JP7438566B2 - patch - Google Patents

Description

The present invention relates to a patch containing a diclofenac salt, an organic acid, and a metal oxide, and more specifically, a patch containing a diclofenac salt, an organic acid as a main drug solubilizing agent, and a metal oxide as a stabilizer for the diclofenac salt. This invention relates to a patch made of

Diclofenac or its salts have excellent anti-inflammatory and analgesic effects, and are therefore widely used in clinical settings as oral agents or suppositories. It has also been made into a transdermal absorption formulation and is widely used for the treatment or prevention of various inflammatory diseases such as chronic rheumatism, spondylosis osteoarthritis, and low back pain.

It is well known that when diclofenac or a salt thereof is incorporated into an oil-based patch (plaster), decomposition products of diclofenac are formed in the oil-based base during storage. In particular, when a patch is manufactured using a hot-melt method, the coating process is performed while the adhesive composition containing the drug is melted at a high temperature. Impurities are generated by thermal reactions with additives. Typical decomposition products of diclofenac include indolinone (1-(2,6-dichlorophenyl)-2-indolinone), and in the case of patches containing L-menthol, L-menthol ester One example is the body. In particular, with respect to patches containing L-menthol, various attempts have been made to suppress the production of L-menthol esters (Patent Documents 1 to 3). On the other hand, regarding the suppression of the production of indolinone bodies, Patent Document 4 states that dehydration reaction products (indolinone bodies) can be suppressed by maintaining the relative humidity inside the packaging bag in which the patch is enclosed within a certain range. However, no literature has been found that examines the inhibition of indolinone production from the aspect of pharmaceutical composition.

In order to suppress the production of indolinone bodies, the solubility of diclofenac or its salt in the patch base is suppressed, and the production of decomposition products can be suppressed to some extent by creating a drug-dispersed patch. However, such drug-dispersed patches have poor drug release properties and cannot provide sufficient therapeutic or preventive effects. Therefore, there is a need for a patch that suppresses the formation of diclofenac decomposition products, including indolinone derivatives, without reducing drug release properties.

Japanese Patent Application Publication No. 2002-226366 International Publication No. 96/08245 Japanese Patent Application Publication No. 2010-90098 Japanese Patent Application Publication No. 2008-061862

The present invention solves the above-mentioned problems, and the present invention provides a patch containing diclofenac salt that does not reduce drug release properties and generates drug decomposition products even during long-term storage or manufacturing under high-temperature conditions. The objective is to provide a highly stable adhesive patch that can suppress

As a result of extensive research in order to solve the above-mentioned problems, the present inventor has found that by incorporating a metal oxide into a patch containing diclofenac salt and an organic acid, the drug release properties can be reduced. The present invention has been completed based on the discovery that the production of decomposition products such as indolinone can be suppressed.

That is, the present invention relates to the following.
1. Patch and its manufacturing method [1]
A patch containing diclofenac salt, organic acid, and metal oxide in the plaster.
[2]
the diclofenac salt is diclofenac sodium;
the organic acid is one or more selected from oleic acid, isostearic acid, myristic acid, capric acid, caprylic acid, and lactic acid; and
The patch according to [1], wherein the metal oxide is one or more selected from zinc oxide, aluminum oxide, and titanium oxide.
[3]
The patch according to [1] or [2], wherein the organic acid is isostearic acid and the metal oxide is zinc oxide.
[4]
The content of diclofenac salt is 0.1% to 10% by weight relative to the weight of the plaster, the content of organic acid is 0.1% to 10% by weight, and the content of metal oxide is is 0.01% to 5% by weight, the patch according to any one of [1] to [3].
[5]
The adhesive patch according to any one of [1] to [4], further comprising a base polymer, a tackifier resin, and a softener in the plaster.
[6]
the base polymer is natural rubber, polyisoprene, polybutadiene, styrene-isoprene-styrene block copolymer, styrene-butadiene rubber, or styrene-isoprene rubber;
the tackifier resin is one or more selected from rosin resins, petroleum resins, and terpene resins; and
The softening agent is one or more selected from polyisobutylene, liquid polyisoprene, polybutene, lanolin, castor oil, almond oil, olive oil, camellia oil, persic oil, peanut oil, process oil, extender oil, and liquid paraffin. The patch according to [5], which is.
[7]
The adhesive patch according to [5], wherein the base polymer is a styrene-isoprene-styrene block copolymer, the tackifier resin is an alicyclic saturated hydrocarbon resin, and the softener is polybutene and liquid paraffin.
[8]
Based on the weight of the paste, the content of the base polymer is 5% to 30% by weight, the content of the tackifying resin is 10% to 60% by weight, and the content of the softener is 10% by weight. The patch according to any one of [5] to [7], which has a content of 75% by weight.
[9]
The adhesive patch according to any one of [5] to [8], further comprising a cooling agent in the plaster.
[10]
The patch according to [9], wherein the cooling agent is L-menthol.
[11]
The patch according to any one of [1] to [10], which comprises a step of applying a composition containing a diclofenac salt, an organic acid, and a metal oxide onto a support or a release liner under heating. Production method.
[12]
Further steps include heating and stirring the mixture containing the base polymer, tackifying resin, and softener to obtain an adhesive solution, and then adding diclofenac salt, an organic acid, and a metal oxide to the adhesive solution to obtain a composition. The manufacturing method according to [11].

