm, the softness was low, and floating was observed when bent.
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000016
［評価結果まとめ］
　以上述べたように、シリカ粒子を含有しない比較例１は、薬物の皮膚透過性には優れる結果が得られたが、皮膚付着性に課題を残す結果となった。
　カルボキシル基を持つモノマーを用いたアクリル系粘着剤を使用した場合（比較例２及び比較例３、比較例７及び比較例８）、薬物の皮膚透過性及び薬物利用率が著しく低下した。
　また、ゴム系粘着剤を使用した場合、プロピレングリコールモノラウレートを３０％含有させると、粘着力が殆ど発現しないとする結果となった（比較例４）。
　さらに、透過促進剤であるプロピレングリコールモノラウレートを使用しない場合、或いは使用したとしても少量の使用であった場合には、薬物が殆ど皮膚透過しないという結果となった（比較例５及び比較例６）。
　そして、含有するシリカ粒子の粒子径を本発明で規定する大きさ（５μｍ以下）を超えるものを使用した場合、皮膚付着性にやや欠けるという結果となった（比較例９）。
　また、粘着剤としてヒドロキシ基含有アクリル系粘着剤を用いた場合、累積透過量、薬物利用率が非常に劣るとする結果となった（比較例１０～比較例１７）。
　また、経皮吸収型製剤の支持体として高い透湿性を有する支持体を使用した場合は、薬物の皮膚透過性が大幅に低下した（比較例１８）。
　なお、酸性薬物（インドメタシン、アスピリン）を用いた場合の製剤は、塩基性薬物を用いた製剤において粘着剤の種類を変えた場合の挙動とは異なる挙動を示し、薬物の種類によって好適な粘着剤が全く異なることが確認された（比較例２１～３２）。
　さらに、剛軟度が８０ｍｍ未満の支持体を用いた場合の製剤は、柔軟性が低く屈曲部への付着に劣るとする結果となった（比較例１９及び比較例２０） [Summary of evaluation results]
As described above, Comparative Example 1 which does not contain silica particles obtained results excellent in drug skin permeability, but left a problem in skin adhesion.
When an acrylic pressure-sensitive adhesive using a monomer having a carboxyl group was used (Comparative Example 2 and Comparative Example 3, Comparative Example 7 and Comparative Example 8), the skin permeability and drug utilization rate of the drug were significantly reduced.
Further, in the case of using a rubber-based pressure-sensitive adhesive, when 30% of propylene glycol monolaurate was contained, the result was that the adhesive force hardly developed (Comparative Example 4).
Further, when propylene glycol monolaurate, which is a permeation enhancer, is not used, or when used in a small amount, even if used, the result is that the drug hardly permeates the skin (Comparative Example 5 and Comparative Example). 6).
And when the thing which exceeds the magnitude | size (5 micrometers or less) prescribed | regulated by this invention for the particle diameter of the silica particle to contain was used, it resulted in lacking in skin adhesion a little (Comparative Example 9).
Further, when the hydroxy group-containing acrylic pressure-sensitive adhesive was used as the pressure-sensitive adhesive, the results showed that the cumulative permeation amount and the drug utilization rate were very poor (Comparative Example 10 to Comparative Example 17).
In addition, when a support having high moisture permeability was used as a support for the transdermal preparation, the skin permeability of the drug was significantly reduced (Comparative Example 18).
It should be noted that the preparation using an acidic drug (indomethacin, aspirin) shows a behavior different from that when changing the type of adhesive in a preparation using a basic drug, and a suitable adhesive depending on the type of drug. Were completely different (Comparative Examples 21 to 32).
Furthermore, the formulation in the case of using a support having a bending resistance of less than 80 mm resulted in low flexibility and poor adhesion to the bent part (Comparative Example 19 and Comparative Example 20).
　一方、本発明の経皮吸収型製剤である実施例１乃至実施例１２は、いずれも薬物の皮膚透過性に優れ、また皮膚付着性にも優れるものであり、本製剤が経皮吸収型製剤として優れた特性を有するものであることが確認された。
　さらに、剛軟度が８０ｍｍ以上の支持体を使用することで、柔軟性が高く、皮膚への追従性が上がり、付着性が増すことが確認された。 On the other hand, Examples 1 to 12 which are the percutaneous absorption preparations of the present invention all have excellent drug skin permeability and skin adhesion, and this preparation is a percutaneous absorption preparation. As a result, it was confirmed that they have excellent characteristics.
Furthermore, it was confirmed that by using a support having a bending resistance of 80 mm or more, the flexibility is high, the followability to the skin is increased, and the adhesion is increased.
