JP2014156497A - Water-containing patch - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a water-containing patch excellent in stability of active ingredients containing loxoprofen.SOLUTION: Disclosed is a water-containing patch which contains loxoprofen sodium dihydrate, partially neutralized polyacrylic acid product, polyacrylic acid Na, carmellose Na, methyl acrylate/2-ethylhexyl acrylate copolymer, dried aluminium hydroxide gel, inorganic powder, pH regulator, l-menthol, N-methyl-2-pyrrolidone, glycerol, nonionic surfactant, and a purified water, wherein the nonionic surfactant is polyoxyethylene hardened castor oil (addition mol number of ethylene oxide is 5).

Description

  The present invention relates to a hydrous patch.

  In recent years, a patch in which an adhesive layer containing an active ingredient in an adhesive is positioned on a support has been developed for transdermal administration instead of oral administration of drugs and intravenous administration by injection. The patch is useful in that it can percutaneously absorb a substantially constant amount of the active ingredient over a long period of time from when it is applied to the skin until it is peeled off.

  On the other hand, the adhesive layer of the patch contains various components including an adhesive in addition to the active ingredient, whereby the active ingredient in the patch is likely to deteriorate over time, It is important to improve its stability.

  There are two types of patches: water-containing patches (paps) containing water and non-aqueous patches (tapes, plasters, etc.). Among these, for non-aqueous patches, it has been suggested that the stability of active ingredients can be improved by using an antioxidant such as 2-mercaptobenzimidazole (Patent Document 1).

Japanese Patent Application Laid-Open No. 11-79980

  However, in the water-containing patch, since the adhesive layer further contains water, it is considered necessary to improve the stability of the active ingredient from a viewpoint different from that of the non-aqueous patch. In addition, since the decomposition of the active ingredient varies depending on the active ingredient, it is necessary to examine measures necessary for improving the stability for each active ingredient.

  The present invention has been made in view of the above circumstances, and an object thereof is to provide a water-containing patch excellent in the stability of an active ingredient (drug) having a predetermined cyclic ketone structure such as loxoprofen.

  The present inventors have found that the reactivity (decomposability) of an active ingredient having a predetermined cyclic ketone structure in an aqueous system is suppressed by a nonionic surfactant, and have completed the present invention. Specifically, the present invention provides the following.

・・・・・・一般式１
（式中、ｎは０、１、又は２であり、Ｒは有機基である。） (1) A hydrous patch comprising a support and a pressure-sensitive adhesive layer located on the support,
The pressure-sensitive adhesive layer is a hydrous patch containing an active ingredient comprising a compound represented by the general formula 1, a pharmacologically acceptable salt or solvate thereof, a nonionic surfactant, and water. Agent.

.... General formula 1
(In the formula, n is 0, 1, or 2, and R is an organic group.)

  (2) The water-containing patch according to (1), wherein the compound is loxoprofen.

  (3) The water-based patch according to (1) or (2), wherein the nonionic surfactant has an HLB value of 6.0 or more and 9.5 or less.

  (4) The water-containing patch according to any one of (1) to (3), wherein the nonionic surfactant is an ethylene oxide addition type, and the number of moles of ethylene oxide added is 5 mol or less.

  (5) The nonionic surfactant is selected from the group consisting of polyoxyethylene hydrogenated castor oil (5 moles of added ethylene oxide) and polyoxyethylene lauryl ether (2 moles of added ethylene oxide). The water-containing patch according to (4), which is one or more types.

・・・・・・一般式１

・・・・・・一般式２

・・・・・・一般式３
（一般式１〜３中、ｎは０、１、又は２であり、Ｒは有機基である。） (6) About a hydrous patch comprising a support and an adhesive layer located on the support,
In the pressure-sensitive adhesive layer, the compound represented by the general formula 1, an active ingredient comprising a pharmacologically acceptable salt or solvate thereof, and water together with a nonionic surfactant, Is a method for suppressing the change to a compound represented by Formula 2 or Formula 3.

.... General formula 1

.... General formula 2

.... General formula 3
(In general formulas 1 to 3, n is 0, 1 or 2, and R is an organic group.)

(6) About a hydrous patch comprising a support and an adhesive layer located on the support,
The pressure-sensitive adhesive layer is blended together with an active ingredient comprising a compound represented by general formula 1, a pharmacologically acceptable salt or solvate thereof, and water, and the compound is represented by general formula 2 or general formula 3. Used to suppress the change to a compound
A preparation comprising a nonionic surfactant.