Further, the present invention relates to the following.
2. Applications of patches [13]
For treating or preventing osteoarthritis, rheumatoid arthritis, low back pain, shoulder periarthritis, tenosynovitis, peritendinitis, humeral epicondylitis, myalgia, or post-traumatic swelling or pain, [1] The patch according to any one of ~[10].
[14]
In the manufacture of medicaments for the treatment or prevention of osteoarthritis, rheumatoid arthritis, low back pain, shoulder periarthritis, tenosynovitis, peritendinitis, epicondylitis, myalgia, or post-traumatic swelling or pain. , use of the patch according to any one of [1] to [10].
[15]
Osteoarthritis, chronic rheumatoid arthritis, low back pain, shoulder periarthritis, tenosynovitis, peritendinitis, suprahumerus, comprising the step of administering the patch according to any one of [1] to [10]. A method of treating or preventing condylitis, myalgia, or post-traumatic swelling or pain.

The present invention makes it possible to provide a patch that suppresses the production of diclofenac decomposition products that occur in the formulation during storage and manufacturing processes without reducing drug release properties.

In this specification, "contain" or "comprising" may be used interchangeably with "combining". Moreover, in this specification, "content" may be used interchangeably with "blending amount".

The adhesive patch of the present invention contains a diclofenac salt, an organic acid, and a metal oxide in the adhesive. A paste is usually a paste-like composition containing an adhesive base mainly composed of an adhesive and a drug, and may also be referred to as an adhesive composition.

Examples of diclofenac salts to be incorporated into the patch of the present invention include diclofenac sodium, diclofenac potassium, diclofenac diethylammonium, and diclofenac hydroxyethylpyrrolidine. A preferred diclofenac salt is diclofenac sodium.

The content of diclofenac salt in the patch of the present invention is not particularly limited as long as it can be formulated, but it is usually 0.1% to 10% by weight, preferably 0.5% by weight based on the weight of the patch. % to 6% by weight, more preferably 1% to 4% by weight. If the content of diclofenac salt in the formulation is less than 0.1% by weight, transdermal absorption will be insufficient, and if it exceeds 10% by weight, it will not only impair the physical properties of the patch but also be economically disadvantageous. Undesirable.

The organic acid blended into the patch of the present invention functions as a dissolving agent for diclofenac salt. Examples of organic acids that can be used include propionic acid, oleic acid, linoleic acid, linolenic acid, isostearic acid, myristic acid, lauric acid, citric acid, isobutyric acid, caproic acid, caprylic acid, lactic acid, maleic acid, pyruvic acid, and sulfuric acid. Examples include aliphatic carboxylic acids such as succinic acid, malic acid, and tartaric acid; and aromatic carboxylic acids such as phthalic acid, salicylic acid, benzoic acid, and acetylsalicylic acid, and only one of these may be used. However, two or more types may be used in combination. Aliphatic carboxylic acids are preferred, one or more selected from oleic acid, isostearic acid, myristic acid, capric acid, caprylic acid, and lactic acid are more preferred, and one or more selected from oleic acid and isostearic acid Two types are more preferred, and isostearic acid is particularly preferred.

