SI9620016A - Antiinflammatory agent for external use - Google Patents

Abstract

An external antiinflammatory agent containing an active ingredient comprising nimesulide dispersed in the base component and being readily absorbable, safe and nondiscolorable.

Description

The field of technology

The present invention relates to an anti-inflammatory external use agent (application) containing nimesulide as an effective ingredient. The present invention relates specifically to an anti-inflammatory exterior agent comprising nimesulide as an effective ingredient and a base component in which nimesulide is mixed in a dispersed state in the base component, and to a process for its preparation.

The state of the art

Non-steroidal anti-inflammatory preparations have the disadvantage of causing gastrointestinal disorders when administered orally. In order to avoid this defect, various studies have been conducted to develop an anti-inflammatory agent for external use and make available a number of commercial products for clinical use. However, anti-inflammatory drugs developed to date have insufficient clinical effects, even when they show effects in basic tests.

Nimesulide (4-nitro-2-phenoxymethanesulfonanilide), one of the non-steroidal anti-inflammatory agents, was first synthesized by Riker Co. then developed it 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 is a new type of pharmaceutical agent that is expected to be effective in clinical use.

As the state of the art relating to nimesulide, we can refer to US Pat. 3,480,597 pertaining to substance and patents pertaining to processes, i.e. tested Japanese patent application (Kokoku) Sho-58-35989, tested Japanese patent application (Kokoku) Sho-58-50984, and tested Japanese patent application (Kokoku) Sho-59-44311. However, those prior art do not have descriptions or embodiments that refer to actual pharmaceutical preparations, although they do mention dosage forms such as capsule, cream, gel, patch and the like.

In addition, the Japanese patent application (Kohyo) Hei-6-502842, which is publicly available and filed on the basis of an international patent application, may be cited as a reference to the pharmaceutical preparation nimesulide. According to this patent document, an inclusion (inclusion compound) of nimesulide with cyclodextrin is prepared to convert nimesulide to a water-soluble form by increasing water solubility and increasing the absorption of nimesulide in the gastrointestinal tract. Therefore, it is not intended for external use. There is therefore no known reference to illustrate the use of nimesulide as an external preparation, and there is no known case for the actual external use of nimesulide in such specific dosage form.

This will be 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 many unresolved problems of topical use as an external preparation. Namely, Nimesulide (1) is hardly soluble and cannot be easily dissolved in water and various organic solvents. (2) It must be mixed with a solvent with a strong dissolving ability to dissolve nimesulide, causing problems such as skin irritation, skin cracking, itching and inflammation. (3) Even if nimesulide is dissolved, the resulting pharmaceutical preparation becomes dark yellow and thus its appearance deteriorates. (4) The applied pharmaceutical preparation soothes the clothing which comes into contact with the preparation.

So there was such a situation that they abandoned the use of nimesulide as an external preparation.

The solution to the problem of the invention

It is an object of the present invention to provide an anti-inflammatory extramural agent comprising nimesulide for topical use, which is a nimesulide extrinsic preparation with excellent absorption and non-problematic skin coloration and protection.

How to solve problems

As a result of extensive studies considering the above described nimesulide defects as a preparation for external use, the inventors have determined that all the problems described above have been solved by mixing the nimesulide in the dispersed state in the basic component, and have realized the present invention. That is, when mixed in the dispersed state, the nimesulide surprisingly exhibits pharmacological effects equal to or greater than the effect of the pharmaceutical composition in which the nimesulide is mixed in the dissolved form. In addition, the amount of the dissolving agent can be reduced, thereby improving skin safety. It is further demonstrated that the coloring of the pharmaceutical preparation does not occur unlike the fully dissolved pharmaceutical formulation. Therefore, all the problems described above in connection with the external administration preparation can be solved.

The purpose of the present invention can be achieved in more detail by mixing nimesulide as an active ingredient in the dispersed state in a basic component comprising an oily substance, a non-ionic surfactant, a basic substance, water and / or an absorption enhancer. In further detail, 0.1 to 5% by weight of nimesulide is dispersed as an effective component in the form of fine particles and mixed in a basic component further comprising a hydrophilic polymer or white petroleum to prepare an exterior preparation such as a cream or ointment.

