JP2017226623A - Nonaqueous patch - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a nonaqueous patch in which a nonsteroidal anti-inflammatory agent is maintained in the patch stably for the long term.SOLUTION: A nonaqueous patch contains (A) a salicylic acid-, acetic acid- or propionic acid-based nonsteroidal anti-inflammatory agent, (B) at least one component selected from hydroxy acid and menthol, and (C) magnesium aluminometasilicate of 0.25-1.8 mass% in an adhesive layer.SELECTED DRAWING: None

Description

  The present invention relates to a non-aqueous patch containing a non-steroidal anti-inflammatory drug.

  For non-aqueous patches containing non-steroidal anti-inflammatory drugs typified by ketoprofen and loxoprofen sodium, the combination of rosin ester derivatives and menthol is useful in order to increase drug release and transdermal absorption. It is known that there is (Patent Document 1). However, menthol has the problem of forming esters with carboxyl groups of non-steroidal anti-inflammatory drugs. In order to suppress this esterification, means for adding a urea derivative (Patent Document 2), sodium bisulfite, 2-mercaptobenzimidazole (Patent Document 3), and a metal oxide (Patent Document 4) has been reported.

  In addition, non-steroidal anti-inflammatory drugs in the form of alkali metal salts are enhanced in transdermal absorbability in patches having a pressure-sensitive adhesive material layer by the addition of organic acids such as citric acid, maleic acid, and succinic acid. (Patent Document 5). However, the carboxyl group of non-steroidal anti-inflammatory drugs has a problem of forming an ester with an organic acid having a hydroxy group, and it is known that it is useful to add a strongly acidic inorganic acid instead of the organic acid. (Patent Document 6). In addition, it has been reported that by adding aluminum glycinate in addition to loxoprofen sodium and an organic acid, it is possible to suppress the generation of decomposition products generated by the reaction between loxoprofen sodium and the organic acid (Patent Document 7).

Japanese Patent No. 2816765 JP 2010-90100 A JP 2010-90099 A JP 2002-226366 A JP-A-62-126119 International Publication No. 2006/048939 JP 2013-18745 A

However, the above-mentioned technology cannot sufficiently suppress the esterification reaction between the carboxyl group of a non-steroidal anti-inflammatory drug and menthol or hydroxy acid in a non-aqueous patch, and an effective amount of the non-steroidal anti-inflammatory drug is prolonged. It could not be kept stable for a period.
Accordingly, an object of the present invention is to provide a non-aqueous patch in which a non-steroidal anti-inflammatory drug is stably maintained in a patch for a long period of time.

  Accordingly, the present inventor manufactured a non-aqueous patch containing a non-steroidal anti-inflammatory drug having a carboxyl group and menthol and / or hydroxy acid, and studied various long-term stability thereof. Magnesium aluminate metasilicate It was found that a stable anti-inflammatory analgesic patch in which the esterification reaction between a non-steroidal anti-inflammatory drug and menthol or hydroxy acid was remarkably suppressed could be obtained by blending a specific amount of.

  That is, the present invention provides the following [1] to [5].

[1] (A) Salicylic acid-based, acetic acid-based or propionic acid-based non-steroidal anti-inflammatory drug, (B) one or more components selected from hydroxy acid and menthol, and (C) aluminate metasilicate A non-aqueous patch containing 0.25 to 1.8% by mass of magnesium in the adhesive layer.
[2] The non-aqueous patch according to [1], wherein (A) the non-steroidal anti-inflammatory drug is a propionic acid non-steroidal anti-inflammatory drug.
[3] The non-aqueous patch according to [1] or [2], wherein (A) the nonsteroidal anti-inflammatory drug is loxoprofen sodium or ketoprofen.
[4] The non-aqueous patch according to any one of [1] to [3], wherein the component (B) is one or two components selected from lactic acid and menthol.
[5] The component (A), the component (B), and the component (C) are contained in a pressure-sensitive adhesive layer containing a rubber base, a tackifier, and a softener. The non-aqueous patch as described.

  In the non-aqueous patch of the present invention, the non-steroidal anti-inflammatory drug, which is an active ingredient, does not form an ester with menthol or hydroxy acid in the preparation, and is stably maintained for a long period of time. Is done.

