JP6702810B2 - Non-aqueous patch - Google Patents

Description

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

In a non-aqueous patch containing a non-steroidal anti-inflammatory drug typified by ketoprofen or loxoprofen sodium, it is useful to use a rosin ester derivative and menthol together in order to release the drug from the preparation and enhance transdermal absorbability. It is known that there is (Patent Document 1). However, menthol has the problem of forming an ester with the carboxyl group of a nonsteroidal anti-inflammatory drug. In order to suppress this esterification, a 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, for non-steroidal anti-inflammatory drugs in the form of alkali metal salts, the addition of organic acids such as citric acid, maleic acid, and succinic acid promotes transdermal absorbability in patches having a pressure-sensitive adhesive material layer. It has been reported (Patent Document 5). However, the carboxyl group of a nonsteroidal anti-inflammatory drug has a problem of forming an ester with an organic acid having a hydroxy group, and it is known that it is useful to mix a strongly acidic inorganic acid in place 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 an 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, in the above-mentioned technique, the esterification reaction of the carboxyl group of the non-steroidal anti-inflammatory drug with the menthol or hydroxy acid in the non-aqueous patch cannot be sufficiently suppressed, and an effective amount of the non-steroidal anti-inflammatory drug is prolonged. It could not be held stable for a period of time.
Therefore, an object of the present invention is to provide a non-aqueous patch in which a nonsteroidal anti-inflammatory drug is stably retained in the patch for a long period of time.

Therefore, 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 variously examined its long-term stability. It was found that a stable anti-inflammatory analgesic patch in which the esterification reaction between a nonsteroidal anti-inflammatory drug and menthol or hydroxy acid is significantly suppressed can be obtained by blending the compound in a specific amount, and the present invention has been completed.

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) alumino-metasilicate A non-aqueous patch containing magnesium in an amount of 0.25 to 1.8 mass% in the pressure-sensitive adhesive layer.
[2] The non-aqueous patch according to [1], wherein the non-steroidal anti-inflammatory drug (A) is a propionic acid non-steroidal anti-inflammatory drug.
[3] The non-aqueous patch according to [1] or [2], wherein the non-steroidal anti-inflammatory drug (A) 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] Any one of [1] to [4] in which 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 softening agent. The non-aqueous patch described.

The non-aqueous patch of the present invention is a non-steroidal anti-inflammatory drug, which is an active ingredient, does not form an ester with menthol or hydroxy acid in the preparation, is stably maintained for a long time, and maintains an excellent anti-inflammatory and analgesic effect for a long time. To be done.

LX shows the menthol ester production rate (%). The LX lactate production rate (%) is shown. The 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 aluminometasilicate is contained in the pressure-sensitive adhesive layer in an amount of 0.25 to 1.8% by mass.

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

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

The component (B) is one or more selected from hydroxy acids and menthol. Hydroxy acid and menthol are usually used as a percutaneous absorption enhancer and a dissolving agent for the component (A).
Examples of the hydroxy acid include lactic acid, tartaric acid, citric acid, malic acid, glycolic acid and the like. Of these, lactic acid, citric acid, and malic acid are more preferable, and lactic acid is particularly preferable. Examples of menthol include 1-menthol and dl-menthol. When menthol is to be blended, a menthol-containing fragrance, peppermint oil or the like can also be used. The hydroxy acid and menthol may be used alone or in combination of two or more.

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

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

The content of the component (C) is 0.25 to 1.8 in the pressure-sensitive adhesive layer, because the non-steroidal anti-inflammatory drug is stably maintained in the non-aqueous patch for a long period of time by the ester formation-inhibiting effect. It is% by mass. If it is less than 0.25% by mass, the effect of inhibiting ester formation cannot be obtained, and if it exceeds 1.8% by mass, the component (C) may not be uniformly dispersed in the non-aqueous patch. The content of the component (C) is preferably 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. , And particularly preferably 0.5 to 1.3% by mass.

