SK282637B6 - Anti-inflammatory agent and method for producing thereof - Google Patents

Abstract

Anti-inflammatory agent for external use containing nimesulide as an active substance, which is dispersed in the base component.

Description

Technical field

The invention relates to an anti-inflammatory composition for external use comprising nimesulide as an active ingredient in a base component. In particular, the present invention relates to an anti-inflammatory composition for external use comprising nimesulide as an active ingredient and a base component, as well as a process for its preparation.

BACKGROUND OF THE INVENTION

Non-steroidal anti-inflammatory agents have the disadvantage that they cause gastrointestinal disorders when administered orally. To avoid this disadvantage, various studies have been conducted to develop an anti-inflammatory agent for external use and several commercial products have been developed for clinical use. However, the anti-inflammatory compositions developed so far for external use have inadequate clinical effects, although they are also effective in basic tests.

Nimesulide 4-nitro-2-phenoxymethanesulfonanilide, one of the non-steroidal anti-inflammatory agents, was first synthesized by Riker Co. in the United States and then developed as an oral preparation in Europe by Helsinn Co. in Switzerland. Unlike conventional acidic anti-inflammatory agents, nimesulide is known to selectively inhibit PGE2 (COX2), and it is a novel type of pharmaceutical that is expected to have effects in clinical practice.

As for the prior art with respect to nimesulide, reference may be made to the compound disclosed in U.S. Pat. No. 3,480,597, and the manufacturing patents described in Japanese Patent (Kokoku) Sho-58-35989, Japanese Patent (Kokoku) Sho-58-50984, and Japanese Patent (Kokoku) Sho-59-44311. However, these references do not include descriptions of preparation examples relating to actual pharmaceutical preparations, although they mention dosage forms such as capsules, cream, gel, patch and the like.

In addition, Japanese Patent Application Publication (Kohyo) Hei-6-502842, based on the International Patent Application, may be cited as a reference for a pharmaceutical composition of nimesulide. This patent relates to the preparation of an inclusive compound of nimesulide with cyclodextrin to make nimesulide water-soluble so as to increase water solubility and increase the absorption of nimesulide in the digestive tract. It is therefore not intended for external use. Thus, no reference is made to illustratively illustrate the use of nimesulide as an external preparation, and no case is known concerning a particular external use of nimesulide in a particular dosage form.

This is probably due to the fact that although nimesulide has pharmacological effects equal to or greater than those of indomethacin, which is considered to be a potent anti-inflammatory agent, it has several unresolved problems when applied topically as an external formulation. These are: (1) Nimesulide is sparingly soluble and does not readily dissolve in water and various organic solvents. (2) A solvent that has a strong dissolving capacity should be mixed to dissolve the nimesulide, but it causes problems such as skin irritation, cracked skin, itching and redness of the skin. (3) Although nimesulide is dissolved, the resulting pharmaceutical preparation is dark yellow and hence its appearance is poor. (4) The applied pharmaceutical preparation contaminates clothing that comes into contact with the preparation.

Thus, attempts have been made to use nimesulide no more.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide an anti-inflammatory composition for topical use which comprises nimesulide for topical use, which is a non-insulinic exterior composition which exhibits excellent absorption and which does not cause any dyeing and skin safety problems.

As a result of extensive studies that have taken into account the above-mentioned disadvantages of nimesulide as an external preparation, the inventors have found that all these disadvantages are eliminated when nimesulide is mixed in a dispersed state into the base component. That is, when nimesulide is mixed in a dispersed state into the base component, it surprisingly has pharmacological effects equal to or higher than those of a pharmaceutical composition in which nimesulide is admixed in dissolved form. In addition, the amount of dissolving agent can be reduced, thus improving the safety of the skin. Furthermore, it has been shown that the color of the pharmaceutical preparation does not occur, which is a difference from the completely dissolved type of the pharmaceutical preparation. This means that all these problems can be solved.

In particular, the object of the invention is achieved by a composition according to the invention wherein nimesulide is admixed in a dispersed state to a base component comprising an oily substance, a nonionic surfactant, a base, water and / or an absorption enhancer. More specifically, 0.1 to 5 wt. nimesulide as a finely divided active ingredient is dispersed and mixed into a base component which further comprises a hydrophilic polymer or white petrolatum for the preparation of an external preparation such as a cream or ointment.