  According to the present invention, since the reactivity of an active ingredient having a predetermined cyclic ketone structure in an aqueous system is suppressed by a nonionic surfactant, it has a predetermined cyclic ketone structure such as loxoprofen in a hydrous patch. The stability of the active ingredient can be improved.

  Hereinafter, although embodiment of this invention is described, it is not the meaning which limits this invention.

  The patch according to the present invention comprises a support and a pressure-sensitive adhesive layer located on the support, the pressure-sensitive adhesive layer comprising a compound represented by the general formula 1, a pharmacologically acceptable salt thereof, or It contains at least an active ingredient composed of a solvate, a nonionic surfactant, and water.

[Adhesive layer]
Nonionic surfactants have heretofore been used as surfactants in aqueous patches, but were not expected to be useful as drug stabilizers. The inventor has surprisingly discovered that a nonionic surfactant suppresses the reactivity (degradability) of an active ingredient having a predetermined cyclic ketone structure in an aqueous patch. Specifically, a nonionic surfactant having an HLB value of 6.0 or more and 9.5 or less and / or an ethylene oxide addition type and an ethylene oxide addition mole number of 5 mol or less is an aqueous patch. In the method, the compound represented by the general formula 1 is prevented from changing to the compound represented by the general formula 2 or 3. Note that this reaction is completely different from esterification of an active ingredient (particularly, formation of an ester with menthol or the like) (for details, see Journal of Chromatography A, 2008, 1208, p.164-174).

  The change from General Formula 1 to General Formula 2 occurs when the bond between the ketone carbon and the α-position carbon is cleaved, and the change from General Formula 1 to General Formula 3 is the α-position carbon. Is produced by hydroxylation. In any reaction, since it is considered that the carbon number and R of the cyclic structure do not contribute, n may be 0, 1, or 2, and R may be any organic group. The stability of the active ingredient in the present invention means that the sum of the compounds of the general formulas 2 and 3 produced from the compound of the general formula 1 is reduced. Preferably, both the compounds of the general formulas 2 and 3 are produced. Although the amount is reduced, it is sufficient that at least one of the production amounts is reduced.

  Therefore, the compound represented by the general formula 1 is not particularly limited, and may be loxoprofen or the like. The pharmacologically acceptable salt is a salt of the above compound and / or a solvate thereof, and is not particularly limited. However, an alkali metal salt such as a sodium salt or a potassium salt, an alkali salt such as a calcium salt or a magnesium salt is used. It may be one kind or two or more kinds of earth metal salts. The solvate is a solvate of the above compound and / or a pharmacologically acceptable salt thereof, and is not particularly limited, but is generally a hydrate. The active ingredient (drug) may be formulated in any form such as a salt, a free form, a solvate (for example, hydrate), and a non-solvate (for example, non-hydrate).

・・・・化学式１ Specifically, loxoprofen is generally compounded in the form of a sodium salt / dihydrate represented by the following chemical formula 1, but is not particularly limited, and other salts, free forms, non-hydrated You may mix | blend in any form of a thing.

.... Chemical formula 1

・・・・化学式２

・・・・化学式３ And a nonionic surfactant suppresses the production | generation of the compound shown by the following Chemical formula 2 or 3 in an aqueous system.

.... Chemical formula 2

.... Chemical formula 3

  The nonionic surfactant having an HLB value of 6.0 or more and 9.5 or less is not particularly limited, and glyceryl stearate (containing 20% monoglyceride, HLB value 7.0), polyglyceryl monostearate (HLB value 9) 0.0), polyglyceryl tristearate (HLB value 9.5), decaglyceryl tristearate (HLB value 7.5), polyglyceryl trioleate (HLB value 7.0), polyoxyethylene glyceryl monostearate (oxidized) Ethylene addition mole number 5. HLB value 9.5), palm oil fatty acid sorbitan (HLB value 8.6), sorbitan monopalmitate (HLB value 6.7), monostearate polyoxyethylene sorbitan (ethylene oxide addition mole number) 6. HLB value 9.5), tetraoleic acid polyoxyethylene sorbit (ethylene oxide) Addition mole number 6. HLB value 8.5), polyoxyethylene hydrogenated castor oil (ethylene oxide addition mole number 5. HLB value 6.0), polyoxyethylene hydrogenated castor oil (ethylene oxide addition mole number 10. HLB value 6) .5), polyoxyethylene phytosterol (methylene oxide addition mole number 5. HLB value 9.5), polyoxyethylene lauryl ether (ethylene oxide addition mole number 2. HLB value 9.5), polyoxyethylene stearyl ether (oxidation) Ethylene addition mole number 2. HLB value 8.0), polyoxyethylene lauryl ether (ethylene oxide addition mole number 4. HLB value 9.0), polyoxyethylene oleyl ether (ethylene oxide addition mole number 2. HLB value 7. 5), polyoxyethylene behenyl ether (methylene oxide addition mole number 5. HLB value 7.0) , Polyoxyethylene polyoxypropylene cetyl ether (ethylene oxide addition mole number 1. propylene oxide addition mole number 4. HLB value 9.5), polyoxyethylene polyoxypropylene cetyl ether (ethylene oxide addition mole number 1. propylene oxide addition) Mole number 8. HLB value 9.5), monooleic acid polyethylene glycol (ethylene oxide addition mole number 6, HLB value 8.5), etc. Moreover, it is an ethylene oxide addition type | mold, and the thing whose ethylene oxide addition mole number is 5 mol or less is preferable, Specifically, a reoxyethylene hydrogenated castor oil (ethylene oxide addition mole number is 5 mol), and polyoxyethylene 1 type or 2 types of lauryl ether (2 mol of ethylene oxide addition moles) are preferable.