The non-aqueous patch of the present invention is a patch containing the component (A), the component (B) and the component (C) in the non-aqueous pressure-sensitive adhesive layer. Further, 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 adhesive include styrene-isoprene-styrene block copolymer, polyisobutylene, polyisoprene, polybutadiene, styrene-butadiene-styrene block copolymer, styrene isoprene rubber, styrene butadiene rubber, raw rubber and the like. Among them, 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. The content of the styrene-isoprene-styrene block copolymer in the pressure-sensitive adhesive layer is preferably 5 to 40% by mass, more preferably 10 to 30% by mass. The content of polyisobutylene in the pressure-sensitive adhesive layer is preferably 0.5 to 15% by mass, more preferably 1 to 10% by mass. Further, polyisobutylene having different molecular weights may 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 them, hydrogenated rosin glycerin ester and alicyclic saturated hydrocarbon resin are preferable. The tackifier is preferably contained in the pressure-sensitive adhesive layer in an amount of 10 to 50% by mass. The hydrogenated rosin glycerin ester is preferably contained in the pressure-sensitive adhesive layer in an amount of 10 to 50% by mass, 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, more preferably 25 to 45% by mass.

Examples of the softening agent include liquid paraffin, light liquid paraffin, polybutene and the like. The softening agent is preferably contained in the pressure-sensitive adhesive layer in an amount of 10 to 70% by mass, more preferably 30 to 50% by mass.

In the non-aqueous pressure-sensitive adhesive layer of the present invention, in addition to the above components, organic acids other than hydroxy acids, solubilizers, cooling agents, flavoring agents, transdermal absorption promoters, antioxidants, excipients, etc. Can be included.

Examples of the organic acid 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 and the like. Be done. The content of the organic acid in the pressure-sensitive adhesive layer is preferably 0.1 to 10% by mass, more preferably 0.5 to 5% by mass.

As the 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 ester such as dextrin palmitate, propylene glycol fatty acid ester, polyhydric alcohol fatty acid ester such as sorbitan fatty acid ester, propylene glycol, macrogol, cetomacrogol, triethylene glycol, 1,3-butanediol, dipropylene glycol, iso Alcohols such as stearyl alcohol, glycerin, stearyl alcohol, benzyl alcohol, cetostearyl alcohol, crotamiton, squalane, squalene, triacetin, N-methyl-2-pyrrolidone, olive oil, hydrogenated oil, rapeseed oil, castor oil, polyoxyethylene hardening Castor oil, polysorbate and the like can be mentioned. The dissolution agent is preferably contained in the pressure-sensitive adhesive layer in an amount of 0.1 to 10% by mass, more preferably 0.5 to 5% by 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 hydrogen sulfite.
The antioxidant is preferably contained in the pressure-sensitive adhesive layer in an amount of 0.1 to 5% by mass, more preferably 0.1 to 3% by mass.

As the excipient, kaolin, clay, talc, bentonite, light anhydrous silicic acid, anhydrous silicic acid, hydrous silicic acid, aluminum silicate, zinc oxide, starch acrylate, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, Examples thereof include hydroxypropylmethyl cellulose, povidone, sodium polyacrylate and the like.

Examples of the support include a knitted cloth, a woven cloth or a non-woven cloth made of polyethylene terephthalate, polypropylene or 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 the method for producing the non-aqueous patch of the present invention, for example, a solvent method of dissolving/mixing prescription components in an organic solvent such as toluene, hexane, ethyl acetate and distilling off the organic solvent after coating; A hot melt method in which a melt containing an active ingredient is added and then melted after being heat-melted under an atmosphere of an inert gas such as nitrogen or helium or under reduced pressure so that oxidation of the base component can be suppressed. Is mentioned. Among these, the hot melt method is preferable from the viewpoint of productivity and environmental load.

Next, the present invention will be described in more detail with reference to examples.

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 1-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.
0.25 to 2 parts by mass of magnesium aluminometasilicate was dispersed in 9 parts by mass of light liquid paraffin to obtain a magnesium aluminometasilicate dispersion. In Comparative Example 3, 0.5 parts by mass of aluminum glycinate was used instead of magnesium aluminometasilicate.
A mixture of alicyclic saturated hydrocarbon resin, styrene-isoprene-styrene block copolymer (SIS), polyisobutylene (PIB), dibutylhydroxytoluene (BHT), liquid paraffin and light liquid paraffin under a nitrogen atmosphere at 130 The mixture was heated and stirred at ˜170° C. and melted to obtain a base mixture.
After allowing the base mixture to cool to 110° C., magnesium aluminometasilicate dispersion was added, and the mixture was stirred and mixed in a nitrogen atmosphere until uniform. In Comparative Example 1, light liquid paraffin was added alone.
Next, the active ingredient solution was added, and the mixture was stirred and mixed under a nitrogen atmosphere until it became uniform to obtain an adhesive.
The obtained pressure-sensitive adhesive was applied onto a silicone-treated polyethylene terephthalate film to form a pressure-sensitive adhesive layer. A polyester knitted fabric was laminated on the obtained pressure-sensitive adhesive layer and cut into 7 cm×10 cm to prepare a patch.
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, magnesium aluminometasilicate could not be uniformly dispersed by the present preparation method, and the patch could not be obtained.