Nimesulide as an active ingredient can be used in any form as long as it can be dispersed in the base component. In view of the ease of grinding of the particles to be dispersed and the cost, the mean particle diameter of the nimesulide is preferably 0.01 µm or more. On the other hand, in terms of transdermal absorbency and delivery sensation (rough feeling), it is preferably 75 µm or less, i. j. particle sizes that pass through a 200 mesh sieve, and more preferably from 0.5 to 50 µm, even more preferably from 1 to 30 µm.

The anti-inflammatory composition for external use of the present invention can be prepared as follows. For example, a cream composition is prepared by mixing and mixing the oil phase of the heat-melted oil components and the aqueous phase in which the water-soluble components have been dissolved; adding nimesulide in the form of fine particles; and further by stirring and cooling. The ointment is prepared by adding nimesulide in the form of fine particles to the heat-melted oil components with stirring and cooling, followed by stirring and cooling.

It may be desirable to adjust the pH of the pharmaceutical composition from 4 to 8, more preferably from 5 to 7, with respect to skin irritation and transdermal absorbability.

Examples of the basis for the preparation of an anti-inflammatory composition for external use according to the invention include a so-called gel cream comprising a hydrophobic polymer, an oily substance, a non-ionic surfactant, a base and water; a basic skin cream made from a higher alcohol, a hydrocarbon, a fatty acid ester, a polyhydroxy alcohol, a base, an antiseptic, water, and the like; a cream with hydrophilic ointment or absorbent ointment according to The Japanese Pharmacopeia, made from white petrolatum, surfactant, higher alcohol, hydrocarbon, fatty acid ester, polyhydroxy alcohol, alkali, antiseptic, water and the like; and a FAPG base comprising a higher alcohol, a polyhydroxy alcohol, and the like. Regarding the prescription for a cream composition, from the point of view of transdermal absorbability, the most advantageous pharmaceutical composition is obtained by mixing 0.1 to 5% by weight. % of nimesulide to a so-called gel cream base containing 0.2 to 3 wt. % hydrophilic polymer, 2 to 20 wt. 0.5 to 7 wt. % nonionic surfactant, 0.01 to 5 wt. % of a basic material and 50 to 90 wt. water. With respect to the prescription for an ointment preparation, the pharmaceutical preparation obtained by mixing 0.1 to 5 wt. % nimesulide to a petrolatum ointment containing 35 to 80 wt. % white petrolatum, 2 to 20 wt. % of an oily substance and 0.5 to 7 wt. a nonionic surfactant.

Further, the base components of the present invention are described in more detail.

Examples of the hydrophobic polymer include carboxyvinyl polymers (CARBOPOL 940, 941, manufactured by BF Goodrich Chemical Co., HIBISWAKO 104, 105, manufactured by Wako Purc Chemical Industries, Ltd., and the like), hydroxypropylcellulose (HPC-L, HPC-M, manufactured by by Nippon Soda Co., Ltd., and the like), a polyoxyethylene polyoxypropylene block polymer (Lutrol F68, manufactured by BASF Co., and the like). These hydrophilic polymers can be used alone or as a mixture of two or more thereof, and preferably admixed in an amount of 0.2 to 3% by weight, more preferably 0.5 to 2% by weight, in terms of cream viscosity and tackiness.

Examples of the oily substance include fatty acid esters such as diisopropyl adipate, diisopropyl sebacate, diethyl sebacate, medium length fatty acid triglycerides, medium length propylene glycols, isopropyl myristate and the like; fatty acids such as stearic acid, oleic acid, myristic acid and the like: higher alcohols such as cetanol, stearyl alcohol, cetostearyl alcohol, oleyl alcohol, behenyl alcohol and the like; hydrocarbons such as petrolatum, liquid paraffin, squalane and the like; vegetable oils and fats such as olive oil, jojoba oil, castor oil and the like; and other oily substances such as crotamitone, benzyl alcohol and the like. In the case of a cream preparation, the oily substance is mixed in an amount of from 2 to 20% by weight, preferably from 5 to 15% by weight, in terms of cream spreading, transdermal absorbability, tackiness, gloss and instability in the preparation of the preparations (e.g. liquid separation); Similarly. In the case of an ointment preparation, it is mixed in an amount of from 2 to 20% by weight, preferably from 3 to 7% by weight.

