JP2016155779A - Patches and percutaneous absorption-promoting agent of non-steroidal anti-inflammatory agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide patches with high percutaneous absorption-promoting effect of non-steroidal anti-inflammatory agents, and to provide percutaneous absorption promoting agents of non-steroidal anti-inflammatory agents.SOLUTION: The invention provides a patch comprising an attachment layer containing component A): a non-steroidal anti-inflammatory agent, and component (B): one or more kinds selected from the group consisting of hyaluronic acid and hyaluronic acid salt, wherein the mass ratio (B)/(A) of the component (B) to the component (A) is more than 1; and a percutaneous absorption promoting agent of non-steroidal anti-inflammatory agents, the percutaneous absorption promoting agent containing one or more kinds selected from the group consisting of hyaluronic acid and hyaluronic acid salt.SELECTED DRAWING: None

Description

  The present invention relates to a transdermal absorption enhancer for a patch and a non-steroidal anti-inflammatory agent.

  As an external preparation that can relieve pain by suppressing inflammation of the skin, a patch comprising an adhesive layer containing a non-steroidal anti-inflammatory agent that exhibits an excellent anti-inflammatory analgesic effect is known. However, non-steroidal anti-inflammatory agents have a problem that they are difficult to be absorbed through the skin.

  Therefore, it has been proposed to add a component having an effect of promoting percutaneous absorption of the non-steroidal anti-inflammatory agent to the adhesive layer in addition to the non-steroidal anti-inflammatory agent. Specifically, for example, a patch (Patent Document 1) in which a non-steroidal anti-inflammatory agent and oxybuprocaine are blended in the adhesive layer can be mentioned. However, even in the patch, the effect of promoting percutaneous absorption of a nonsteroidal anti-inflammatory agent is not sufficient.

By the way, it is known that hyaluronic acid is blended as a moisturizing agent in an adhesive layer containing a non-steroidal anti-inflammatory agent (Patent Documents 1 to 3). When hyaluronic acid is blended as a moisturizing agent, the blending amount is usually a small amount of 1 or less in terms of mass ratio to the nonsteroidal anti-inflammatory agent.
As in Patent Documents 1 to 3, hyaluronic acid is sometimes incorporated as a moisturizing agent, but the percutaneous absorption promoting effect of non-steroidal anti-inflammatory agents has not been considered.

JP 2009-298741 A JP 60-260513 A JP 2014-114291 A

  An object of the present invention is to provide a patch having a high transdermal absorption promoting effect of a non-steroidal anti-inflammatory agent and a transdermal absorption promoting agent of a non-steroidal anti-inflammatory agent.

  The patch of the present invention comprises an adhesive layer containing (A) component: a non-steroidal anti-inflammatory agent and (B) component: one or more selected from the group consisting of hyaluronic acid and hyaluronate. The mass ratio (B) / (A) of the component (B) to the component (A) is more than 1.

The component (A) is preferably felbinac.
The adhesive layer preferably further contains (C) component: alkanolamine.

  The transdermal absorption enhancer of the non-steroidal anti-inflammatory agent of the present invention contains one or more selected from the group consisting of hyaluronic acid and hyaluronate.

The patch of the present invention can provide a transdermal absorption promoting effect of a non-steroidal anti-inflammatory agent.
By using the non-steroidal anti-inflammatory agent transdermal absorption enhancer of the present invention, the transdermal absorption promoting effect of the non-steroidal anti-inflammatory agent can be obtained.

  The patch of the present invention includes an adhesive layer containing the component (A) and the component (B). The patch of the present invention may be composed only of an adhesive layer, or may be an adhesive layer provided on a support.

[Adhesive layer]
The adhesive layer contains the component (A) and the component (B) as essential components.

((A) component)
The component (A) is a non-steroidal anti-inflammatory agent. The non-steroidal anti-inflammatory agent is not particularly limited as long as it can be dispersed in the adhesive layer.
Non-steroidal anti-inflammatory agents include, for example, salicylic acid, salicylate, salicylic acid derivatives (such as aspirin), acetaminophen, aminopyrine, antipyrine, oxyphenbutazone, sulpyrine, indomethacin, diclofenac sodium, ibuprofen, sulindac, naproxen, ketoprofen. , Etofenamate, salicylamide, triethanolamine salicylate, flufenamic acid, flufenamic acid salt, flufenamic acid derivative, meclofenamic acid, meclofenamic acid salt, meclofenamic acid derivative, colchicine, bufexamac, ibufenac, loxoprofen, fenbufen, diflunisal , Alclofenac, phenylbutazone, mefenamic acid, mefenamic acid salt, mefenamic acid derivative, fenoprof Emissions, bendazac, piroxicam, flurbiprofen, zaltoprofen, etodolac, and the like.