Nimesulide as an effective ingredient can be used in any form, only to be processed in the dispersed state into a basic component. In terms of the ease of grinding the particles to be dispersed and the cost, the average particle diameter of nimesulide is preferably 0.01 µm or more. On the other hand, with respect to transdermal absorption and application (roughness), preferably 75 pm or less, i.e. particle size passing through a 200-mesh sieve, more preferably from 0.5 to 50 pm, and even more preferably from 1 to 30 pm.

The anti-inflammatory exterior use agent of the present invention can be prepared as follows. So e.g. a cream-form agent can be prepared by mixing the oil phase and heating the molten oil components and the aqueous phase in which the water-soluble components are dissolved, by adding nimesulide in the form of fine particles, and by continuing stirring and by cooling. The ointment is prepared by adding nimesulide in the form of fine particles to the oil components, which are melted by heating, stirring and cooling, and by continuing stirring and cooling.

The pH of the pharmaceutical composition can optionally be controlled between 4 and 8, more preferably between 5 and 7, with respect to skin irritation and transdermal absorption.

Examples of a base for the preparation of an anti-inflammatory exterior use agent of the present invention include a so-called gel cream comprising a hydrophilic polymer, an oily substance, a non-ionic surfactant, a basic substance and water, a "daily" cream made from higher alcohol, hydrocarbon, fatty acid ester, polyvalent alcohol, base, antiseptic, water, etc .; hydrophilic ointment or absorbent ointment cream produced according to the Japanese Pharmacopoeia from white petroleum, surfactant, higher alcohol, hydrocarbon, fatty acid ester, polyvalent alcohol, antiseptic, water, etc .; and an FAPG base comprising higher alcohol, multivalent alcohol, and the like. As a formulation for cream formulations, from a transdermal absorption point of view, the most preferred pharmaceutical preparation is obtained by mixing 0.1 to 5 wt% nimesulide in a so-called gel cream base comprising 0.2 to 3 wt% hydrophilic polymer, 2 to 20 wt% oily substance , 0.5 to 7% by weight of non-ionic surfactant, 0.01 to 5% by weight of basic substance and 50 to 90% by weight of water. The most preferred pharmaceutical formulation is a pharmaceutical preparation obtained by mixing 0.1 to 5% by weight of nimesulide in a light petroleum ointment comprising 35 to 80% by weight of white petroleum, 2 to 20% by weight of an oily substance and 0.5 to 7% by weight of a non-ionic surfactant funds.

The basic components of the present invention are described in more detail.

Examples of the hydrophilic polymer include carboxyvinyl polymers (CARBOPOL 940, 941 manufactured by BF Goodrich Chemical Co., HIBISWAKO 104, 105 manufactured by Wako Pure Chemical Industries, Ltd., etc.), hydroxypropylcellulose (HPC-L, HPC-M manufactured by Nippon Soda Co., Ltd., etc.), a block polymer of polyoxyethylenepolyoxypropylene (Lutrol F68 manufactured by BASF Co., etc.). These hydrophilic polymers can be used alone or in a mixture of two or more and preferably mixed in an amount of 0.2 to 3% by weight, more preferably 0.5 to 2% by weight, with respect to the viscosity and stickiness of the cream.

Examples of oily substances include fatty acid esters such as diisopropyl adipate, diisopropyl sebacate, diethyl sebacate, medium chain fatty acid triglycerides, medium chain propylene glycols, isopropyl myristate, etc .; fatty acids such as stearic acid, oleic acid, myristic acid, etc .; higher alcohols such as cetanol, stearyl alcohol, cetostearyl alcohol, oleyl alcohol, behenyl alcohol, etc .; hydrocarbons such as white petrolatate, liquid paraffin, squalane, etc .; vegetable oils and fats such as olive oil, jojoba oil, castor oil, etc .; and other oily substances such as crotamiton, benzyl alcohol and the like. In the case of cream formulations, the oily substance is mixed in an amount of 2 to 20% by weight, preferably 5 to 15% by weight, depending on the lubricity of the cream, transdermal absorption, stickiness, gloss and instability in the production of the preparations (eg liquid separation), etc. . In the case of a lubricant preparation, it is mixed in an amount of 2 to 20% by weight, preferably 3 to 7% by weight.