Examples of the surfactant include sorbitan fatty acid esters such as sorbitan monostearate, sorbitan sesquistearate and the like; glycerol fatty acid esters such as glyceryl monostearate, diglyceryl monooleate and the like; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate and the like; polyoxyethylene glycol fatty acid esters such as polyoxyethylene (10) monostearate polyoxyethylene (10) monolaurate and the like; polyoxyethylene alkyl ethers such as polyoxyethylene (9) lauryl ether, polyoxyethylene (23) cetyl ether and the like, polyoxyethylene alkylphenyl ethers such as polyoxyethylene (10) nonylphenyl ether, polyoxyethylene (10) octylphenylether and the like; and polyoxyethylene hydrogenated castor oil, such as polyoxyethylene (10) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, and the like. These surfactants may be used alone or as a mixture of two or more thereof and admixed in an amount of from 0.5 to 7% by weight, preferably from 1 to 5% by weight.

Examples of the base include inorganic or organic bases such as potassium hydroxide, sodium hydroxide, triethanolamine, diisopropanolamine, monoethanolamine and the like, and organic bases are preferred for transdermal absorption. These bases can be admixed in an amount of from 0.01 to 5% by weight, preferably from 0.1 to 2% by weight.

In addition, to enhance the transdermal absorption of nimesulide, an absorption enhancer may be admixed to the described pharmaceutical formulation depending on the type of pharmaceutical prescription. Examples of absorption enhancers include organic bases, crotamitone, medium-length fatty acid esters, L-menthol, benzyl alcohol and the like. The organic base facilitates the release of nimesulide from the base since it makes nimesulide water soluble by forming a salt with nimesulide. Examples of the organic base include diisopropanolamine, meglumine, triethanolamine and 1- (2-hydroxyethyl) pyrrolidine, and diisopropanolamine and 1- (2-hydroxyethyl) pyrrolidine are most preferred. The absorption enhancer is admixed in an amount of from 0.1 to 20% by weight, preferably from 0.2 to 10% by weight, alone or as a mixture of two or more thereof.

The described base and organic base as an absorption enhancer also act as pH regulators of the formulation. That is, when the pH of the pharmaceutical formulation is too low (e.g., 3 or less), high acidity causes severe skin irritation. When the pH is too high (e.g., 9 or more), the transdermal absorbability of the medicament will decrease, the skin irritation will increase, and the pharmaceutical will turn yellow. Accordingly, the pH of the pharmaceutical composition is preferably regulated in the range of from 4 to 8 by the amount of the base or absorption enhancer described to be admixed.

In addition to the above ingredients, animal oils and fats, waxes, hydrocarbons, antiseptics, humectants and the like can be added and mixed. Examples of animal oils and fats include beef tallow, pork fat, horse oil and the like. Examples of waxes include microcrystalline wax, natural wax, beeswax and the like. Examples of hydrocarbons include paraffin, ceresin and the like. Examples of antiseptics include methylparaben, propylparaben, butylparaben and the like. Examples of humectants include polyhydroxy alcohols such as glycerol, 1,3-butylene glycol, propylene glycol, dipropylene glycol and the like. These additives may be admixed in amounts generally used for cream and ointment preparations.

The invention is illustrated in more detail with reference to the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

% Wt.

1. Nimesulide (particle diameter: 5 to 20 µm) 3

2. Carboxyvinyl polymer1

3. Diisopropyl sebacate5

4. Isopropyl myristate10

5. Crotamiton3

6. Polyoxyethylene (20) sorbitan monostearate5

7. Methylparaben 0.1

8. Propylparaben 0.1

9. Diisopropanolamine 0.5

10. Deionized water72.3 iÔÔTÔ

Components (3), (4), (5), (6) and (8) were melted by heating to 75 ° C. A solution, which was previously prepared separately by dissolving component (7) in about 90% of component (10) at 75 ° C, was added, and the mixture was stirred to emulsify. Component (2) was gradually added at 50 ° C and the mixture was vigorously stirred. Then component (1) was gradually added and dispersed by stirring. Then a solution was prepared which was prepared by dissolving component (9) in the remaining component (10), and the mixture was stirred until it was homogeneous to obtain an anti-inflammatory cream composition containing nimesulide.

Example 2

% Wt.