As the component (A), fervinac, indomethacin, methyl salicylate, and ketoprofen are preferable because the effect of promoting percutaneous absorption by the component (B) is easy to obtain. Particularly preferred.
(A) A component may be used individually by 1 type and may be used in combination of 2 or more type.

((B) component)
The component (B) is one or more selected from the group consisting of hyaluronic acid and hyaluronate. By including the component (B) in the adhesive layer of the patch, the effect of promoting percutaneous absorption of the component (A) can be obtained. That is, the component (B) acts as a transdermal absorption enhancer of a nonsteroidal anti-inflammatory agent.

The origin of hyaluronic acid is not particularly limited, and hyaluronic acid commonly used for external preparations for skin can be used, and examples thereof include hyaluronic acid derived from chicken crowns and microorganisms.
As hyaluronic acid salts, pharmaceutically and physiologically acceptable salts can be used, for example, alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (magnesium salts, calcium salts, etc.), ammonium salts, etc. And alkanolamine salts (monoethanolamine and the like). Of these, alkali metal salts are preferred as the hyaluronate.

The mass average molecular weight of hyaluronic acid (as well as hyaluronate) is preferably 1,000 to 5,000,000, more preferably 2,000 to 4,000,000, and 3,000 to 2,500,000. Further preferred.
In addition, the mass average molecular weight in the present invention is a value measured by gel permeation chromatography.

As the component (B), one type may be used alone, or two or more types may be used in combination.
As the component (B), hyaluronic acid or hyaluronic acid salts having different mass average molecular weights are preferably used in combination because the effect of promoting percutaneous absorption with respect to the component (A) is easily obtained, and the mass average molecular weight is 1,000. It is more preferable to use a combination of hyaluronic acid or hyaluronic acid salt of 10,000 to hyaluronic acid or hyaluronic acid salt having a mass average molecular weight of 100,000 to 5,000,000.

((C) component)
In addition to the component (A) and the component (B), the adhesive layer preferably further contains (C) component: alkanolamine. By containing (C) component, the percutaneous absorption promotion effect of (A) component further increases.

The alkanolamine may be a monoalkanolamine, a dialkanolamine, or a trialkanolamine.
1-10 are preferable and, as for carbon number of the hydroxyalkyl group which alkanolamine has, 2 or 3 is more preferable.

Specific examples of the alkanolamine include, for example, monoethanolamine, diethanolamine, triethanolamine, monopropanolamine, dipropanolamine, tripropanolamine, monoisopropanolamine, diisopropanolamine, triisopropanolamine and the like.
As the component (C), one type may be used alone, or two or more types may be used in combination.

(Optional component)
Optional components other than the components (A) to (C) may be contained in the adhesive layer. Arbitrary components may be used individually by 1 type, and may be used in combination of 2 or more type.
In the adhesive layer used in the present invention, a water-containing pressure-sensitive adhesive, a rubber-based pressure-sensitive adhesive, and an acrylic pressure-sensitive adhesive can be used as a pressure-sensitive adhesive base for the purpose of imparting pressure-sensitive adhesiveness.

<Water-containing adhesive>
The water-containing pressure-sensitive adhesive preferably contains a water-soluble polymer or a cross-linked product thereof.
Preferred water-soluble polymers include polyacrylic acid polymers, gelatin, polyvinyl alcohol and the like.

As the crosslinked body of the water-soluble polymer, for example, a polyacrylic acid-based water-based pressure-sensitive adhesive composed of crosslinked polyacrylic acid (salt) obtained by crosslinking a mixture of polyacrylic acid and polyacrylate with various crosslinking agents is preferable. The polyacrylic acid-based water-based pressure-sensitive adhesive is a pressure-sensitive adhesive base having a high water content and excellent adhesion to the skin. Therefore, by using the polyacrylic acid-based water-based pressure-sensitive adhesive, it is possible to obtain a patch particularly excellent in terms of percutaneous absorption of active ingredients.
The polyacrylic acid may be linear or branched.

Examples of polyacrylates include monovalent metal salts of polyacrylic acid such as sodium polyacrylate and potassium polyacrylate; polyacrylic acid monoethanolamine, polyacrylic acid diethanolamine, polyacrylic acid triethanolamine and the like. Examples include amine salts of acrylic acid; ammonium salts of polyacrylic acid. A polyacrylate may be used individually by 1 type, and 2 or more types may be combined and used for it.
The polyacrylate may be linear or branched.