  Although the compounding quantity of a nonionic surfactant is not specifically limited, It is preferable that it is 10-500 mass% with respect to the compounding quantity of an active ingredient. The blending amount of the nonionic surfactant may generally be selected from a range of 3.0% by mass or less with respect to the pressure-sensitive adhesive layer.

  Since the stability of the active ingredient is considerably improved by the nonionic surfactant, the blending amount of other components for the purpose of stability may be small or may not be blended. Specifically, the pressure-sensitive adhesive layer may contain one or more selected from the group consisting of sulfite, hydrogen sulfite, and pyrosulfite, but the compounding amount is based on the compounding amount of the active ingredient, It may be 1% by mass or less.

  The sulfite may be an alkali metal salt such as sodium salt or potassium salt of hydrogen sulfite, an alkaline earth metal salt such as calcium salt or barium salt, and the bisulfite is an alkali metal such as sodium salt or potassium salt. It may be a salt, an ammonium salt, or the like, and the pyrosulfite may be an alkali metal salt such as a sodium salt or a potassium salt, specifically sodium sulfite, sodium bisulfite, or sodium pyrosulfite.

  The pressure-sensitive adhesive layer in the hydrous patch according to the present invention contains water. Although the compounding quantity of water is not specifically limited, About 30-70 mass% may be sufficient with respect to an adhesive layer.

  In addition to the above-mentioned components, the pressure-sensitive adhesive layer may be prepared by dissolving excipients such as polyacrylic acid and / or a salt thereof, a surfactant, a cross-linking agent, a cross-linking control agent, an adhesion enhancing agent, a moisturizing agent, and a drug. An optional component such as an auxiliary agent, a pH adjuster, a cooling agent, a water-soluble polymer compound, an inorganic powder, an antioxidant, a preservative, and a pigment may be included.

  Examples of polyacrylic acid and / or salts thereof include polyacrylic acid, sodium polyacrylate, and partially neutralized polyacrylic acid “NP-800 (trade name)” and “NP-700 (trade name)” (Showa Denko) These may be included alone or in combination of two or more.

  In addition to the nonionic surfactant, a general surfactant may be blended. Examples of such surfactants include anionic surfactants such as sodium dioctyl sulfosuccinate, alkyl sulfate salts, sodium 2-ethylhexyl alkyl sulfate, sodium normal dodecylbenzene sulfonate; hexadecyltrimethylammonium chloride, octadecyldimethylbenzyl Cationic surfactants such as ammonium chloride and polyoxyethylene dodecyl monomethyl ammonium chloride may be added.

  Examples of the crosslinking agent include polyvalent metal salts, and among them, aluminum compounds are preferable. Aluminum compounds include hydroxides such as dihydroxyaluminum aminoacetate and aluminum hydroxide, or salts of inorganic or organic acids such as aluminum chloride, aluminum sulfate, aluminum acetate and aluminum stearate, and aluminum alum. Examples thereof include double salts, aluminates such as sodium aluminate, inorganic aluminum complex salts, and organic aluminum chelate compounds. These aluminum compounds may be water-soluble or sparingly soluble.

  Moreover, although aluminum hydroxide gel may be used as a crosslinking agent, in this case, the pH is preferably 4.5 or more and 6.0 or less. When the pH exceeds 6.0, aluminum in the aluminum hydroxide gel is difficult to elute, the crosslinking reaction of the pressure-sensitive adhesive is insufficient, and the shape retention tends to deteriorate. On the other hand, when dihydroxyaluminum aminoacetate is used, the pH of the pressure-sensitive adhesive layer may be more than 6.0.