Examples of the surfactant include fatty acid sorbitan esters such as sorbitan monostearate, sorbitan sesquistearate, etc .; glycerol esters with fatty acids such as glyceryl monostearate, diglyceryl monooleate, etc .; polyoxyethylene sorbitan esters with fatty acids such as polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate and the like; polyoxyethylene glycol esters of fatty acids such as polyoxyethylene (10) monostearate, polyoxyethylene (10) monolaurate, etc .; 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) octylphenyl ether and the like; and polyoxyethylene hydrogenated castor oil as polyoxyethylene (10) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil and the like. These surfactants can be used alone or as a mixture of two or more and mixed in an amount of from 0.5 to 7% by weight, preferably from 1 to 5% by weight.

Examples of a basic substance include inorganic or organic bases such as potassium hydroxide, sodium hydroxide, triethanolamine, diisopropanolamine, monoethanolamine, etc., and from a transdermal absorption standpoint, organic bases are preferred. These basic substances can be mixed in an amount of from 0.01 to 5% by weight, preferably from 0.1 to 2% by weight.

In order to improve the transdermal absorption of nimesulide, an absorption enhancer, depending on the type of pharmaceutical formulation, may be incorporated into the pharmaceutical preparation described above. Examples of absorption enhancers include organic bases, crotamiton, medium chain fatty acid esters, / -mentol, benzyl alcohol, and the like. The organic base facilitates the release of nimesulide from the base by converting nimesulide into a water-soluble form to form salt.

Examples of organic bases include diisopropanolamine, meglumine, triethanolamine, most preferably 1- (2-hydroxyethyl) pyrrolidine, diisopropanolamine and 1- (2-hydroxyethyl) pyrrolidine. The absorption enhancer is mixed in an amount of from 0.1 to 20% by weight, preferably from 0.2 to 10% by weight; alone or in a mixture of two or more.

The basic substance described above and the organic base as an absorption enhancer also act as a means of controlling the pH of the preparation. When the pH of the pharmaceutical preparation is too low (i.e. 3 or less), the skin irritation is severe due to the high degree of acidity. If the pH is too high (i.e., 9 or higher), the transdermal absorption of the drug is reduced, the skin irritation becomes severe and the pharmaceutical preparation turns yellow. Therefore, the pH of the pharmaceutical preparation is preferably controlled in the range of 4 to 8 by the amount of the basic substance or absorption enhancer mixed, described above.

In addition to the components described above, animal oils and fats, waxes, hydrocarbons, antiseptics, wetting agents and the like can also be added and mixed. Examples of animal oils and fats include beef, pork and horse fat, and the like. Examples of waxes include microcrystalline wax, montane wax, beeswax and the like. Examples of hydrocarbons include paraffin, ceresin and the like. Examples of antiseptic agents include methylparaben, propylparaben, butylparaben, and the like. Examples of wetting agents include multivalent alcohols such as glycerol, 1,3-butylene glycol, propylene glycol, dipropylene glycol and the like. These additives can be mixed in the amounts commonly used for creams and ointments.

EXAMPLES

The present invention is explained in more detail with reference to the following Examples.

Example 1

The mass component. %

(1) Nimesulide (particle diameter: 5 to 20 pm) 3 (2) Carboxyvinyl polymer 1 (3) Diisopropyl sebacate 5 (4) Isopropyl myristate 10 (5) Crotamiton 3 (6) Polyoxyethylene (20) sorbitan monostearate 5 (7) Methylparaben 0.1 (8) Propylparaben 0.1 (9) Diisopropanolamine 0.5 (10) Purified water 72.3

100.0

Components (3), (4), (5), (6) and (8) were melted at 75 ° C. A solution specially prepared by dissolving component (7) in about 90% of component (10) at 75 ° C was added and the mixture stirred to obtain an emulsification. The component (2) was gradually added at 50 ° C and the mixture was stirred thoroughly. 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 stirred until the mixture became homogeneous to obtain an anti-inflammatory preparation in the form of a cream containing nimesulide.