  In the polyacrylic acid-based water-based pressure-sensitive adhesive, it is preferable to use polyacrylic acid having a mass average molecular weight of 10,000 to 10,000,000 and a polyacrylate having a mass average molecular weight of 10,000 to 10,000,000. In particular, one or more types of polyacrylic acid having a weight average molecular weight of 10,000 to less than 500,000, less than 500,000 to less than 2,000,000, or 2,000,000 to 5,000,000, and a weight average molecular weight of 10,000 to less than 500,000, 500,000 or more It is preferable to use a combination of at least one of the polyacrylic acid salts of less than 2 million or 2 million or more and 5 million with at least the different molecular weight ranges. Thereby, further better adhesive force and usability can be obtained.

  The blending ratio (mass ratio) of polyacrylate and polyacrylic acid is preferably 1: 0.1 to 1:10, more preferably 1: 1 to 1: 9. You may use what partly neutralized polyacrylic acid and made the mixture ratio into the said ratio.

  As the crosslinking agent, any compound may be used as long as it acts on the carboxyl groups of polyacrylic acid and polyacrylate to form a crosslinked structure and has at least two reactive sites in the molecule. Specific examples of the crosslinking agent include compounds having an epoxy group such as bisepoxide, dialdehyde starch, glycidyl ether, dibenzylidene sorbitol, polyvalent metal compounds, polycationic polymers or salts thereof. Especially, as a crosslinking agent, a polyvalent metal compound, a polycationic polymer, or its salt is especially preferable.

Examples of the polyvalent metal compound include magnesium compounds, calcium compounds, zinc compounds, cadmium compounds, aluminum compounds, titanium compounds, tin compounds, iron compounds, chromium compounds, manganese compounds, cobalt compounds, nickel compounds, and the like. Since the patch of the present invention is applied to the skin, an aluminum compound, a magnesium compound, and a calcium compound are particularly preferable as the polyvalent metal compound from the viewpoint that the adverse effect on the skin is small.
The aluminum compound, magnesium compound and calcium compound are not particularly limited. Specifically, alums such as potassium alum, ammonium alum, iron alum, aluminum hydroxide, aluminum sulfate, aluminum chloride, aluminum glycinate, aluminum acetate, aluminum oxide, aluminum silicate, aluminum metasilicate, calcium hydroxide, Calcium carbonate, calcium sulfate, calcium nitrate, calcium chloride, calcium acetate, calcium oxide, calcium phosphate, magnesium hydroxide, magnesium carbonate, magnesium sulfate, magnesium nitrate, magnesium chloride, magnesium acetate, magnesium silicate, magnesium oxide, magnesium alumina hydroxide , Magnesium aluminate metasilicate, magnesium aluminate silicate, synthetic hydrotalcite, and double salts containing these metals Water-soluble compounds or sparingly water-soluble compounds, and the like. These may be used alone or in combination of two or more.

  When a polyvalent metal compound is used as the cross-linking agent, the blending amount of the polyvalent metal compound in the polyacrylic acid aqueous adhesive (100% by mass) is preferably 0.001 to 10% by mass, and 0.01 to 5%. Is more preferable, and 0.02 to 2% by mass is more preferable. When the blending amount of the polyvalent metal compound is at least the lower limit value, sufficient cohesive force can be easily obtained, and the adhesive is less likely to remain on the skin when the patch is peeled off. If the blending amount of the polyvalent metal compound is not more than the upper limit value, sufficient adhesive force can be easily obtained, and it becomes difficult to peel off when the patch is applied, so that the original support function is easily exhibited.

  0.5-20 mass% is preferable and, as for the ratio of the polyacrylic acid type water-based adhesive in a hydrous adhesive (100 mass%), 1-15 mass% is more preferable. If the ratio of the polyacrylic acid-based water-based pressure-sensitive adhesive is not less than the lower limit value, sufficient adhesive force can be easily obtained. When the ratio of the polyacrylic acid-based water-based pressure-sensitive adhesive is not more than the upper limit value, it is easy to suppress the viscosity from becoming too high, and the workability at the time of manufacture is improved.

  The water-containing pressure-sensitive adhesive is not particularly limited, and known ones can be used. JP-A-59-110614, 59-110616, 59-110617, 60-99180, 60 The hydrous adhesive containing the metal crosslinked body of polyacrylic acid and polyacrylic acid salt described in -260512 gazette, 60-260513 gazette, etc. is preferred.

  The water-containing pressure-sensitive adhesive is not limited to a polyacrylic acid-based water-based pressure-sensitive adhesive, and is a polymer obtained by polymerizing acrylic acid, or acrylic acid such as Carbopol (trade name: manufactured by Goodrich, USA). A polymer partially cross-linked can also be suitably used.

