FI118953B - Inflammatory, nimesulide containing substance for external use - Google Patents

Description

118953

Externally used Nimesulide anti-inflammatory agent Inflammationsmotverkande, nimesulid innefattande ämne för utvärtes användning 5 Industrial applicability

The present invention relates to an topically applied anti-inflammatory agent comprising nimesulide as an active ingredient. More particularly, the present invention relates to an topically applied anti-inflammatory agent comprising the active ingredient nimesulide and a base component wherein the nimesulide is in dispersed form mixed with this base component.

BACKGROUND OF THE INVENTION Non-steroidal anti-inflammatory preparations have the disadvantage that they cause gastrointestinal disorders when administered orally. To avoid this disadvantage, numerous studies have been carried out in the art to develop topically applied anti-inflammatory agents, and numerous commercial products have been obtained for clinical use. , to work. However, the clinical effects of the exogenously developed anti-inflammatory agents hitherto developed are insufficient, although they appear to be active in the basic experiments.

• · · · · · · · · ·

Nimesulide (4-nitro-2-phenoxymethane sulfonanilide), a non-steroidal anti-inflammatory agent, was first synthesized by Riker Co. In the United States, followed by the Helsinn Co. of Switzerland developed it into an oral * * · * · formulation in Europe. It is known that, unlike conventional acidic anti-inflammatory agents, nimesulide selectively inhibits PGE2 (COX2) and is a novel type of · · ·,. |; a pharmaceutical agent which is expected to be clinically useful.

With regard to the state of the art in the field of nimesulide, a patent for a drug may be mentioned. nita U.S. Patent No. 3,480,597, and method patents include the Japanese Patent Publication (Kokoku) Sho-58-35989, Japanese Patent Publication No. 118953 2 (Kokoku) Sho-58-50984 and Japanese Patent Publication (Kokoku). Patent Publication (Kokoku) Sho-59-44311. However, these state-of-the-art references do not describe the actual pharmaceutical formulations or their working indications, although dosage forms such as capsule, ointment, gel, patch and the like are mentioned.

In addition, a published Japanese Patent Application (Kohyo) Hei-6-502842, based on the International Patent Application, may be cited as a literature reference for a pharmaceutical preparation of nimesulide. According to this patent, nimesulide 10 is formulated with a cyclodextrin to provide a water-soluble form of nimesulide, thereby improving the water-solubility of nimesulide and its absorption in the gastrointestinal tract. Therefore, this publication is not intended for external use. Thus, there is no reference in the appended claims illustrating the use of nimesulide as an externally applied preparation, nor is there any case where nimesulide is actually externally used as a specific dosage form.

This may be due to the fact that while nimesulide has indomethacin, which is considered to be · · *. *: as a potent anti-inflammatory agent, compared to similar or superior pharmacological effects, however, there are many unsolved problems when used topically as an external preparation. In other words, (1) • · · ”nimesulide is sparingly soluble and is not readily soluble in water or in various organic solvents. (2) In order to dissolve a nimesulide, it must be mixed with a solvent having a strong dissolving effect. however, encountering problems such as skin irritation, skin roughening, itching and redness (3) The resulting pharmaceutical product is deeply soluble when the nimesulide dissolves. yellow, and therefore poor in appearance. (4) The used pharmaceutical preparation stains clothing in contact with the preparation.

Thus, the premise is that the goal of using nimesulide was abandoned in the industry. ': As an external preparation.

3, 118953

Problems to be solved by the invention

It is an object of the present invention to provide an externally used anti-inflammatory agent containing nimesulide, which is an externally applied nimesulide preparation, which has excellent absorption and does not pose a problem in terms of ambush or skin safety.

As a result of extensive research, taking into account the above-mentioned drawbacks associated with nimesulide as an externally used preparation, the present inventors have found that all of the drawbacks described above can be overcome by an externally used anti-inflammatory agent comprising nimesulide as the active ingredient and nimesulide. is in dispersed form in an amount of 0.1 to 15% by weight mixed with a gelatinous ointment base comprising an amount of hydrophilic polymer in an amount of 0.2 to 3% by weight, an oily substance in an amount of 2 to 20% by weight, an amount of active substance in the range of 0.5 to 7% by weight, an alkaline agent in the range of 0.01 to 5% by weight • · * .1 ·; and water in an amount of 50 to 90% by weight. In other words, when nimesulide is formulated according to claim 1, it surprisingly exhibits pharmacological effects that are similar or superior to a pharmaceutical preparation to which nimesulide has been administered. • in a soluble form, the amount of solubility enhancer can be reduced, and thus the safety of the skin is improved. ”It remains to be seen that the pharmaceutical,. · · In a pharmaceutical formulation, in other words, all of the above-mentioned problems associated with an externally applied preparation are solved.