LX menthol ester production rate (%) is shown. LX lactic acid ester production rate (%) is shown. KP menthol ester production rate (%) is shown.

  The non-aqueous patch of the present invention comprises (A) a salicylic acid-based, acetic acid-based or propionic acid-based non-steroidal anti-inflammatory drug, (B) one or more components selected from hydroxy acid and menthol, and ( C) Magnesium aluminate metasilicate is contained in the pressure-sensitive adhesive layer in an amount of 0.25 to 1.8% by mass.

The (A) component salicylic acid-based, acetic acid-based or propionic acid-based non-steroidal anti-inflammatory drug is an active ingredient of the patch of the present invention and an antipyretic anti-inflammatory analgesic component. Among the components (A), examples of the salicylic acid non-steroidal anti-inflammatory drug include salicylic acid, acetylsalicylic acid, mefenamic acid, flufenamic acid, and salts thereof. Examples of acetic non-steroidal anti-inflammatory drugs include indomethacin, sulindac, diclofenac, felbinac, etodolac, ampenac and salts thereof. Examples of the propionic non-steroidal anti-inflammatory drug include loxoprofen, ketoprofen, zaltoprofen, flurbiprofen, s-flurbiprofen, ibuprofen, thiaprofenic acid, pranoprofen and salts thereof.
Among these (A) components, propionic acid non-steroidal anti-inflammatory drugs are preferable, loxoprofen, ketoprofen or a salt thereof is more preferable, loxoprofen sodium or ketoprofen is further preferable, and loxoprofen sodium is particularly preferable. In addition, loxoprofen sodium hydrate can be used as loxoprofen sodium.

  The content of the component (A) varies depending on the drug, but may be any amount that is percutaneously absorbed after application and obtains a medicinal effect, but is preferably 1 to 10% by mass, and 1 to 8% by mass in the pressure-sensitive adhesive layer. More preferred. In the case of ketoprofen, it is more preferable to contain 1 to 4% by mass in the pressure-sensitive adhesive layer. In the case of loxoprofen sodium, it is more preferable to contain 2-8 mass% in terms of anhydrous loxoprofen in the pressure-sensitive adhesive layer.

(B) A component is 1 type, or 2 or more types chosen from hydroxy acid and menthol. Hydroxy acid and menthol are usually used as a percutaneous absorption enhancer and a solubilizer for component (A).
Examples of the hydroxy acid include lactic acid, tartaric acid, citric acid, malic acid, glycolic acid and the like. Among these, lactic acid, citric acid, and malic acid are more preferable, and lactic acid is particularly preferable. Examples of menthol include l-menthol and dl-menthol. When trying to mix menthol, a fragrance containing menthol, mint oil, etc. can also be used. One kind of hydroxy acid and menthol may be used, or two or more kinds may be used.

  The content of the component (B) is preferably 0.1 to 10% by mass in the pressure-sensitive adhesive layer from the viewpoint of both the percutaneous absorption promoting action, the dissolving action and the ester formation inhibiting action of the ingredient (A). 5-8 mass% is more preferable, and 1-8 mass% is further more preferable.

  (C) A component is magnesium aluminate metasilicate. Magnesium aluminate metasilicate has an excellent antacid action and is widely incorporated in gastrointestinal drugs and the like. However, it has not been known at all to suppress ester formation between a non-steroidal anti-inflammatory drug and hydroxy acid or menthol in a non-aqueous patch.

  The content of the component (C) is such that the non-steroidal anti-inflammatory drug is stably maintained in the non-aqueous patch for a long period of time by the ester formation inhibitory action, so that 0.25 to 1.8 is contained in the adhesive layer. % By mass. If the amount is less than 0.25% by mass, the effect of inhibiting ester formation cannot be obtained. If the amount exceeds 1.8% by mass, the component (C) may not be uniformly dispersed in the non-aqueous patch. The preferred content of component (C) is 0.5 to 1.8% by mass, more preferably 0.5 to 1.7% by mass, and still more preferably 0.5 to 1.5% by mass. Especially preferably, it is 0.5-1.3 mass%.