In order to improve the feeling of use, a cellulose derivative may be added to the water-containing adhesive. Examples of the cellulose derivative include alkali metal salts of carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and the like. Especially, as a cellulose derivative, alkali metal salts of carboxymethylcellulose, such as sodium carboxymethylcellulose and carboxymethylcellulose potassium, are preferable. Preferred cellulose derivatives are those having a 1 mass% viscosity at 25 ° C. of 500 cp to 8000 cp.
As for the compounding quantity of the cellulose derivative in a water-containing adhesive (100 mass%), 15 mass% or less is preferable. If the blending amount of the cellulose derivative is 15% by mass or less, it is easy to suppress the viscosity from becoming too high, and the workability during production is improved.

In order to improve the physical properties, the water-containing adhesive is further blended with other water-soluble polymers such as polyvinylpyrrolidone, pectin, vinylpyrrolidone / vinyl acetate copolymer, sodium alginate, xanthan gum, tragacanth, etc. May be.
The blending amount of the other water-soluble polymer in the hydrous adhesive (100% by mass) is preferably 10% by mass or less. When the blending amount of the other water-soluble polymer is 10% by mass or less, it is easy to suppress the water-containing pressure-sensitive adhesive from becoming hard, and problems are unlikely to occur in the manufacture of the patch.

<Rubber adhesive>
The rubber-based pressure-sensitive adhesive is a pressure-sensitive adhesive composed of a rubber-based polymer, a plasticizer, a tackifying resin, and the like. Examples of rubber polymers include styrene-isoprene-styrene block copolymer (hereinafter abbreviated as SIS), isoprene rubber, polyisobutylene (hereinafter abbreviated as PIB), and styrene-butadiene-styrene block copolymer. Styrene-butadiene rubber copolymer, polysiloxane and the like. Among these, SIS and PIB are preferable and SIS is more preferable as the rubber-based pressure-sensitive adhesive from the viewpoint of adhesiveness, spreadability, and cohesive force. These are hydrophobic polymers and may be used alone or in combination of two or more.

  10-85 mass% is preferable, as for content of the rubber-type polymer in a rubber-type adhesive (100 mass%), 30-85 mass% is more preferable, and 30-70 mass% is especially preferable. If the content of the rubber polymer is within the above range, the formation of the adhesive layer is good and sufficient permeability is obtained.

  Plasticizers include petroleum oils (eg, paraffinic process oil, naphthenic process oil, aromatic process oil, etc.), squalane, squalene, vegetable oils (eg, olive oil, camellia oil, castor oil, tall oil, peanut Oil), silicon oil, dibasic acid ester (eg, dibutyl phthalate, dioctyl phthalate, etc.), liquid rubber (eg, polybutene, liquid isoprene rubber, etc.), and the like. Of these, liquid paraffin and liquid polybutene are preferred as the plasticizer because they have good compatibility with rubber-based polymers and excellent cohesion. A plasticizer may be used individually by 1 type and may be used in combination of 2 or more type.

  10-70 mass% is preferable, as for content of the plasticizer in a rubber-type adhesive (100 mass%), 10-60 mass% is more preferable, and 10-50 mass% is especially preferable. If the content of the plasticizer is within the above range, sufficient permeability is easily obtained, and sufficient cohesive force as a rubber-based pressure-sensitive adhesive used for a patch is easily maintained.

  Examples of the tackifier resin include rosin derivatives (eg, rosin, glycerin ester of rosin, hydrogenated rosin, glycerin ester of hydrogenated rosin, pentaerythrester ester of rosin), alicyclic saturated hydrocarbon resin (eg, trade name) : Alcon P100, manufactured by Arakawa Chemical Industries), aliphatic hydrocarbon resins (for example, trade name: Quinton B170, manufactured by Nippon Zeon), terpene resin (for example, trade name: Clearon P-125, manufactured by Yasuhara Chemical), maleic resin Etc. Among these, as the tackifier resin, glycerol ester of hydrogenated rosin, alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin, and terpene resin are preferable. One type of tackifier resin may be used alone, or two or more types may be used in combination.

  5-70 mass% is preferable, as for content of tackifying resin in a rubber-type adhesive (100 mass%), 5-60 mass% is more preferable, and 10-50 mass% is more preferable. When the content of the tackifying resin is within the above range, sufficient adhesive force as a patch is easily obtained, and skin irritation at the time of peeling of the patch is reduced.