  The pH can be set using a pH adjuster, such as tartaric acid, phosphoric acid, malic acid, citric acid, hydrochloric acid, sodium hydroxide, triethanolamine, diethanolamine, diisopropanolamine, etc. These may be included singly or in combination of two or more, but tartaric acid is preferred.

  Examples of the adhesion enhancer include methacrylic acid / n-butyl acrylate copolymer, methyl acrylate / 2-ethylhexyl acrylate copolymer, polybutene, ester gum, terpene resin, and alicyclic saturated hydrocarbon resin. . The blending amount thereof may be 1% by mass or more and 30% by mass or less, and preferably 2% by mass or more and 10% by mass or less with respect to the pressure-sensitive adhesive layer.

  Examples of the crosslinking control agent include sodium edetate (disodium ethylenediaminetetraacetate), citric acid, and the like. These may be used alone or in combination of two or more, but sodium edetate is preferred.

  Examples of humectants include concentrated glycerin, sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, liquid paraffin, 1,3-propanediol, 1,3-butylene glycol, polyhydric alcohols such as maltitol and xylitol. These may be included singly or in combination of two or more, and among them, concentrated glycerin is preferable. In addition, the blending amount of glycerin may be appropriately set in consideration of the manufacturing cost, the tendency of bleeding, and the like.

  Drug dissolution aids include crotamiton, pyrrolidone derivatives such as N-methyl-2-pyrrolidone, mint oil, 1,3-butylene glycol, etc., and these are included alone or in combination of two or more. It's okay.

  As a refreshing agent, in addition to camphor and thymol, l-menthol, dl-menthol, 2-methyl-3- (l-menthyloxy) propane-1,2-diol, 3-l-mentoxypropane-1, Examples include menthol derivatives such as 2-diol and 5-methyl-2- (l-methylethyl) -cyclohexyl-2-hydroxypropionate, and these may be included singly or in combination of two or more. .

  Examples of water-soluble polymer compounds include gelatin, agar, polyvinyl alcohol, polyvinyl pyrrolidone, propylene carbonate, carboxymethylcellulose, carmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, sodium alginate, maleic anhydride copolymer , Carrageenan and the like, and these may be included singly or in combination of two or more.

  Examples of the inorganic powder include kaolin, zinc oxide, titanium oxide, and silicic anhydride, and these may be used alone or in combination of two or more.

  Examples of the antioxidant include tocopherol acetate, ascorbic acid and / or a derivative thereof, sodium sulfite, dibutylhydroxytoluene and the like, and these may be used alone or in combination of two or more.

  Examples of the preservative include methylparaben, butylbaraben, propylparaben, thymol, and the like, and these may be included singly or in combination of two or more.

  The type of the dye is not particularly limited, and examples thereof include dyes described in the Legal Dye Handbook, and these can be used alone or in combination of two or more.

[Support]
The support may be composed of a fabric such as a woven fabric, a non-woven fabric, and a knitted fabric used for conventionally known patches, a resin film, paper, and a laminate thereof. The material of the support may be one or more selected from the group consisting of polypropylene, polyethylene, polybutylene, polyethylene terephthalate, rayon, cotton, and polyurethane, and is not particularly limited, but is preferably polyethylene terephthalate. From the viewpoint of cost, a support composed of a nonwoven fabric made of polyethylene terephthalate is preferably used. In addition, when using a resin film, it is possible to use a support that has been printed or kneaded with white, skin color, or colored or filled with characters, etc., improving the anchoring property of the adhesive. In order to achieve this, it is also possible to use a support that has been subjected to polyurethane treatment, matting treatment, or the like.

[Peeling liner]
The patch according to the present invention may further include a release liner that covers the pressure-sensitive adhesive layer. As such a release liner, a resin film such as polyethylene terephthalate or polypropylene is preferable, and a release film such as silicon or an embossed film may be used. Moreover, what printed or kneaded paints, such as white, can also be used as a peeling liner.

(Preparation method)
The patch of the present invention can be prepared by a conventional method, and the above-mentioned essential components and, if necessary, the above optional components are appropriately blended and kneaded until uniform by a known method. After spreading on the release liner so that the pressure-sensitive adhesive mass is 0.03 to 0.15 g / cm ² , a support is further laminated on the surface of the pressure-sensitive adhesive layer, and then cut into a 100 mm × 140 mm rectangular shape Can be prepared. It can also be prepared by first spreading a pressure-sensitive adhesive on a support and then laminating a release liner thereon.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not limited to an Example.