Example 2

The mass component. %

(1) Nimesulide (particle diameter: 20 to 40 pm) 3 (2) Carboxyvinyl polymer 1 (3) Diisopropyl sebacate 5 (4) Isopropyl myristate 10 (5) Crotamiton 3 (6) Polyoxyethylene (20) sorbitan monostearate 5 (7) Methylparaben 0.1 (8) Propylparaben 0.1 (9) Diisopropanolamine 0.5 (10) Purified water 72.3

100.0

Components (3), (4), (5), (6) and (8) were melted at 75 ° C. A solution specially prepared by dissolving component (7) in about 90% of component (10) at 75 ° C was added and the mixture stirred to obtain an emulsification. The component (2) was gradually added at 50 ° C and the mixture was stirred thoroughly. 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 stirred until the mixture became homogeneous to obtain an anti-inflammatory preparation in the form of a cream containing nimesulide.

Example 3

The mass component. % (1) Nimesulide (particle diameter: 5 to 20 pm) (2) Carboxyvinyl polymer

(3) Diethyl sebakat 5 (4) Fatty acid triglyceride with medium chain 8 (5) Crotamiton 3 (6) Polyoxyethylene (20) sorbitan monostearate 5 (7) Methylparaben 0.1 (8) Propylparaben 0.1 (9) 1- (2-Hydroxyethyl) pyrrolidine 0.5 Q0) Purified water 74.3

100.0

Components (3), (4), (5), (6) and (8) were melted at 75 ° C. A solution specially prepared by dissolving component (7) in about 90% of component (10) at 75 ° C was added and the mixture stirred to obtain an emulsification. The component (2) was gradually added at 50 ° C and the mixture was stirred thoroughly. 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 the mixture became homogeneous to obtain an anti-inflammatory preparation in the form of a cream containing nimesulide.

Example 4

The mass component. %

(1) Nimesulide (particle diameter: 5 to 20 pm) 5 (2) Carboxyvinyl polymer 1 (3) Diethyl sebakat 5 (4) Fatty acid triglyceride with medium chain 8 (5) Crotamiton 3 (6) Polyoxyethylene (20) sorbitan monostearate 5 (7) Methylparaben 0.1

(8) Propylparaben 0.1 (9) 1- (2-Hydroxyethyl) pyrrolidine 0.5 (10) Purified water 72.3

100.0

Components (3), (4), (5), (6) and (8) were melted at 75 ° C. A solution specially prepared by dissolving component (7) in about 90% of component (10) at 75 ° C was added and the mixture stirred to obtain an emulsification. The component (2) was gradually added at 50 ° C and the mixture was stirred thoroughly. 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 stirred until the mixture became homogeneous to obtain an anti-inflammatory preparation in the form of a cream containing nimesulide.

Example 5

The mass component. %

(1) Nimesulide (particle diameter: 0.5 to 10 pm) 3 (2) Carboxyvinyl polymer 1 (3) Diisopropyl adipate 5 (4) Isopropyl myristate 10 (5) 7-Menthol 2 (6) Polyoxyethylene (20) sorbitan monostearate 5 (7) Methylparaben 0.1 (8) Propylparaben 0.1 (9) Diisopropanolamine 0.5 (10) Purified water 73.3

100.0

Components (3), (4), (5), (6) and (8) were melted at 75 ° C. A solution specially prepared by dissolving component (7) in about 90% of component (10) at 75 ° C was added and the mixture stirred to obtain an emulsification. The component (2) was gradually added at 50 ° C and the mixture was stirred thoroughly. 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 stirred until the mixture became homogeneous to obtain an anti-inflammatory preparation in the form of a cream containing nimesulide.