The active ingredient nimesulide may be used in any form as long as it is present in the dispersed form in the base component. Preferably, the average particle size of the nimesulide is 0.01 µm or more. On the other hand, with respect to transdermal absorption and sensation of application (rough feel), the particle size is preferably 75 µm or less, that is to say, 200 mesh permeable particle sizes and more preferably 5 to 50 µm.

The externally applied anti-inflammatory agent of the present invention may be prepared as follows. For example, the ointment is prepared by mixing and stirring with an oil phase consisting of melted oil components 10 and an aqueous phase in which the water-soluble components are dissolved; adding nimesulide as fine particles; and then further mixing and cooling is carried out.

It is desirable to adjust the pH of this pharmaceutical preparation to a range of 4 to 8, preferably 15 to 7, for skin irritation and absorption through the skin.

The basic material from which the externally applied, anti-inflammatory agent of the present invention can be made is a so-called gel cream comprising a hydrophilic polymer, an oily substance, a nonionic surfactant, an alkaline base. substance and water. The most preferred pharmaceutical formulation for transdermal absorption as a solid ointment is one obtained by mixing 0.1 to 5% by weight of nimesulide in a so-called gel cream base comprising 0.2 to 3%. % by weight of hydrophilic polymer, 2-20% by weight of oily substance, 0.5-7% by weight of non-ionic • · · * surfactant, 0.01-5% by weight of basic material and 50- 90% by weight of water.

25 • ♦ * • · · l, '. Examples of a hydrophilic polymer include carboxyvinyl polymers (CARBOPOL 940, 941 manufactured by BF Goodrich Chemical Co., HIBIS-WAKO 104, 105 manufactured by Wako Pure Chemical Industries, Ltd., and • · * ·; · * Others), hydroxypropyl cellulose (HPL-L, HPC-M manufactured by a * ·, · · · · · · · · · · · · · · · · · · · · · · · 30 Nippon Soda Co., Ltd. and the like), polyoxyethylene polyoxypropylene block copolymer (Lutrol F68, manufactured by BASF Co., and the like) These hydro- 118953 5 polymers can be used singly or in a mixture of two or more and are mixed in an amount of 0.2 to 3% by weight, preferably 0.5 - 2% by weight for viscosity and tackiness of the ointment.

Examples of an oily substance include fatty acid esters such as diisopropyl adipate, diisopropyl sebacate, diethyl sebacate, medium-length fatty acid triglycerides, medium-length fatty acid 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, cetostealyl alcohol, oleyl alcohol, behenyl alcohol and the like; hydrocarbons such as white pharmaceutical petrolatum, liquid paraffin, squalene and the like; vegetable oils and fats such as olive oil, hobo oil, castor oil, and the like; and other oily substances such as crotamitone, benzyl alcohol and the like. The oily substance is preferably mixed in an amount ranging from 5% to 15% by weight with respect to spreadability, dermal absorption, tackiness, gloss and unsteadiness in the preparation of the formulations (e.g. liquid separation) and the like.

• ·

Exemplary surfactants include zybitol fatty acid esters, such as sorbitan monostearate, sorbitan sesquistearate, and the like; glyse- mm m mmm! Role fatty acid esters such as glycerol monostearate, diglyceryl mono-oleate and the like; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan mono-oleate and the like; polyethylene glycol fatty acid esters such as polyoxyethylene (10) mono-. 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) octylphenyl ether and the like and polyoxyethylene (10) hydrogenated castor oil, polyoxyethylene (10) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil and the like These surfactants may be used alone or in a mixture of two or more, in the range of 0.5 to 7% by weight, e. in an amount of from 1 to 5% by weight.

Examples of a basic substance include inorganic and organic bases such as potassium hydroxide, sodium hydroxide, triethanolamine, diisopropanolamine, monoethanolamine and the like, and organic bases are preferred for percutaneous absorption. These basic substances may be mixed in an amount ranging from 0.01 to 5% by weight, preferably 0.1 to 2% by weight.

Further, in order to improve the absorption of nimesulide through the skin, the above described pharmaceutical preparation may be mixed with an absorption enhancer, depending on the use of the pharmaceutical preparation. Examples of absorption enhancers include organic bases, crotamiton, medium-length fatty acid esters, 1-menthol, benzyl alcohol, and the like. The organic base 15 facilitates the release of the nimesulide from the basic component as it renders the nimesulide water-soluble by forming a salt with it. Examples of the organic base include diisopropanolamine, noluminium, triethanolamine, and 1- (2-hydroxyethyl) pyrrolidine, with diisopropanolamine and 1- (2-hydroxyethyl) pyrrolidone · * * · * · * · being the most preferred. in the range of 0.1 to m · · *] “· * 20 in an amount of 20% by weight, preferably 0.2 to 10% by weight, either • · · * (1 alone or in a mixture of two or more.