[Test Example 1]
Each component shown in Table 1 was stirred and mixed for a certain period of time, and then uniformly spread on the release liner so that the adhesive mass per patch (140 mm × 100 mm) was about 10 g. Then, the patch was prepared by bonding together the nonwoven fabric made from a polyethylene terephthalate on the surface of an adhesive layer.

Table 1 shows the surfactants in Table 1, and prepared patches. Each patch was allowed to stand at 40 ° C. or 60 ° C., and then a piece having a surface area of 10 cm ² was cut out and its mass was accurately measured. Thereafter, the release liner film was peeled off, placed in a 50 mL centrifuge tube, methanol was added thereto, and the drug was extracted by shaking for 30 minutes. The extract was centrifuged at high speed, and the mass of the glycerol ester (referred to as “GE”) and menthol ester (referred to as “ME”) of chemical formulas 1 to 3, loxoprofen was measured by HPLC using the filtered solution as a sample solution. . The results are shown in Table 3.

  As shown in Tables 2 and 3, the generation of Chemical Formula 3 was particularly suppressed in all Examples, and in particular, in Examples 8 to 13, the generation of both Chemical Formulas 2 and 3 was further suppressed. As a result, the nonionic surfactant is an ethylene oxide addition type having an HLB value of 6.0 or more and 9.5 or less, which suppresses the production of Chemical Formula 3 in the aqueous system, Certain non-surfactants have been found to further inhibit the formation of both Formulas 2 and 3. On the other hand, the amount of loxoprofen ester produced was not significantly different between the patches. Thereby, it turned out that a nonionic surfactant suppresses specifically the change from Chemical formula 1 to Chemical formula 2 and 3 in an aqueous system.

The patch of Example 8 and a commercially available product (Loxonin (registered trademark) Pap 100 mg: compounded with polysorbate 80 as a surfactant) was allowed to stand at 40 ° C. and 60 ° C. for 1 to 6 months, and an adhesive layer (drug surface) ) Was evaluated by the color difference (ΔE) to determine how much color was immediately after the preparation of the patch. The results are shown in Table 4. The color difference (ΔE) is determined by measuring the chromaticity of the surface of the pressure-sensitive adhesive layer with a color difference meter (Model SP64, manufactured by X-Rite Inc.), immediately after preparation of the patch, and at 40 ° C and 60 ° C for 1 to 6 months The difference in chromaticity after being allowed to stand was obtained by calculating with the following formula. That is, when the white-black degree is represented by the L-scale, the red-green degree is represented by the a-scale, and the blue-yellow degree b-scale, respectively, the color difference is the square root of the square sum of the differences between the scales, ΔE ( = ((Δa) ² + (Δb) ² + (ΔL) ² ) ^1/2 ).

  As shown in Table 4, it was confirmed that coloring of the pressure-sensitive adhesive layer with the passage of time was suppressed in Example 8 in comparison with the commercially available product.

Claims (4)

Loxoprofen sodium dihydrate, partially neutralized polyacrylic acid, polyacrylic acid Na, carmellose Na, methyl acrylate / 2-ethylhexyl acrylate copolymer, dry aluminum hydroxide gel, inorganic powder, pH adjuster , 1-menthol, N-methyl-2-pyrrolidone, glycerin, nonionic surfactant, water-containing patch containing purified water,
A water-containing patch, wherein the nonionic surfactant is polyoxyethylene hydrogenated castor oil (ethylene oxide addition mole number 5).   The hydrous patch according to claim 1, wherein the inorganic powder is one or more selected from kaolin, zinc oxide, titanium oxide, and silicic anhydride.   The water-containing patch according to claim 1 or 2, wherein the inorganic powder is silicic anhydride. For a water-containing patch comprising a support and an adhesive layer located on the support,
The pressure-sensitive adhesive layer is composed of loxoprofen sodium dihydrate, partially neutralized polyacrylic acid, polyacrylic acid Na, carmellose Na, methyl acrylate / 2-ethylhexyl acrylate copolymer, dry aluminum hydroxide gel, inorganic Combined with powder, PH adjuster, l-menthol, N-methyl-2-pyrrolidone, glycerin, and purified water, used to prevent the loxoprofen from changing to the compound represented by Formula 2 or Formula 3. And
A preparation comprising a nonionic surfactant polyoxyethylene hydrogenated castor oil (5 moles of ethylene oxide added).

・ ・ ・ ・ ・ ・ Chemical formula 2

.... Chemical formula 3