1. Nimesulide (particle diameter: 20 to 40 µm) 3

2. Carboxyvinyl polymer1

3. Diisopropyl sebacate5

4. Isopropyl myristate10

5. Crotamiton3

6. Polyoxyethylene (20) sorbitan monostearate 5

7. Methylparaben 0.1

8. Propylparaben 0.1

9. Diisopropanolamine 0.5

10) Deionized water72.3

100.0

Components (3), (4), (5), (6) and (8) were melted by heating to 75 ° C. A solution, which was previously prepared separately by dissolving component (7) in about 90% of component (10) at 75 ° C, was added, and the mixture was stirred to emulsify. Component (2) was gradually added at 50 ° C and the mixture was vigorously stirred. Then component (1) was gradually added and dispersed by stirring. Then, a solution prepared by dissolving component (9) in the remaining component (10) was added, and the mixture was stirred until homogeneous to obtain an anti-inflammatory cream formulation containing nimesulide.

Example 3

% Wt.

1. Nimesulide (particle diameter: 5 to 20 µm) 3

2. Carboxyvinyl polymer1

3. Diethyl sebacate5

4. Medium-length fatty acid triglyceride 8

5. Crotamiton3

6. Polyoxyethylene (20) sorbitan monostearate5

7. Methylparaben 0.1

8. Propylparaben 0.1

9. 1- (2-hydroxyethyl) pyrrolidine 0.5

10. Deionized water74.3

W

Components (3), (4), (5), (6) and (8) were melted by heating to 75 ° C. A solution, which had previously been prepared separately by dissolving component (7) in about 90% of component (10) at 75 ° C, was added, and the mixture was stirred to emulsify. Component (2) was gradually added at 50 ° C and the mixture was vigorously stirred. Then component (I) was gradually added and dispersed by stirring. Then a solution was prepared which was prepared by dissolving component (9) in the remaining component (10), and the mixture was stirred until it was homogeneous to obtain an anti-inflammatory cream composition containing nimesulide.

5th crotamiton 3 6th Polyoxyethylene (20) sorbitan monostearate 5 7th methylparaben 0.1 8th Propyl 0.1 9th 1- (2-hydroxyethyl) pyrrolidine 0.5 10. Deionized water 72.3

100.0

Components (3), (4), (5), (6) and (8) were melted by heating to 75 ° C. A solution, which was previously prepared separately by dissolving component (7) in about 90% of component (10) at 75 ° C, was added, and the mixture was stirred to emulsify. Component (2) was gradually added at 50 ° C and the mixture was vigorously stirred. Then component (1) was gradually added and dispersed by stirring. Then, a solution prepared by dissolving component (9) in the remaining component (10) was added, and the mixture was stirred until homogeneous to obtain an anti-inflammatory cream formulation containing nimesulide.

Example 5

% Wt.

1. Nimesulide (particle diameter: 0.5 to 10 µm) 3

2. Carboxyvinyl polymer1

3. Diisopropyl adipate5

4. Isopropyl myristate10

5. L-Menthol2

6. Polyoxyethylene (20) sorbitan monostearate5

7. Methylparaben 0.1

8. Propylparaben 0.1

9. Diisopropanolamine 0.5

10. Deionized water73.3

100.0

Components (3), (4), (5), (6) and (8) were melted by heating to 75 ° C. A solution, which was previously prepared separately by dissolving component (7) in about 90% of component (10) at 75 ° C, was added, and the mixture was stirred to emulsify. Component (2) was gradually added at 50 ° C and the mixture was vigorously stirred. Then component (1) was gradually added and dispersed by stirring. Then, a solution prepared by dissolving component (9) in the remaining component (10) was added, and the mixture was stirred until homogeneous to obtain an anti-inflammatory cream formulation containing nimesulide.

Example 6

% Wt.

1. Nimesulide (particle diameter: 0.5 to 10 µm) 0.5

2. Stearic acid5

3. Diisopropyl adipate3

4. Cetanol5

5. Medium length fatty acid triglyceride 7

6. Polyoxyethylene (23) cetyl ether3

7. Sorbitan monostearate1

8. 1,3-butylene glycol5

9. Diisopropanolamine1

10. Sodium benzoate 0.1

11. Deionized water69,4

Γ007Ϊ

Example 4

% Wt.