Example 6

The mass component. %

(1) Nimesulide (particle diameter: 0.5 to 10 pm) 0.5 (2) Stearic acid 5 (3) Diisopropyl adipate 3 (4) Cetanol 5 (5) Fatty acid triglyceride with medium chain 7 (6) Polyoxyethylene (23) cetyl ether 3 (Ό Sorbitan monostearate 1 (8) 1,3-Butylene glycol 5 (9) Diisopropanolamine 1 (10) Sodium benzoate 0.1 (ID Purified water 69.4

100.0

Components (2), (3), (4), (5), (6) and (7) were melted at 75 ° C. A solution specially prepared by dissolving components (8), (9) and (10) in component (11) at 75 ° C was added and the mixture stirred to obtain emulsification. Gradually, component (1) was added at 50 ° C or lower, and the mixture was stirred until it became homogeneous to obtain an anti-inflammatory preparation in the form of a cream containing nimesulide.

Example Ί

The mass component. %

(1) Nimesulide (particle diameter: 0.5 to 10 pm) 3 (2) Crotamiton 3 (3) Diethyl sebakat 5 (4) Microcrystalline wax 10 (5) Fatty acid triglyceride with medium chain 7 (6) Propylene glycol fatty acid ester 10 (7) Behenyl alcohol 4 (8) Diisopropanolamine 0.2 (9) Dipropylene glycol 7 (10) Propylene glycol monostearate 7 OD White petrolatum 43.8

100.0

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

Example 8 (Preparation in the form of a dispersive type cream in which the effective ingredient has a particle diameter of 75 to 180 pm)

The mass component. %

(1) Nimesulide (particle diameter: 75 to 180 pm) 3 (2) Carboxyvinyl polymer 1 (3) Isopropyl myristate 15 (4) Polyoxyethylene (20) sorbitan monostearate 5 (5) Methylparaben 0.1 (6) Propylparaben 0.1

(Ό Propylene glycol 3 (8) Diethanolamine 0.5 (9) Purified water 72.3

100.0

Components (3), (4), and (6) were melted to 75 ° C. A solution specially prepared by dissolving components (5) and (7) in about 90% of component (9) at 75 ° C was added and the mixture stirred to obtain an emulsification. The component (2) was gradually added at 50 ° C and the mixture was stirred thoroughly. Then component (1) was gradually added and dispersed by stirring. Then a solution prepared by dissolving component (8) in the remaining component (9) was added and the mixture stirred until the mixture became homogeneous to obtain an anti-inflammatory preparation in the form of a cream containing nimesulide.

Reference Example (Cream preparation in which the effective ingredient is dissolved)

The mass component. %

(1) Nimesulide 3 (2) Carboxyvinyl polymer 1 (3) Isopropyl myristate 15 (4) Polyoxyethylene (20) sorbitan monostearate 5 (5) Methylparaben 0.1 (6) Propylparaben 0.1 (7) 1,3-Butylene glycol 3 (8) Diethanolamine 6 (9) Purified water 66.8

100.0

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

Test Example 1: Suppression test for carrageenan-induced rat edema

The anti-inflammatory efficacy of the cream formulations of Examples 1, 2, 5, 7 and 8 and the Reference Example, as well as the commercially available indomethacin-containing cream formulation, was investigated on the basis of suppression of carrageenin-induced rat edema.

Test method

The test substance was applied to the sole of the right foot of male Wister rats weighing 132 to 150 g, and fixed to the right sole with a cover film. When applied, the animals were fitted with a plastic collar and transferred to individual cages to prevent the drug from being consumed. After 4 hours of application, the product was completely removed with absorbent cotton wool. Subsequently, saline containing 1% carrageenin (0.1 ml) was injected subcutaneously into the sole of the foot. After three hours, the volume of the leg was measured and the degree of swelling (edematization) was calculated based on the volume of the leg before the injection of the prophlogistic substance. The test results are shown in Table 1.

Table 1

The pattern (plural given: lOOmg / locus) Number of animals Rate of edematization (%) (after 3 hours) Control 8 77.6 Cream preparation from Of Example 1 8 38.9

Cream preparation from Of Example 2 8 35.1 Cream preparation from Of Example 5 8 45.6 Cream preparation from Of Example 7 8 50.6 Cream preparation from Of Example 8 8 64.6 Cream preparation from Reference case 8 53.1 Cream preparation from available indomethacin 8 68.6

The results in Table 1 clearly show that the pharmaceutical preparations of Examples 1, 2, 5, 7 and 8 showed a better anti-inflammatory effect compared to the commercially available formulation in the form of an indomethacin-containing cream, and was even or higher in compared to the cream formulation of Reference Example containing nimesulide in the dissolved state.