The content of organic acid is usually in the range of 0.1% to 10% by weight, preferably 0.5% to 8% by weight, more preferably 0.7% to 7% by weight based on the weight of the paste. It is. If the organic acid content is less than 0.1% by weight, it will be difficult to sufficiently dissolve diclofenac salt in the paste, resulting in decreased transdermal absorption of the drug or crystal precipitation of the active drug in the preparation during storage. On the other hand, if the organic acid content exceeds 10% by weight, problems such as skin irritation or deterioration of the physical properties of the preparation may occur.

The metal oxide compounded in the patch of the present invention has the function of suppressing the production of decomposition products of diclofenac without reducing the drug release properties of diclofenac. Examples of metal oxides that can be used include zinc oxide, calcium oxide, aluminum oxide, magnesium oxide, iron oxide, and titanium oxide. Only one type of these may be used, or two or more types may be used in combination. It's okay. One or more types selected from zinc oxide, aluminum oxide, and titanium oxide are preferred, one or two types selected from zinc oxide and titanium oxide are more preferred, and zinc oxide is particularly preferred.

The content of the metal oxide compounded in the patch of the present invention is usually 0.01% to 5% by weight, preferably 0.1% to 3% by weight, more preferably 0.01% to 5% by weight, based on the weight of the patch. It ranges from .3% to 1.5% by weight. If it is less than 0.01% by weight, the effect of suppressing the generation of decomposition products is insufficient, and even if it is added in excess of 5% by weight, no further effect is observed, and the physical properties of the preparation deteriorate. do.

In one embodiment, a base polymer, a tackifier resin, and a softener are further blended into the plaster of the patch of the present invention, and other components can be further blended as appropriate.

The base polymer used in the patch of the present invention can be, for example, an acrylic adhesive, a rubber adhesive, a silicone adhesive, etc., but it is preferable to use a rubber adhesive. Examples of rubber adhesives include natural rubber, polyisoprene, polybutadiene, styrene-isoprene-styrene block copolymer, styrene-butadiene rubber, and styrene-isoprene rubber, but styrene-isoprene-styrene block copolymer It is preferable to use coalescence (hereinafter also referred to as SIS). The content of the base polymer is determined taking into consideration the content of other components, but is usually 5% to 30% by weight, preferably 10% to 25% by weight, based on the weight of the plaster. It is preferably in the range of 10% to 20% by weight. If the content is less than 5% by weight, the cohesive force and shape retention of the base will decrease. On the other hand, if the above-mentioned content exceeds 30% by weight, it will cause a decrease in adhesive strength, non-uniformity of the paste, and decrease in workability in the manufacturing process.

The tackifying resin is not particularly limited as long as it is commonly blended into adhesive patches, such as rosin-based resins such as rosin ester and hydrogenated rosin glycerin ester; petroleum resins such as alicyclic saturated hydrocarbon resins. and terpene resins, and one type of these resins may be used alone, or two or more types may be used in combination. Alicyclic saturated hydrocarbon resins are preferred. The content of the tackifier resin is not particularly limited as long as it can be formulated, but it is usually 10% to 60% by weight, preferably 15% to 50% by weight, more preferably 25% by weight based on the weight of the paste. It ranges from % to 40% by weight. If the content of the tackifying resin in the formulation is less than 10% by weight, the physical properties of the formulation will deteriorate, resulting in undesirable effects such as adhesive residue. Moreover, if it is blended in an amount exceeding 60% by weight, it may cause skin irritation, which is not preferable.

The softener used in the patch of the present invention is not particularly limited as long as it is compatible with other base components and imparts flexibility to the base. Softeners that can be used include, for example, polyisobutylene, liquid polyisoprene, polybutene, lanolin, castor oil, almond oil, olive oil, camellia oil, persic oil, peanut oil, process oil, extender oil, liquid paraffin, and the like. Only one type of these may be used, or two or more types may be used in combination. Preferably, one or two selected from polybutene and liquid paraffin are used. The content of the emollient is determined by taking into consideration the content of other liquid components added to the formulation, and is usually 10% to 75% by weight, preferably 20% to 50% by weight based on the weight of the paste. %, more preferably in the range of 30% to 45% by weight.

In the patch of the present invention, it is also possible to incorporate a solubilizer or an absorption promoter other than the organic acid and metal oxide, if necessary. These solubilizers or absorption enhancers include, for example, fatty acid esters such as isopropyl myristate, diethyl sebacate, diisopropyl sebacate, diisopropyl adipate, and isopropyl palmitate; propylene glycol, polyethylene glycol, butylene glycol, and glycerin. Examples include polyhydric alcohols; pyrrolidone compounds such as N-methyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, and N-octyl-2-pyrrolidone; crotamiton; and surfactants. can.