The above-described basic substance and the organic base acting as an absorption enhancer also act as a pH-adjusting agent in the preparation. In other words, when the pH of the pharmaceutical preparation is too low (e.g. 3 or less), then high acidity severely irritates the skin. When the pH is too high (eg 9 • 4 or more), the absorption of the drug through the skin is reduced, the skin is irritated | * intensified and the pharmaceutical preparation becomes yellow in color. Thus, the pH of this pharmaceutical bulk preparation is preferably adjusted to a range of 4-8 to the amount of a basic substance or absorption enhancer described above to be blended with 30%. .

118953 7

In addition to the components described above, oils and fats of animal origin, waxes, hydrocarbons, antiseptics, wetting agents and the like may be added and mixed. Examples of animal oil and fat include beef fat, pig fat, horse oil and the like. Examples of waxes include microcrystalline wax, montan wax, beeswax and the like. Examples of hydrocarbons include paraffin, ceresine and the like. Examples of antiseptic agents include methylparaben, propylparaben, butylparaben and the like. Examples of wetting agents include polyhydric alcohols such as glycerol, 1,3-butylene glycol, propylene glycol, dipropylene glycol-10, and the like. These additives may be admixed in amounts commonly used in solid cream and lotion formulations.

EXAMPLES 1S The present invention is illustrated in more detail with reference to the following examples.

Example 1 • Component 1% by weight · · · · ·, 2I (1) Nimesulide (particle diameter 5 - 20 µm) 3 • # ♦ *, 1. (2) Carboxyvinyl polymer 1 • # ··.! (3) Diisopropyl sebacate 5 • ·· (4) Isopropyl myristate 10 • ♦ «« * (5) Crotamitone 3, (6) Polyoxyethylene (20) Sorbitan monostearate 5 (7) Methylparaben 0.1 7 (8) Propyl Paraben 0.1 * 1 (9) Diisopropanolamine 0.5 ··· (10) Purified Water 72.3 100.0 * ♦ · • · · ·· 2 • 1 8 11: 89¾ 3

Components (3), (4), (5), (6) and (8) were thawed at 75 ° C. Then, a solution prepared separately by dissolving component (7) in about 90% component (10) at 75 ° C was added and the mixture was stirred to emulsify. Component (2) was added gradually at 50 ° C and the mixture was thoroughly mixed. The 5 component (1) was then added gradually and dispersed with stirring. Thereafter, a solution prepared by dissolving component (9) in the remainder of component (10) was added and the mixture was stirred until homogeneous to give a nimesulide solid ointment anti-inflammatory preparation.

Example 2

Component% by weight (1) Nimesulide (particle diameter 20-40 µm) 3 (2) Carboxyvinyl polymer 1 (3) Diisopropyl sebacate 5 (4) Isopropyl myristate 10 (5) Crotamitone 3 (6) Polyoxyethylene (20) Sorbitan monostearate 5 ·. * ·· (7) Methyl Paraben 0,1 · · ·, (8) Propyl Paraben 0,1 me • *. * (9) Diisopropanolamine 0,5 · * ·: (10) Purified Water 72 , 3 F '»100,0 • · · • · e • ·«

Components (3), (4), (5), (6) and (8) were thawed at 75 ° C. A solution prepared separately by dissolving component (7) in about 90 ··· i · * ··· * 15% of component (10) at 75 ° C was then added and the mixture mixed to emulsify it. The Component (2) component (2) was gradually added at 50 ° C and the mixture was thoroughly mixed. The * * component (1) was then added gradually and dispersed with stirring. Then: V: a solution prepared by dissolving component (9) in the remainder of component (10) * 118953 and stirring until homogeneous to give nimesulide is a solid ointment that produces inflammation.

Example 3 5

Component% by weight (1) Nimesulide (particle diameter 5-20 µm) 3 (2) Carboxyvinyl polymer 1 (3) Diethyl sebacate 5 (4) Medium fatty acid triglyceride 8 (5) Crotamitone 3 (6) Polyoxyethylene (20) Sorbitan monostearate 7) Methylparaben 0,1 (8) Propylparaben 0,1 (9) 1- (2-hydroxyethyl) pyrrolidime 0.5 (10) Purified water 74.3 100.0, ·, · Components (3), (4) , (5), (6) and (8) were thawed by heating at 75 ° C. Then add- • # ·. a solution prepared separately by dissolving component (7) in about 90 · · · ··· »i1. % component (10) at 75 ° C, and the mixture was stirred to emulsify. The component: (2) was added gradually at 50 ° C and the mixture was thoroughly mixed. Then, 1 of component (1) was added gradually and dispersed with stirring. Thereafter, a · · · f Y · solution prepared by dissolving component (9) in the remainder of component (10) was added and this mixture was stirred until it became homogeneous, whereby · · ·. V was obtained as an anti-inflammatory preparation containing nimesulide as a solid ointment.