<Acrylic adhesive>
As the acrylic pressure-sensitive adhesive, a copolymer (X) obtained by copolymerization using at least one monomer (x) selected from the group consisting of (meth) acrylic acid and (meth) acrylic acid derivatives is preferable. The copolymer (X) may be a copolymer obtained by copolymerizing only two or more types of monomers (x). One or more types of monomers (x) and the monomers (x ) And a copolymerizable ethylenically unsaturated monomer (hereinafter also referred to as monomer (y)) may be a copolymer under copolymerization.
“(Meth) acrylic acid” means one or both of methacrylic acid and acrylic acid.

  Representative examples of (meth) acrylic acid derivatives include 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, 2-hydroxyethyl acrylate, and 2-ethylhexyl methacrylate.

Moreover, as another (meth) acrylic acid derivative, the following are mentioned, for example.
-Hydroxyl group-containing acrylic monomers: 2-hydroxyethyl methacrylate, hydroxypropyl (meth) acrylate, and the like.
Amide group-containing acrylic monomers: (meth) acrylamide, dimethyl (meth) acrylamide, N-butyl (meth) acrylamide and the like.
Amino group-containing acrylic monomers: aminoethyl (meth) acrylate, dimethylaminoethyl (meth) acrylate, diethylaminoethyl (meth) acrylate, and the like.
-Alkoxy group-containing acrylic monomers: methoxyethyl (meth) acrylate, ethoxyethyl (meth) acrylate, and the like.
-Sulfoxyl group-containing acrylic monomers: sulfopropyl acrylate and the like.
Sugar chain-containing acrylic monomers: glycosyloxyethyl (meth) acrylate, galactosyloxyethyl (meth) acrylate, etc.
Other acrylic monomers: urethane ester acrylate, urea ester of acrylic acid, isocyanate ester of acrylic acid, etc.
Monomer (x) may be used individually by 1 type, and may be used in combination of 2 or more type.

Examples of the monomer (y) include a hydroxyl group-containing monomer (such as vinyl alcohol), a carboxyl group-containing monomer (such as itaconic acid, crotonic acid, maleic acid, and maleic anhydride), and a sulfoxyl group-containing single amount. Bodies (styrene sulfonic acid, allyl sulfonic acid, etc.), amino group-containing monomers (vinyl pyrrolidone, etc.), vinyl monomers (N- (meth) acryloylamino acid, (meth) acrylonitrile, vinyl acetate, vinyl propionate, Vinyl chloride, vinyl pyrrolidone, vinyl pyridine, vinyl pyrazine, vinyl piperazine, vinyl piperidone, vinyl pyrimidine, vinyl pyrrole, vinyl imidazole, vinyl caprolactam, vinyl oxazole, vinyl thiazole, vinyl morpholine, styrene, α-methyl styrene, bis (N, N -Dimethylamino Chill) maleate and the like) and the like.
A monomer (y) may be used individually by 1 type, and 2 or more types may be combined and used for it.

  As the acrylic adhesive, for example, those listed in the Pharmaceutical Additives Dictionary 2000 (edited by the Japan Pharmaceutical Additives Association) as an adhesive can be used. Specifically, for example, acrylic acid / octyl acrylate copolymer, acrylic ester / vinyl acetate copolymer, 2-ethylhexyl acrylate / vinyl pyrrolidone copolymer, 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / dodecyl methacrylate copolymer , Methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, Acrylic polymer alkanolamine liquid adhesive, DURO-TAK acrylic adhesive series (National Starch and Chemical Co., Ltd.), Eudragit series (Higuchi Shokai). These components may be used alone or in combination of two or more.

<Other optional components>
As optional components, in addition to the adhesive base, glycerin as a wetting agent, pH adjuster (except for component (C)), emulsifier, stabilizer, cross-linking agent, and promotion of transdermal absorption other than component (B) An agent or the like may be used.
The adhesive layer may contain water. As the water, for example, JP refined water, outside original purified water or the like can be used.

(Form)
The dosage form of the patch of the present invention is not particularly limited, and examples thereof include a tape, a poultice, and an acrylic patch.

(Ratio of each component)
Content of each component shall mean content after drying, when drying of an adhesive layer is required in manufacture of a patch.
The content of the component (A) in the adhesive layer (100% by mass) can be appropriately set depending on the effective drug amount of each component, and is preferably 1 to 10% by mass. If content of (A) component is more than the said lower limit, transdermal absorption of (A) component will be easy to be accelerated | stimulated. If content of (A) component is below the said upper limit, manufacture of a patch will become easy.