Examples 5-8 and Comparative Examples 4-5
A patch having the formulation shown in Table 2 was prepared by the following method.
Ketoprofen and 1-menthol were added to isopropyl myristate and dissolved by heating and stirring (60 to 80° C.) to obtain an active ingredient solution.
0.25 to 2 parts by mass of magnesium aluminometasilicate was dispersed in 9 parts by mass of liquid paraffin to obtain a magnesium aluminometasilicate 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 under a nitrogen atmosphere. It melted and it was set as the base mixture.
After allowing the base mixture to cool to 110° C., magnesium aluminometasilicate dispersion was added, and the mixture was stirred and mixed in a nitrogen atmosphere until uniform. In Comparative Example 4, liquid paraffin was added alone.
Next, the active ingredient solution was added, and the mixture was stirred and mixed under a nitrogen atmosphere until it became uniform to obtain an adhesive.
The obtained pressure-sensitive adhesive was applied onto a silicone-treated polyethylene terephthalate film to form a pressure-sensitive adhesive layer. A polyester knitted fabric was laminated on the obtained pressure-sensitive adhesive layer and cut into 7 cm×10 cm to prepare a patch.
The coating amount of the pressure-sensitive adhesive was adjusted so that the amount of ketoprofen in one patch was 20 mg.
Further, in Comparative Example 5, magnesium aluminometasilicate could not be uniformly dispersed by the present preparation method, and the patch could not be obtained.

(Stability test)
Seven patches of each patch were packaged in an aluminum bag and stored at 60° C. for 2 weeks.
The preparation after storage was prepared by removing the silicone-treated polyester film, placing it in a centrifuge tube (50 mL), adding tetrahydrofuran and shaking until the adhesive layer was dissolved, and then adding methanol to precipitate the adhesive component. It was shaken until. The supernatant liquid after shaking was used as a sample solution. The sample solution was diluted with methanol and then tested by a high performance liquid chromatography method (HPLC method).
In Examples 1 to 4 and Comparative Examples 1 and 3, loxoprofen sodium, an esterified product of loxoprofen sodium and 1-menthol (hereinafter, LX menthol ester), an esterified product of loxoprofen sodium and 1-lactic acid, and loxoprofen sodium and d-lactic acid. The esterification products of and were quantified, and the production rate (%) of each esterification product was calculated.
The total production rate of the esterification product of loxoprofen sodium and 1-lactic acid and the esterification product of loxoprofen sodium and d-lactic acid was defined as the production rate of loxoprofen lactate ester (hereinafter, LX lactate ester).
In Examples 5 to 8 and Comparative Example 4, ketoprofen and the esterified product of ketoprofen and 1-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 FIGS. 1, 2 and 3.
In the loxoprofen sodium patch, Examples 1 to 4 in which magnesium aluminometasilicate was added, both the production rates of LX menthol ester and LX lactate ester were suppressed, as compared to Comparative Example 1 in which no magnesium metasilicate was added.
The suppression effect was dependent on the addition amount of magnesium aluminometasilicate in LX lactate. On the other hand, in the case of LX menthol ester, the effect tended to reach the limit when the addition amount was 0.75 mass %.
When Comparative Example 5 containing 0.5% by mass of aluminum glycinate and Example 2 are compared, magnesium aluminometasilicate is more highly suppressed in the formation of any esterified product of LX menthol ester and LX lactate ester. Showed the effect.
In particular, the effect was high with LX lactate.
In the ketoprofen patch, in Examples 5 to 8 to which magnesium aluminometasilicate was added, the production rate of KP menthol ester was suppressed as compared with Comparative Example 4 in which it was not added.

Claims (2)

0.25 to 1.8 mass% of (A) loxoprofen sodium or ketoprofen , (B) one or more components selected from lactic acid and menthol, and (C) magnesium aluminometasilicate in the adhesive layer Non-aqueous patch containing. (A), (B) component and the (C) component, the rubber base material, non-aqueous patch according to claim 1, wherein contained in the pressure-sensitive adhesive layer containing a tackifier and a softening agent.

Images