In addition, various base components used in ordinary patches can be used in the patch of the present invention, as long as they do not affect others. Such base components include, but are not particularly limited to, water-soluble polymers such as polyvinylpyrrolidone, polyvinyl alcohol, and polyacrylic acid; cellulose derivatives such as ethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose; peppermint oil and L-menthol. Cooling agents such as; silicon compounds such as silicic anhydride and light silicic anhydride; dibutylhydroxytoluene (also referred to as BHT), pentaerythrityl-tetrakis-[3-(3,5-di-t-butyl-4-) antioxidants such as hydroxyphenyl) propionate], tocopherol acetate, and ascorbic acid; and inorganic fillers such as silicas and zinc stearate. The adhesive patch of the present invention may further contain a preservative, a bactericidal agent, a flavoring agent, a coloring agent, and the like, if necessary.

In one embodiment, the patch of the present invention contains one or two cooling agents selected from peppermint oil and L-menthol. L-menthol is preferred as the cooling agent. The content of the cooling agent is in the range of 0.5% to 10% by weight, preferably 1% to 8% by weight, more preferably 2% to 6% by weight based on the weight of the paste.

In another embodiment, the patch of the invention contains dibutylhydroxytoluene, pentaerythrityl-tetrakis-[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate], tocopherol acetate, and ascorbic acid. One or more antioxidants selected from the following are blended. Dibutylhydroxytoluene is preferred as the antioxidant. The content of the antioxidant is 0.1% to 5% by weight, preferably 0.3% to 3% by weight, more preferably 0.5% to 2% by weight based on the weight of the paste. .

In one embodiment, the patch of the present invention contains a diclofenac salt, an organic acid, a metal oxide, a base polymer, a tackifying resin, and a softening agent in the plaster.
In another embodiment, the patch of the present invention contains a diclofenac salt, an organic acid, a metal oxide, a base polymer, a tackifier resin, a softener, an antioxidant, and a cooling agent in the plaster.
In another embodiment, the patch of the present invention contains a diclofenac salt, an organic acid, a metal oxide, a base polymer, a tackifier resin, a softener, an antioxidant, and a cooling agent in the paste, and optionally , a solubilizer or absorption enhancer other than organic acids and metal oxides, a water-soluble polymer, a cellulose derivative, a silicon compound, an inorganic filler, a preservative, a bactericide, a flavoring agent, and a coloring agent. Or it contains two or more kinds of components.
In another embodiment, the plaster of the present invention comprises a diclofenac salt, an organic acid, a metal oxide, a base polymer, a tackifier resin, a softener, an antioxidant, and a cooling agent, and as optional ingredients. One or more selected from solubilizers or absorption enhancers other than organic acids and metal oxides, water-soluble polymers, cellulose derivatives, silicon compounds, inorganic fillers, preservatives, bactericidal agents, flavoring agents, and coloring agents. Consists of two or more components.
In another embodiment, the paste of the patch of the invention consists of a diclofenac salt, an organic acid, a metal oxide, a base polymer, a tackifying resin, a softener, an antioxidant, and a cooling agent.

In another embodiment, the plaster of the patch of the present invention is
Diclofenac sodium;
One or more organic acids selected from oleic acid, isostearic acid, myristic acid, capric acid, caprylic acid, and lactic acid;
One or more metal oxides selected from zinc oxide, aluminum oxide, and titanium oxide;
a base polymer selected from natural rubber, polyisoprene, polybutadiene, styrene-isoprene-styrene block copolymer, styrene-butadiene rubber, and styrene-isoprene rubber;
One or more tackifier resins selected from rosin resins, petroleum resins, and terpene resins;
One or more softening agents selected from polyisobutylene, liquid polyisoprene, polybutene, lanolin, castor oil, almond oil, olive oil, camellia oil, persic oil, peanut oil, process oil, extender oil, and liquid paraffin. ;
Oxidation of one or more selected from dibutylhydroxytoluene, pentaerythrityl-tetrakis-[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate], tocopherol acetate, and ascorbic acid an inhibitor; and one or two cooling agents selected from peppermint oil and L-menthol.