(A) When a component is felbinac, 0.5-7 mass% is more preferable, and, as for content of felbinac in a sticking layer (100 mass%), 1-5 mass% is further more preferable.
When the component (A) is indomethacin, the content of indomethacin in the adhesive layer (100% by mass) is more preferably 1 to 7% by mass, and further preferably 1 to 5% by mass.

  5-80 mass% is preferable, as for content of (B) component in an adhesion layer (100 mass%), 10-75 mass% is more preferable, and 15-70 mass% is further more preferable. If content of (B) component is more than the said lower limit, the percutaneous absorption promotion effect of (A) component will be easy to be acquired. If content of (B) component is below the said upper limit, manufacture of a patch will become easy.

  The mass ratio (B) / (A) of the component (B) to the component (A) in the adhesive layer is more than 1, preferably 5 to 20, more preferably 10 to 20, and still more preferably 12 to 18. . If mass ratio (B) / (A) exceeds 1, the percutaneous absorption promotion effect of (A) component will be acquired. If the mass ratio (B) / (A) is less than or equal to the above upper limit, the viscosity (formulation viscosity) of the adhesive layer will not be too high, the manufacture of the patch will be easy, and a high transdermal absorption promoting effect will be obtained. Easy to obtain.

  1-15 mass% is preferable, as for content of (C) component in an adhesion layer (100 mass%), 5-10 mass% is more preferable, and 5-8 mass% is further more preferable. If content of (C) component is more than the said lower limit, the percutaneous absorption promotion effect of (A) component will improve. If content of (C) component is below the said upper limit, manufacture of a patch will become easy.

What is necessary is just to adjust the moisture content of a sticking layer suitably with the dosage form to select.
In the case of a tape agent, the moisture content of the adhesive layer is preferably 5 to 30% by mass, more preferably 5 to 20% by mass, and further preferably 5 to 15% by mass. If the moisture content of the adhesive layer is not less than the lower limit, the production of the patch becomes easy. If the moisture content of the adhesive layer is less than or equal to the above upper limit value, it is easy to apply the patch to the skin.

  In the case of a cataplasm, for the same reason as in the case of a tape agent, the moisture content of the adhesive layer is preferably more than 30% by mass and 90% by mass or less, more preferably 40-80% by mass, and even more preferably 50-70% by mass. preferable.

  In the case of an acrylic patch, the water content of the adhesive layer is preferably 0 to 5% by mass, more preferably 0 to 1% by mass, and even more preferably 0% by mass (non-water). When the moisture content of the adhesive layer is not more than the above upper limit value, the manufacture of the patch becomes easy and the adhesiveness becomes good.

[Support]
The patch of the present invention may include a support.
The support is not particularly limited, and a known support that is usually used as a support for patches can be used. Examples of the support include a resin film, a cloth, and a composite sheet in which the resin film and the cloth are integrated.

  Examples of the resin film include films made of resins such as polyethylene, polypropylene, polyester, rayon, polyamide, polyvinyl chloride, urethane / vinyl chloride copolymer, and polyurethane.

The fabric may be a non-woven fabric, a woven fabric, or a knitted fabric.
As a nonwoven fabric, what was manufactured by the needle punch method, the spunlace method, the spun bond method, the stitch bond method, the melt blown method etc. is mentioned, for example.
The weaving method of the woven fabric and the knitting method of the knitted fabric are not particularly limited. For example, warp knitting (tricot knitting, denby tricot knitting, satin knitting, atlas knitting, flat knitting, rim knitting, pearl knitting), circular knitting (both sides) Knitting, single-sided knitting, and milling knitting).

  Examples of the material of the fibers constituting the fabric include polyester, rayon, nylon, polypropylene, polyethylene, polyamide, and polyurethane.

  Examples of the composite sheet include a sheet in which a resin film and a fabric are bonded by thermal fusion, an adhesive, or the like, a sheet formed by extruding a molten resin on a fabric, and the like.

[Release liner]
The patch of the present invention may be provided with a release liner that can be peeled off at the time of use on the surface of the adhesive layer for the purpose of preventing the adhesive layer from drying.
As the release liner, known ones can be used as patch liners (plaster coverings), and examples thereof include vinyl chloride films, polyethylene films, polypropylene films, polyester films, polyethylene terephthalate separators, release papers (release papers) and the like. .

[Production method]
The method for producing the patch of the present invention is not particularly limited, and a known method can be adopted.
When the patch of the present invention does not have a support, for example, a mixture of (A) component and (B) component, and (C) component and optional component used as necessary is dispersed in water. A method of forming an adhesive layer by pouring and drying until a desired water content is achieved.
When the patch of the present invention is provided with a support, for example, a mixture of (A) component and (B) component and (C) component and optional components used as necessary is dispersed on water on the support. Examples of the method include, after coating, drying until a desired moisture content is obtained to form an adhesive layer.