  The non-aqueous patch of the present invention is a patch containing a component (A), a component (B) and a component (C) in a non-aqueous pressure-sensitive adhesive layer. The non-aqueous patch preferably has a structure in which a support, a non-aqueous pressure-sensitive adhesive layer, and a release liner are laminated in this order.

  The non-aqueous pressure-sensitive adhesive layer preferably contains a pressure-sensitive adhesive, a tackifier and a softening agent in addition to the components (A) to (C). Examples of the pressure-sensitive adhesive include acrylic pressure-sensitive adhesives and rubber-based pressure-sensitive adhesives, and rubber-based pressure-sensitive adhesives are preferable.

  Examples of the rubber-based pressure-sensitive adhesive include styrene-isoprene-styrene block copolymer, polyisobutylene, polyisoprene, polybutadiene, styrene-butadiene-styrene block copolymer, styrene isoprene rubber, styrene butadiene rubber, and raw rubber. Of these, styrene-isoprene-styrene block copolymer and polyisobutylene are preferable. The rubber-based pressure-sensitive adhesive is preferably contained in the pressure-sensitive adhesive layer in an amount of 5 to 50% by mass. 5-40 mass% is preferable in an adhesive layer, and, as for content of a styrene-isoprene-styrene block copolymer, 10-30 mass% is more preferable. The content of polyisobutylene is preferably 0.5 to 15% by mass in the pressure-sensitive adhesive layer, and more preferably 1 to 10% by mass. Polyisobutylene having different molecular weights can be used in combination.

  Examples of the tackifier include hydrogenated rosin glycerin ester, alicyclic saturated hydrocarbon resin, aliphatic saturated hydrocarbon resin, ester gum, rosin, phenol resin, terpene resin, petroleum resin and the like. Among these, hydrogenated rosin glycerin ester and alicyclic saturated hydrocarbon resin are preferable. It is preferable to contain 10-50 mass% of tackifiers in an adhesive layer. The hydrogenated rosin glycerin ester is preferably contained in the pressure-sensitive adhesive layer in an amount of 10 to 50% by mass, and more preferably 15 to 35% by mass. The alicyclic saturated hydrocarbon resin is preferably contained in the pressure-sensitive adhesive layer in an amount of 10 to 50% by mass, and more preferably 25 to 45% by mass.

  Examples of the softening agent include liquid paraffin, light liquid paraffin, polybutene and the like. It is preferable to contain 10-70 mass% of softening agents in an adhesive layer, and it is more preferable to contain 30-50 mass%.

  In addition to the above components, the non-aqueous pressure-sensitive adhesive layer of the present invention contains an organic acid other than hydroxy acid, a solubilizer, a refreshing agent, a flavoring agent, a transdermal absorption accelerator, an antioxidant, an excipient and the like. It can be included.

  Examples of organic acids include acetic acid, butyric acid, succinic acid, maleic acid, fumaric acid, isostearic acid, caprylic acid, capric acid, propionic acid, oxalic acid, adipic acid, stearic acid, malonic acid, myristic acid, palmitic acid, etc. It is done. 0.1-10 mass% is preferable in an adhesive layer, and, as for content of an organic acid, 0.5-5 mass% is more preferable.

  As a solubilizer, isopropyl myristate, isopropyl palmitate, butyl stearate, butyl myristate, myristyl myristate, cetyl myristate, octyldodecyl myristate, diethyl sebacate, diisopropyl sebacate, diisopropyl adipate, cetyl palmitate, Fatty acid esters such as dextrin palmitate, polyhydric alcohol fatty acid esters such as propylene glycol fatty acid ester and sorbitan fatty acid ester, propylene glycol, macrogol, cetomacrogol, triethylene glycol, 1,3-butanediol, dipropylene glycol, iso Stearyl alcohol, glycerin, stearyl alcohol, benzyl alcohol, cetostearyl alcohol and other alcohols, crotami Emissions, squalane, squalene, triacetin, N- methyl-2-pyrrolidone, olive oil, hardened oil, rapeseed oil, castor oil, polyoxyethylene hardened castor oil, polysorbate and the like. It is preferable to contain 0.1-10 mass% of solubilizers in an adhesive layer, and it is more preferable to contain 0.5-5 mass%.