1. Nimesulide (particle diameter: 5 to 20 µm) 5

2. Carboxyvinyl polymer1

3. Diethyl sebacate5

4. Medium-length fatty acid triglyceride 8

Components (2), (3), (4), (5), (6) and (7) were melted by heating to 75 ° C. A solution, which was previously prepared separately by dissolving components (8), (9) and (10) in component (11) at 75 ° C, was added, and the mixture was stirred to emulsify. Component (1) was added sequentially at 50 ° C or lower and the mixture was stirred until homogeneous to obtain an anti-inflammatory cream composition containing nimesulide.

Example 7

% Wt.

1. Nimesulide (particle diameter: 0.5 to 10 µm) 3

2. Crotamiton3

3. Diethylsebacate5

4. Microcrystalline wax10

5. Medium length fatty acid triglyceride7

6. Propylene glycol fatty acid ester10

7. Behenyl alcohol4

8. Diisopropanolamine 0.2

9. Dipropylene glycol7

10. Propylene glycol monostearate7

11. White Vaseline43,8

100.0

Components (2), (3), (4), (5), (6), (7), (8), (9), (10) and (11) were melted by heating to 80 ° C. Component (1) was gradually added at 50 ° C and dispersed by stirring to obtain an anti-inflammatory ointment formulation containing nimesulide.

Example 8 (Cream composition of the dispersed type in which the active ingredient has a particle diameter of 75 to 180 µm)

% Wt.

1. Nimesulide (particle diameter: 75 to 180 µm) 3

2. Carboxyvinyl polymer1

3. Isopropyl myristate15

4. Polyoxyethylene (20) sorbitan monostearate5

5. Methylparaben 0.1

6. Propylparaben 0.1

7. Propylene glycol3

8. Diethanolamine 0.5

9. Deionized water72.3

100.0

Components (3), (4) and (6) were melted by heating to 75 ° C. A solution, which was previously prepared separately by dissolving components (6) and (7) in about 90% of component (9) at 75 ° C, was added, and the mixture was stirred to emulsify. Component (2) was gradually added at 50 ° C and the mixture was vigorously stirred. Then component (1) was gradually added and dispersed by stirring. Then a solution was prepared which was prepared by dissolving component (8) in the remaining component (9), and the mixture was stirred until homogeneous to obtain an anti-inflammatory cream composition containing nimesulide.

Comparative Example (Creamy formulation in which the active ingredient is dissolved)

component % wt. First nimesulide 3 Second Carboxyvinyl polymer 1 Third isopropyl 15 4th Polyoxyethylene (20) sorbitan monostearate 5 5) methylparaben 0.1 6th Propyl o, l 7th 1,3-butylene glycol 3 8th diethanolamine 6 9) Deionized water 66.8

100.0

Components (3), (4) and (6) were melted by heating to 75 ° C. A solution, which was previously prepared separately by dissolving components (5) and (7) in about 90% of component (9) at 75 ° C, was added, and the mixture was stirred to emulsify. Component (2) was gradually added at 50 ° C and the mixture was stirred vigorously to dissolve component (2). Then component (1) was gradually added and mixed by stirring. Then, a solution prepared by dissolving component (8) in the remaining component (9) was added, and the mixture was stirred until homogeneous to obtain an anti-inflammatory cream formulation containing nimesulide.

Test Example 1

Test for suppression of carrageenin-induced swelling of rat legs

The anti-inflammatory effect of the cream preparations of Examples 1, 2, 5, 7 and 8 and of the Reference Example, as well as a commercially available cream formulation containing indomethacin, was tested by suppressing the carrageenin-induced swelling of the feet of rats.

Test method

The test substance was applied to the right foot of male Wister rats, each weighing 132-150 g, and the right foot was fixed with a thin coating. When the drug was applied, the animal was strapped to a neck plastic collar and placed in an individual cage to prevent oral drug ingestion. After 4 hours of drug loading, the drug was completely removed with hygroscopic cotton wool containing lukewarm water. Immediately thereafter, saline containing 1% carrageenin (0.1 ml) was injected subcutaneously into the foot of the foot. After 3 hours, the foot volume was measured and the swelling ratio was calculated based on the foot volume before injection of the pro-drug. The test results are shown in Table 1.