[Function and effect]
In the patch of the present invention described above, the (B) component is contained in a specific ratio together with the (A) component in the adhesive layer, and therefore, due to the high percutaneous absorption promoting effect by the (B) component, The component A) can be efficiently absorbed from the skin and exert an anti-inflammatory analgesic effect.

EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited by the following description.
[material]
The raw materials used in this example are shown below.

((A) component)
A-1: Felbinac (manufactured by HANSEO CHEMICAL).
A-2: Indomethacin (manufactured by Kongo Chemical Co., Ltd.).

((A ′) component: comparative component)
A′-1: Amsinoid (manufactured by LGM PHARMA).

((B) component)
B-1: Sodium hyaluronate (mass average molecular weight: 100,000 to 2,000,000, trade name “FCH-SU”, manufactured by Kibun Food Chemical Co., Ltd.).
B-2: Sodium hyaluronate (mass average molecular weight: 1,000 to 10,000, trade name “Hiro-oligo”, manufactured by Kewpie Corporation).

((C) component)
C-1: Diisopropanolamine (Mitsui Chemical Fine Co., Ltd.).

(Optional component)
D-1: Gelatin (manufactured by Rousselot).
D-2: Concentrated glycerin (trade name “Pharmacopoeia Concentrated Glycerin”, Sakamoto Pharmaceutical Co., Ltd.).
D-3: Sodium polyacrylate (trade name “Aronbis S”, manufactured by Toagosei Co., Ltd.).
D-4: Polyacrylic acid (trade name “Jurimer AC-10Hα”, manufactured by Toagosei Co., Ltd.).
D-5: Sodium carboxymethylcellulose (trade name “Daicel CMC1380”, manufactured by Daicel Chemical Industries, Ltd.).
D-6: Synthetic hydrotalcite (trade name “Alkamak SH”, manufactured by Kyowa Chemical Industry Co., Ltd.).
D-7: Disodium edetate (manufactured by Chubu Kirest Co., Ltd.).
D-8: Methacrylic acid / n-butyl acrylate copolymer (trade name “RODERM”, manufactured by Rohm and Haas Co., Ltd.).
D-9: Potassium aluminum sulfate (manufactured by Junsei Chemical Co., Ltd.).
D-10: Isopropyl myristate (manufactured by Nippon Surfactant Co., Ltd.).

[Production Examples 1 to 14]
Each component was mixed in the ratio shown in Table 1 using the Henschel mixer, and the liquid mixtures 1-14 for sticking layer formation were prepared.

[Example 1]
The liquid mixture 1 obtained in Production Example 1 is filled into a vat so that the thickness is about 5 mm, and is left to stand for about 10 hours until the water content reaches the ratio shown in Table 2 at 25 ° C. and 40% RH. And dried to prepare a patch (tape) consisting only of the adhesive layer shown in Table 2.
The obtained patch was an inner bag (paper (basis weight: 64 g / m ² ) / polyethylene (thickness 15 μm) / aluminum foil (thickness 7 μm) / ethylene / methacrylic acid copolymer (EMAA, thickness 20 μm). And was sealed by heat sealing.

[Examples 2 to 8, Comparative Examples 1 to 6]
A patch (tape) shown in Table 2 was prepared in the same manner as in Example 1 except that the type of the mixed solution used was changed as shown in Table 2. The obtained patch was placed in an inner bag in the same manner as in Example 1 and sealed by heat sealing.

[Example 9]
Using a Henschel mixer, each component was mixed at a ratio shown in Table 3 to prepare a mixed solution for forming an adhesive layer, and an adhesive patch (a patch) consisting only of the adhesive layer was produced. The obtained cataplasm was filled in the support so that the coating amount per 1 cm ² was 1 g and covered with a liner. A polyester nonwoven fabric (trade name: PAL-90, manufactured by Kurashiki Fiber Processing Co., Ltd.) was used as the support. As the liner, a polyethylene terephthalate film (trade name: Emblet S-25, manufactured by Unitika Ltd.) was used.

[Comparative Example 7]
A patch (a patch) was prepared in the same manner as in Example 9 except that the composition of the mixed solution was changed as shown in Table 3.

[Example 10]
Using paddle feathers, each component was mixed at the ratio shown in Table 3 to prepare a mixed liquid for forming an adhesive layer, and a liner (polyethylene terephthalate silicon film, trade name “NS separator”, manufactured by Nakamoto Pax Co., Ltd.) ) On top of this, the mixture is applied so that the coating amount per 1 cm ² is 1 g, dried at 100 ° C. until it becomes a constant weight, and the support (polyurethane film, trade name “Espancione”, Seiren Co., Ltd.) A patch (acrylic patch) having an adhesive layer formed thereon was prepared.