In another embodiment, the plaster of the patch of the present invention is
Diclofenac sodium;
One or two organic acids selected from oleic acid and isostearic acid;
One or two metal oxides selected from zinc oxide and titanium oxide;
Styrene-isoprene-styrene block copolymer;
Alicyclic saturated hydrocarbon resin;
one or two softeners selected from polybutene and liquid paraffin;
It consists of dibutylhydroxytoluene; and L-menthol.

In another embodiment, the plaster of the present invention includes diclofenac sodium; isostearic acid; zinc oxide; styrene-isoprene-styrene block copolymer; alicyclic saturated hydrocarbon resin; polybutene and liquid paraffin; dibutyl hydroxy Consists of toluene; and L-menthol.

In one embodiment, the plaster of the patch of the present invention has a weight of:
0.1% to 10% by weight, preferably 0.5% to 6% by weight, more preferably 1% to 4% by weight of diclofenac salt;
0.1% to 10% by weight, preferably 0.5% to 8% by weight, more preferably 0.7% to 7% by weight of organic acids;
0.01% to 5% by weight, preferably 0.1% to 3% by weight, more preferably 0.3% to 1.5% by weight of metal oxide;
5% to 30% by weight, preferably 10% to 25% by weight, more preferably 10% to 20% by weight of the base polymer;
10% to 60% by weight, preferably 15% to 50% by weight, more preferably 25% to 40% by weight of tackifying resin;
10% to 75% by weight, preferably 20% to 50% by weight, more preferably 30% to 45% by weight of a softener;
0.1% to 5% by weight, preferably 0.3% to 3% by weight, more preferably 0.5% to 2% by weight of antioxidant; and 0.5% to 10% by weight; Preferably it contains 1% to 8% by weight of the cooling agent, more preferably 2% to 6% by weight.

Examples of the support for the adhesive patch include films, nonwoven fabrics, woven fabrics, knitted fabrics, and laminate composites of nonwoven fabrics and films. Examples of materials for these supports include polyethylene, polypropylene, polyvinyl chloride, polyester, polyethylene terephthalate, nylon, polyurethane, rayon, polyacrylonitrile, polystyrene, and polyethylene naphthalate.

The release liner used in the patch can be made of, for example, polyethylene terephthalate, polypropylene, or paper, with polyethylene terephthalate being particularly preferred. The release liner may optionally be siliconized to optimize release force.

The method for producing the adhesive patch of the present invention is not limited, but is characterized by, for example, dissolving the adhesive composition in an organic solvent such as toluene or hexane, and removing the organic solvent through a coating and drying process. and a hot melt method, which is characterized in that the coating step is carried out in a state in which the adhesive composition is melted at a high temperature of 100° C. or higher. In one embodiment, the patch of the present invention is manufactured by a hot melt method.

In one embodiment, the patch of the present invention comprises applying a composition comprising a diclofenac salt, an organic acid, and a metal oxide to a support or release liner under heat (e.g., 100-200°C, preferably 100-150°C). It is manufactured using a manufacturing method that includes a step of coating on top. In another embodiment, the composition comprises heating and stirring a mixture comprising a base polymer, a tackifying resin, and a softener to obtain an adhesive solution, and then adding a diclofenac salt, an organic acid, and a metal oxide to the adhesive. Obtained by adding it to the solution.

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples.

[Example 1]
SIS (SIS5002; manufactured by JSR Corporation), alicyclic saturated hydrocarbon resin (Alcon P-100; manufactured by Arakawa Chemical Industries, Ltd.), polybutene (HV-300F; manufactured by JXTG Energy Corporation), liquid paraffin (Hicor M- 352; manufactured by Kaneda Corporation) and BHT were dissolved by heating and stirring under a nitrogen atmosphere to obtain an adhesive solution. Next, the main ingredients diclofenac sodium, L-menthol, isostearic acid, and zinc oxide were added to the adhesive solution and mixed with stirring to prepare an adhesive composition.

The prepared adhesive composition was applied onto a silicon-treated polyethylene terephthalate film to form an adhesive layer with a thickness of about 100 μm. The resulting adhesive layer was laminated onto a polyester woven fabric as a support to obtain a patch of the present invention. The content of each component is shown in Table 1.

[Examples 2 to 7]
Each patch of Examples 2 to 7 was obtained according to the manufacturing method of Example 1 using the composition shown in Table 1 or Table 2.