Examples of the transdermal absorption enhancer include C8-C18 fatty acids and aliphatic alcohols.
Examples of the antioxidant include dibutylhydroxytoluene, butylhydroxyanisole, benzotriazole, 2-mercaptobenzimidazole, sodium edetate, sulfite, and bisulfite.
It is preferable to contain 0.1-5 mass% of antioxidants in an adhesive layer, and it is more preferable to contain 0.1-3 mass%.

  Excipients include kaolin, clay, talc, bentonite, light silicic anhydride, silicic anhydride, hydrous silicic acid, aluminum silicate, zinc oxide, starch acrylate, methylcellulose, ethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, Hydroxypropyl methylcellulose, povidone, sodium polyacrylate and the like can be mentioned.

  Examples of the support include polyethylene terephthalate, polypropylene, knitted fabric, woven fabric, and nonwoven fabric made of polyethylene.

  Examples of the release liner include those obtained by subjecting a film made of polyethylene terephthalate, polyethylene, or polypropylene to a silicone treatment or a fluorine treatment.

  As a method for producing the non-aqueous patch of the present invention, for example, a solvent method in which prescription components are dissolved / mixed in an organic solvent such as toluene, hexane, ethyl acetate, and the organic solvent is distilled off after coating; Hot melt method in which a melt containing an active ingredient is added after heat melting under conditions that can suppress oxidation of the base component under an inert gas atmosphere such as nitrogen or helium or under reduced pressure. Is mentioned. Among these, the hot melt method is preferable from the viewpoint of productivity and environmental load.

  EXAMPLES Next, an Example is given and this invention is demonstrated still in detail.

Examples 1-4 and Comparative Examples 1-3
A patch having the formulation shown in Table 1 was prepared by the following method.
Loxoprofen sodium and l-menthol were added to a mixture of isopropyl myristate and lactic acid and dissolved by heating and stirring (60 to 70 ° C.) to obtain an active ingredient solution.
In 9 parts by mass of light liquid paraffin, 0.25 to 2 parts by mass of magnesium aluminate metasilicate was dispersed to obtain a magnesium aluminate metasilicate dispersion. In Comparative Example 3, 0.5 parts by mass of aluminum glycinate was used instead of magnesium aluminate metasilicate.
A mixture of alicyclic saturated hydrocarbon resin, styrene-isoprene-styrene block copolymer (SIS), polyisobutylene (PIB), dibutylhydroxytoluene (BHT), liquid paraffin and light liquid paraffin is added under a nitrogen atmosphere. It was heated and stirred to ˜170 ° C. and melted to obtain a base mixture.
After allowing the base mixture to cool to 110 ° C., a magnesium aluminate metasilicate dispersion was added, and the mixture was stirred and mixed until uniform in a nitrogen atmosphere. In Comparative Example 1, light liquid paraffin was added alone.
Next, the active ingredient solution was added and stirred and mixed until uniform in a nitrogen atmosphere to obtain an adhesive.
The obtained adhesive was coated on a silicone-treated polyethylene terephthalate film to form an adhesive layer. A polyester knitted fabric was laminated to the obtained pressure-sensitive adhesive layer, and cut into 7 cm × 10 cm to prepare a patch.
In addition, the coating amount of the adhesive was adjusted so that the amount of loxoprofen sodium in one patch was 50 mg.
Further, in Comparative Example 2, this preparation method could not uniformly disperse magnesium aluminate metasilicate, and a patch could not be obtained.