特開平６－１４５０５１号公報JP-A-6-145051 特開平８－０４０９３７号公報JP-A-8-040937

Claims (9)

  1. 支持体に粘着剤層を設けてなる経皮吸収型製剤において、該支持体の透湿度が３００ｇ／ｍ2・２４ｈｒ以下であり、該粘着剤層を形成する粘着剤組成物が、分子内にカルボキシル基を持たないアクリル酸エステル及び／またはメタクリル酸エステルよりなるモノマー又はモノマー混合物を重合してなる樹脂を主とするアクリル系粘着剤、塩基性薬物、平均粒子径が５μｍ以下のシリカ粒子、並びに多価アルコール脂肪酸エステルを含有し、前記多価アルコール脂肪酸エステルは粘着剤組成物の全質量に対して１５～４０質量％の割合で含まれてなる、経皮吸収型製剤。 In a percutaneous absorption type preparation having a pressure-sensitive adhesive layer on a support, the moisture permeability of the support is 300 g / m 2 · 24 hr or less, and the pressure-sensitive adhesive composition forming the pressure-sensitive adhesive layer is formed in the molecule. An acrylic pressure-sensitive adhesive mainly composed of a resin obtained by polymerizing a monomer or a monomer mixture comprising an acrylic ester and / or a methacrylic ester having no carboxyl group, a basic drug, silica particles having an average particle size of 5 μm or less, and A percutaneously absorbable preparation comprising a polyhydric alcohol fatty acid ester, wherein the polyhydric alcohol fatty acid ester is contained in a proportion of 15 to 40% by mass relative to the total mass of the pressure-sensitive adhesive composition.
  2. 前記多価アルコール脂肪酸エステルがプロピレングリコールモノラウレートを主成分とし、粘着剤組成物の全質量に対して２０～３５質量％の割合で含まれてなる、請求項１に記載の経皮吸収型製剤。 The percutaneous absorption type according to claim 1, wherein the polyhydric alcohol fatty acid ester contains propylene glycol monolaurate as a main component and is contained in a proportion of 20 to 35 mass% with respect to the total mass of the pressure-sensitive adhesive composition. Formulation.
  3. 前記アクリル系粘着剤が、分子内にカルボキシル基及びヒドロキシ基を持たないアクリル酸エステル及び／またはメタクリル酸エステルよりなるモノマー又はモノマー混合物を重合してなる樹脂を主とする粘着剤である、請求項１又は請求項２に記載の経皮吸収型製剤。 The acrylic pressure-sensitive adhesive is a pressure-sensitive adhesive mainly composed of a resin obtained by polymerizing a monomer or a monomer mixture composed of an acrylate ester and / or a methacrylic acid ester having no carboxyl group and hydroxy group in the molecule. The transdermally absorbable preparation according to claim 1 or 2.
  4. 前記アクリル系粘着剤が、アクリル酸－２－エチルヘキシル・メタクリル酸－２－エチルヘキシル・メタクリル酸ドデシル共重合体である、請求項３に記載の経皮吸収型製剤。 The transdermally absorbable preparation according to claim 3, wherein the acrylic pressure-sensitive adhesive is 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / dodecyl methacrylate copolymer.
  5. 前記支持体が、５０ｇ／ｍ2・２４ｈｒ以下の透湿度を有する支持体である、請求項１乃至請求項４のうち何れか一項に記載の経皮吸収型製剤。 The transdermally absorbable preparation according to any one of claims 1 to 4, wherein the support is a support having a moisture permeability of 50 g / m 2 · 24 hr or less.
  6. 前記支持体が、８０ｍｍ以上のハートループ法による剛軟度を有する支持体である、請求項１乃至請求項５のうち何れか一項に記載の経皮吸収型製剤。 The transdermally absorbable preparation according to any one of claims 1 to 5, wherein the support is a support having a bending resistance by a heart loop method of 80 mm or more.
  7. 前記支持体が、厚さが１０～７０μｍであるポリエチレンフィルムよりなる、請求項１乃至請求項６のうち何れか一項に記載の経皮吸収型製剤。 The transdermal preparation according to any one of claims 1 to 6, wherein the support is made of a polyethylene film having a thickness of 10 to 70 µm.
  8. 前記アクリル系粘着剤が、１．５～２．５の極限粘度を有する粘着剤である、請求項１乃至請求項７のうち何れか一項に記載の経皮吸収型製剤。 The transdermal preparation according to any one of claims 1 to 7, wherein the acrylic adhesive is an adhesive having an intrinsic viscosity of 1.5 to 2.5.
  9. 前記塩基性薬物が、タムスロシンの塩の形態であるか又は遊離塩基の形態である、請求項１乃至請求項８のうち何れか一項に記載の経皮吸収型製剤。 The transdermal preparation according to any one of claims 1 to 8, wherein the basic drug is in the form of a salt of tamsulosin or in the form of a free base.
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