[Comparative Examples 1 to 5]
Each patch of Comparative Examples 1 to 5 was obtained using the composition shown in Table 3 and according to the manufacturing method of Example 1.

[Test example]
[Test Example 1] In vitro skin permeability test An in vitro hairless rat skin permeability test was conducted for each patch of Examples 1 to 7 and Comparative Examples 1 to 5. The abdominal skin of a male hairless rat (HWY strain, 7 weeks old) was removed and set in a Franz-type diffusion cell, with the dermis side serving as the receptor side, and the inside of the cell filled with phosphate buffered saline. 37°C hot water was refluxed. Each patch was punched out into a circular shape (1.54 cm ² ) and applied to the excised skin, and the receptor fluid was sampled 24 hours after the start of the test, and the amount of drug permeated through the skin was measured by high performance liquid chromatography.
The test results are shown in Tables 1, 2, and 3 above. As is clear from the comparisons between Example 1 and Comparative Example 1, Example 2 and Comparative Example 2, and Example 3 and Comparative Example 3, the combination of zinc oxide does not reduce the release properties of the active ingredient, and It is observed that the drug release property is equivalent to or better than that of the formulation without the combination.

[Test Example 2] Decomposition product quantitative test Each patch of Examples 1 to 7 and Comparative Examples 1 to 5, which had been stored for one month under storage conditions of 60°C, was punched out into 35 cm ² pieces and placed in a 50 mL centrifugal sedimentation tube. , Tetrahydrofuran (hereinafter referred to as THF) was added to this, and ultrasonic extraction and extraction using a shaker were performed. The obtained extract was collected in a 50 mL volumetric flask, and the volume was made up to 50 mL with THF.

Take 1 mL of this extract, make it to 10 mL with 40% acetonitrile aqueous solution, filter it using a membrane filter (0.45 μm), and measure the amount of indolinone formed and menthol ester formed using the HPLC method under the following measurement conditions. The amount produced was measured.

・測定波長：２８２ｎｍ
・注入量：７μＬ The test results are shown in Tables 1, 2, and 3 above. The amounts of indolinone and menthol ester produced are shown as the ratio (%) of the peak area of each decomposition product to the peak area of the main drug component (diclofenac sodium).
[HPLC measurement conditions]
・Column: ACQUITY C8 (2.1 x 100mm)
・Mobile phase A Acetonitrile: Water: Phosphoric acid = 100:900:1
B Acetonitrile:water:phosphoric acid=900:100:1
・Flow rate: 0.4mL/min ・Concentration gradient control

・Measurement wavelength: 282nm
・Injection volume: 7μL

As is clear from the results shown in Tables 1, 2, and 3, compared to the amount of decomposition products produced in each comparative example, (1) Examples 6 and 7 of the present invention, which did not contain menthol; (2) In Examples 1 to 5 of the present invention in which menthol was blended, the production of both indolinone and menthol ester was greatly suppressed.

ADVANTAGE OF THE INVENTION According to the present invention, it is possible to provide a patch that suppresses the production of decomposition products of diclofenac that occur in the preparation during storage and manufacturing processes, and exhibits high drug release properties. The patch of the present invention can be used to treat, for example, osteoarthritis, chronic rheumatoid arthritis, low back pain, shoulder periarthritis, tenosynovitis, peritendinitis, humeral epicondylitis (tennis elbow, etc.), muscle pain, or post-traumatic swelling.・Useful for treating or preventing pain, etc.

Claims (5)

Forming 1-(2,6-dichlorophenyl)-2-indolinone from a diclofenac salt, comprising mixing the diclofenac salt with an organic acid and a metal oxide consisting only of a liquid acid and no solid acid. A method for suppressing
The organic acid consisting only of liquid acids is one or more selected from oleic acid, linoleic acid, linolenic acid, and isostearic acid ,
The metal oxide is one or more selected from zinc oxide, aluminum oxide, and titanium oxide,
Method. 2. The method of claim 1, wherein the diclofenac salt is diclofenac sodium. 3. The method according to claim 1, wherein the organic acid consisting only of liquid acids is one or two selected from oleic acid and isostearic acid. 3. The method according to claim 1, wherein the organic acid consisting only of liquid acid is isostearic acid. The method according to any one of claims 1 to 4 , wherein the metal oxide is zinc oxide.