Sample (amount administered: 100 mg / site) Number of animals Swelling ratio (%) (after 3 hours) inspection 8 77.6 The cream preparation of Example 1 8 38.9 The cream preparation of Example 2 8 35.1 The cream preparation of Example 5 8 45.6 The cream preparation of Example 7 8 50.6 The cream preparation of Example 8 8 64.6 Creamy preparation from reference example 8 53.1 Commercially available indomethacin cream preparation 8 68.6

From the results in Table 1 it is clear that the pharmaceutical formulations of Examples 1, 2, 5, 7 and 8 had an excellent anti-inflammatory effect compared to a commercially available indomethacin cream formulation which is the same or higher even compared to the cream formulation of the reference formulation containing nimesulide in the dissolved state.

Test Example 2

Dye test

The cream compositions of the present invention and the cream composition of the Reference Example were prepared and applied to the cotton fabric and the degree of coloring was monitored. The test results are shown in Table 2.

sample Appearance at the time of preparation Coloring of the substance Creamy preparation 1 Slight yellowish white cream Almost no discoloration Creamy preparation 2 Slight yellowish white cream Almost no discoloration Creamy preparation from reference example Yellow cream Yellowed

As is clear from Table 2, the fabric was stained for the cream formulation of the Reference Example containing nimesulide in the dissolved state, but the cream formulations of Examples 1 and 2 of the present invention showed almost no staining.

The anti-inflammatory composition for external use of the present invention into which nimesulide is mixed in a dispersed state has pharmacological effects equal to or greater than those of the dissolved formulation, does not irritate the skin, is safe and does not pollute the skin and clothing as it is not colored. Accordingly, the invention is particularly useful as an agent in the field of dermatology for the treatment of eczema, dermatitis and the like, and as an anti-inflammatory external agent in the field of orthotics for the treatment of chronic joint rheumatism, osteoarthritis, periarthritis of shoulder muscles and peritendins after injury.

The anti-inflammatory agent for external use according to any one of claims 1 to 7, characterized in that it is in the form of an ointment.

The anti-inflammatory agent for external use according to claim 9, wherein the nimesulide is in an amount of 0.1 to 5% by weight. blended in a petrolatum ointment base component which contains white petrolatum in an amount of from 35 to 80% by weight, an oily substance in an amount of from 2 to 20% by weight. and a nonionic surfactant in an amount of from 0.5 to 7 wt.

11. A process for the manufacture of an anti-inflammatory composition for external use, comprising the stepwise addition of nimesulide as active ingredient in the form of fine particles to the base component and dispersing the nimesulide by stirring.

Method according to claim 11, characterized in that an oil component melted by heating is used as the base component.

The process according to claim 11, characterized in that the oil phase of the heat-melted oil components and the aqueous phase in which the water-soluble components have been dissolved are mixed by stirring and used as a base component.

The process according to any one of claims 11 to 13, characterized in that nimesulide in the form of fine particles is nimesulide having a mean particle diameter of from 0.01 to 75 µm.

Claims (8)

PATENT CLAIMS An anti-inflammatory composition for external use comprising nimesulide as an active ingredient and a base component, characterized in that it comprises nimesulide mixed in a dispersed state into the base component. The anti-inflammatory agent for external use according to claim 1, characterized in that the nimesulide is mixed in an amount of from 0.1 to 5% by weight. The anti-inflammatory agent for external use according to claim 1, having a pH of from 4 to 8. External anti-inflammatory agent according to claim 1, characterized in that the base component comprises a hydrophilic polymer, white petrolatum, an oily substance, a non-ionic surfactant, water, a base and / or an absorption enhancer. The anti-inflammatory agent for external use according to claim 4, characterized in that the absorption enhancer is an organic base, crotamitone, a medium-length fatty acid ester, L-menthol and / or benzyl alcohol. External anti-inflammatory agent according to claim 5, characterized in that the organic base is diisopropanolamine, meglumine, triethanolamine and / or 1- (2-hydroxyethyl) pyrrolidine. The anti-inflammatory agent for external use according to any one of claims 1 to 6, characterized in that it is in the form of a cream preparation. The anti-inflammatory agent for external use according to claim 7, characterized in that nimesulide in an amount of 0.1 to 5% by weight. it is mixed into a gel-like cream base which comprises a hydrophilic polymer in an amount of 0.2 to 3% by weight, an oily substance in an amount of 2 to 20% by weight, a nonionic surfactant in an amount of 0.5 to 7% by weight. %, a base in an amount of 0.01 to 5 wt. and water in an amount of from 50 to 90 wt.