[Comparative Example 8]
A patch (acrylic patch) having an adhesive layer formed on a support was produced in the same manner as in Example 10 except that the composition of the mixed solution was changed as shown in Table 3.

[Measurement of drug penetration]
A transdermal absorbability test was conducted using hairless mice. The outline is shown below.
The mouse skin was placed on a vertical Franz cell and the patch was affixed. Then, the receiver solution was collected 8 hours later, and the permeation amount of the drug (component (A)) was measured by HPLC. The processing conditions are shown below.
(Processing conditions)
Measurement environment: 25 ° C., 50% RH,
Mouse skin: HR-1 7 weeks old Removed from male back,
Receiver solution: phosphate buffer (pH 7.4),
Application area: 5 cm ²
Patch: 1 sheet (about 0.5g),
Franz cell jacket temperature: 37 ° C.

Next, the rate of increase in percutaneous absorption was calculated from the measured drug permeation amount by the following formula.
Percutaneous absorption increase rate (%) = [drug permeation amount (with component (B)) / drug permeation amount (without component (B))] × 100
In the calculation of the percutaneous absorption increase rate of Examples 1, 3, 4, 8 and Comparative Example 6, the drug permeation amount of Comparative Example 3 was adopted as the drug permeation amount (no component (B)). In the calculation of the rate of increase in percutaneous absorption in Example 2, the drug permeation amount of Comparative Example 4 was adopted as the drug permeation amount (no component (B)). In the calculation of the percutaneous absorption increase rate of Examples 5 to 7, the drug permeation amount of Comparative Example 5 was adopted as the drug permeation amount (no component (B)). In the calculation of the percutaneous absorption increase rate of Comparative Example 1, the drug permeation amount of Comparative Example 2 was adopted as the drug permeation amount (no component (B)).
In the calculation of the percutaneous absorption increase rate of Example 9, the drug permeation amount of Comparative Example 7 was adopted as the drug permeation amount (no component (B)). In the calculation of the percutaneous absorption increase rate of Example 10, the drug permeation amount of Comparative Example 8 was adopted as the drug permeation amount (no component (B)).

Tables 2 and 3 show the compositions of the components of the adhesive layers of Examples and Comparative Examples and the measurement results of the rate of increase in percutaneous absorption.
In the column of “mass ratio (B) / (A)” of Comparative Example 1 in Table 2, the mass ratio of the component (B) to the component (A ′) is shown.

As shown in Table 2, the adhesive layers of Examples 1 to 8 in which the adhesive layer contains the component (A) and the component (B) at a mass ratio (B) / (A) of more than 1, B) Compared with the patches of Comparative Examples 3 to 5 not containing the component and Comparative Example 6 in which the mass ratio (B) / (A) is 1, the percutaneous absorption increase rate is high and a high percutaneous absorption promoting effect is obtained. Obtained.
When the component (A ′) that is not a non-steroidal anti-inflammatory agent is used, the component (B) is added to the patch of Comparative Example 2 that does not contain the component (B) by mass ratio (B) / (A). The rate of increase in transdermal absorption of the patch of Comparative Example 1 contained at = 15 was 98.2%, and no transdermal absorption promoting effect was observed. From this, it was confirmed that the component (B) has an effect of specifically promoting percutaneous absorption of the component (A).
Similarly, as shown in Table 3, the rate of increase in percutaneous absorption of Example 9 relative to Comparative Example 7 and the rate of increase in percutaneous absorption of Example 10 relative to Comparative Example 8 are also high. Also in the patch, a high percutaneous absorption promoting effect of the component (A) by the component (B) was obtained.
From the above results, it was confirmed that the component (B) acts as a transdermal absorption enhancer of a non-steroidal anti-inflammatory agent.

Claims (4)

(A) component: a non-steroidal anti-inflammatory agent, and (B) component: one or more selected from the group consisting of hyaluronic acid and hyaluronate, and an adhesive layer containing:
The patch, wherein the mass ratio (B) / (A) of the component (B) to the component (A) is more than 1.   The patch according to claim 1, wherein the component (A) is felbinac.   The patch according to claim 1 or 2, wherein the adhesive layer further contains (C) component: alkanolamine.   A transdermal absorption enhancer of a non-steroidal anti-inflammatory agent, comprising at least one selected from the group consisting of hyaluronic acid and hyaluronate.