Test Example 2: Staining test

Preparations in the form of cream according to the present invention and according to the Reference Example were prepared and coated with a cotton cloth and the degree of staining was observed. The test results are shown in Table 2.

The pattern

The cream formulation of Example 1

The cream formulation of Example 2

Preparation in the form of a cream from the Reference Example

Appearance at the time of preparation Light yellowish white cream Light yellowish white cream Yellow cream

Fabric staining

Almost no staining

Almost no staining

Yellow colored

As can be clearly seen from Table 2, the fabric was stained in the case of the cream in the Reference Example containing nimesulide in the dissolved state, while the cream compositions of Examples 1 and 2 of the present invention showed almost no staining.

Applicability of the invention

An anti-inflammatory exterior agent of the present invention, in which nimesulide is mixed in a dispersed state, has pharmacological effects equal to or greater than those of the solution type preparations, but does not cause skin irritation, is safe and does not contaminate the skin and clothing colored. Therefore, the product of the present invention is extremely useful as an agent in the field of dermatology for the care or treatment. treatment of eczema, dermatitis, etc., and as an anti-inflammatory preparation for external use, in the field of orthoses for the treatment of chronic rheumatism of the extremities, osteoarthritis, periarthritis of the shoulder joint, peritendinitis, myalgia and swelling and pain after injury.

For

HELSINN HEALTHCARE SA:

Claims (14)

PATENT APPLICATIONS What is claimed is: 1. An anti-inflammatory exterior use agent containing nimesulide as an effective ingredient and a basic component, characterized in that nimesulide is incorporated into the basic component in a dispersed state. 2. The anti-inflammatory exterior use according to claim 1, characterized in that the nimesulide is mixed in an amount of 0.1 to 5% by weight. 3. The anti-inflammatory exterior use according to claim 1, characterized in that it has a pH of from 4 to 8. 4. The anti-inflammatory exterior use according to claim 1, characterized in that the basic component comprises a hydrophilic polymer, white petroleum, an oily substance, a non-ionic surfactant, water, a basic substance and / or an absorption enhancer. An anti-inflammatory exterior use according to claim 4, characterized in that the absorption enhancer is an organic base, a crotamiton, a medium chain fatty acid ester, / -mentol and / or benzyl alcohol. 6. An anti-inflammatory exterior use according to claim 5, characterized in that it is organic. base diisopropanolamine, meglumine, triethanolamine and / or 1- (2-hydroxyethyl) pyrrolidine. 7. An anti-inflammatory exterior agent according to any one of claims 1 to 6, characterized in that the dosage form is a cream formulation. 8. An anti-inflammatory exterior use according to claim 7, characterized in that the nimesulide in an amount of 0.1 to 5% by weight is blended into a gel cream base containing a hydrophilic polymer in the amount of 0.2 to 3% by weight, an oily substance. in an amount of 2 to 20% by weight, a non-ionic surfactant in an amount of 0.5 to 7% by weight, a basic substance in the amount of 0.01 to 5% by weight and water in an amount of 50 to 90% by weight. An anti-inflammatory exterior agent according to any one of claims 1 to 7, characterized in that the dosage form is an ointment formulation. 10. An anti-inflammatory exterior agent according to claim 9, characterized in that nimesulide in an amount of 0.1 to 5% by weight is mixed into a basic component of petroleum ointment containing white petroleum 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 non-ionic surfactant in an amount of 0.5 to 7% by weight. A process for the manufacture of an anti-inflammatory exterior agent, characterized in that it comprises the stepwise addition of nimesulide as an effective fine particulate ingredient to the base component and the dispersion of nimesulide by mixing. Process according to claim 11, characterized in that the molten oil component is used as a basic component by heating. Process according to claim 11, characterized in that the oil phase with the heat of the molten oil components and the aqueous phase in which the water-soluble components are dissolved are mixed by mixing and used as a basic component. A method according to any one of claims 11 to 13, characterized in that nimesulide with an average particle size of 0.01 to 75 µm is used as fine particle nimesulide.