Examples 5-8 and Comparative Examples 4-5
Patches having the formulations shown in Table 2 were prepared by the following method.
A solution obtained by adding ketoprofen and l-menthol to isopropyl myristate and dissolving by heating and stirring (60 to 80 ° C.) was used as an active ingredient solution.
In 9 parts by mass of liquid paraffin, 0.25 to 2 parts by mass of magnesium aluminate metasilicate was dispersed to obtain a magnesium aluminate metasilicate dispersion.
A mixture of hydrogenated rosin glycerin ester, styrene-isoprene-styrene block copolymer (SIS), polyisobutylene (PIB), dibutylhydroxytoluene (BHT) and liquid paraffin is heated and stirred at 130 to 170 ° C. in a nitrogen atmosphere. And melted into a base mixture.
After allowing the base mixture to cool to 110 ° C., a magnesium aluminate metasilicate dispersion was added, and the mixture was stirred and mixed until uniform in a nitrogen atmosphere. In Comparative Example 4, liquid paraffin was added alone.
Next, the active ingredient solution was added and stirred and mixed until uniform in a nitrogen atmosphere to obtain an adhesive.
The obtained adhesive was coated on a silicone-treated polyethylene terephthalate film to form an adhesive layer. A polyester knitted fabric was laminated to the obtained pressure-sensitive adhesive layer, and cut into 7 cm × 10 cm to prepare a patch.
In addition, the coating amount of the adhesive was adjusted so that the amount of ketoprofen in one patch was 20 mg.
Further, in Comparative Example 5, in this preparation method, magnesium aluminate metasilicate could not be uniformly dispersed, and a patch could not be obtained.

(Stability test)
Each patch was packaged in aluminum bags seven times and stored at 60 ° C. for 2 weeks.
The preparation after storage is peeled off the polyester film treated with silicone, placed in a centrifuge tube (50 mL), added with tetrahydrofuran, shaken until the adhesive layer is dissolved, and then added with methanol to precipitate the adhesive component. Shake until. The supernatant after shaking was used as a sample solution. The sample solution was diluted with methanol and then tested by high performance liquid chromatography (HPLC method).
In Examples 1 to 4 and Comparative Examples 1 and 3, loxoprofen sodium, loxoprofen sodium and l-menthol esterified product (hereinafter referred to as LX menthol ester), loxoprofen sodium and l-lactic acid esterified product, and loxoprofen sodium and d-lactic acid The esterified product was quantified, and the production rate (%) of each esterified product was calculated.
The total production rate of the esterified product of loxoprofen sodium and l-lactic acid and the esterified product of loxoprofen sodium and d-lactic acid was defined as the production rate of loxoprofen lactic acid ester (hereinafter referred to as LX lactic acid ester).
In Examples 5 to 8 and Comparative Example 4, ketoprofen and an esterified product of ketoprofen and l-menthol (hereinafter referred to as KP menthol ester) were quantified, and the production rate (%) of KP menthol ester was calculated.

(Stability test results)
The results of the stability test are shown in Tables 3 and 4. The results are shown in FIG. 1, FIG. 2 and FIG.
In the loxoprofen sodium patch, in Examples 1 to 4 to which magnesium aluminate metasilicate was added, the production rates of LX menthol ester and LX lactic acid ester were both suppressed as compared with Comparative Example 1 in which no addition was made.
The inhibitory effect was dependent on the amount of magnesium aluminate metasilicate added in LX lactate. On the other hand, with LX menthol ester, the effect tended to peak at an addition amount of 0.75% by mass.
When Comparative Example 5 containing 0.5% by mass of aluminum glycinate and Example 2 are compared, magnesium metasilicate magnesium aluminate is higher in any esterified product of LX menthol ester and LX lactate ester. Showed the effect.
In particular, LX lactate was highly effective.
In the ketoprofen patch, Examples 5 to 8 to which magnesium aluminate metasilicate was added had a suppressed production rate of KP menthol ester as compared to Comparative Example 4 to which no addition was made.

Claims (5)

  (A) Salicylic acid-based, acetic acid-based or propionic acid-based non-steroidal anti-inflammatory drug, (B) one or more components selected from hydroxy acid and menthol, and (C) magnesium aluminate metasilicate A non-aqueous patch containing 0.25 to 1.8% by mass in the preparation layer.   (A) The non-aqueous patch according to claim 1, wherein the non-steroidal anti-inflammatory drug is a propionic acid non-steroidal anti-inflammatory drug.   (A) The non-aqueous patch according to claim 1 or 2, wherein the non-steroidal anti-inflammatory drug is loxoprofen sodium or ketoprofen.   The non-aqueous patch according to any one of claims 1 to 3, wherein the component (B) is one or two components selected from lactic acid and menthol.   The non-aqueous composition according to any one of claims 1 to 4, wherein the component (A), the component (B), and the component (C) are contained in a pressure-sensitive adhesive layer containing a rubber base, a tackifier, and a softener. Patch.

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