• M

• 1. _ • · 15 *: ··· Example 4 · «· • · · ·· 1 .1. Component Weight% • · · l 1. (1) Nimesulide (particle diameter 5-20 µm) 5 · · · · ··· (2) Carboxyvinyl polymer 1 10 1 18953 (cont.)

Component% by weight (3) Diethyl sebacate 5 (4) Medium fatty acid triglyceride 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 thawed at 75 ° C. A solution prepared separately by dissolving component (7) in about 90 to 5% component (10) at 75 ° C was then added and the mixture stirred to emulsify. Component (2) was added gradually at 50 ° C and the mixture was thoroughly mixed. Component (1) was then added gradually and dispersed with stirring. Thereafter, a solution prepared by dissolving component (9) at the end of component (10) was added. . and this mixture was stirred until homogeneous to give a nimesulide solid ointment anti-inflammatory preparation.

• • · • φ · * * · t ·, ·,; Example 5 *

Component% by weight (1) Nimesulide (particle diameter 0.5-10 µm) 3: 1 · *; (2) Carboxyvinyl Polymer 1: ***: (3) Diisopropyl adipate 5 · · · t 4 [t] (4) Isopropyl myristate 10 • m (5) 1-Menthol 2 · · * ”(6) Polyoxyethylene (20) monostearate 5 * · * · * (7) Methyl Paraben 0,1 • · • «* *! (8) Propyl Paraben 0,1 π 118953 (Continued)

Component Weight% (9) Diisopropanolxinine 0.5 (10) Purified water 73.3 100.0

Components (3), (4), (5), (6) and (8) were thawed at 75 ° C. A solution prepared separately by dissolving component (7) in about 90 to 5% component (10) at 75 ° C was then added and the mixture stirred to emulsify. Component (2) was added gradually at 50 ° C and the mixture was thoroughly mixed. Component (1) was then added gradually and dispersed with stirring. Thereafter, a solution prepared by dissolving component (9) in the remainder of component (10) was added and stirred until homogeneous to give a nimesulide solid ointment anti-inflammatory preparation.

Example 6

Dispersion-type ointment formulation having an active agent particle diameter of: 15 76-180 µm *: * Component Weight% (1) Nimesulide (particle diameter 75-180 µm) 3 (2) Carboxyvinyl Polymer 1 (3) Isopropyl Myristate 15 (4) Polyoxyethylene (20) Sorbitan Monostearate 5: V: (5) Methyl Paraben 0.1 (6) Propyl Paraben 0.1 (7) Propylene Glycol 3 • ·. ··· . (8) Diethanolamine 0.5 • · (9) Purified water 72.3 • * · —---- ... I. .....................

• * * - ΑΛ _ • · 100.0 • · 1 • · · · · · 118953 12

Components (3), (4) and (6) were thawed by heating at 75 ° C. A solution prepared separately by dissolving components (6) and (7) in about 90% of component (9) at 75 ° C was then added and the mixture was stirred to emulsify. Component (2) was added gradually at 50 ° C and the mixture was thoroughly mixed. Component (1) was then added gradually and dispersed with stirring. A solution prepared by dissolving component (8) in the remainder of component (9) was then added and stirred until homogeneous to give a nimesulide solid ointment anti-inflammatory preparation.

10 Reference Example

A solid ointment preparation in which the active ingredient is dissolved

Component% by weight (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 • · • 1 · 15 Components (3) , (4) and (6) were thawed by heating at 75. A solution prepared separately by dissolving components (5) and (7) in about 90% of component (9) at 75 was added. Component (2) ··· • · · ··· 1 was added gradually at 50 ° C and the mixture was stirred to dissolve component (2).

The component (1) was then added gradually and stirred with stirring. Thereafter, a solution prepared by dissolving component (8) in the remainder of component (9) 118953 13 was added and the mixture was stirred until homogeneous to give a nimesulide solid ointment with an anti-inflammatory preparation.

Test Example 1

Experiment for Rat Paw Carrageenan-Induced Edema Suppression In this example, the rat paw carrageenan-induced edema suppression test was performed with solid ointment formulations of Examples 1,2, 5 and 6 and the anti-inflammatory activity in preparation.

15

Experimental Procedure

The test substance was applied to the bottom of the right paw of male Wistar rats weighing 132 to 150 g each, and this bottom of the right paw was fixed by covering it with a wrapper. After application of the drug an animal collar was placed in a plastic collar and each animal was placed in its own cage to prevent the drug from getting into the animal's mouth. After 4 hours of application, the drug was completely removed from the warm water-absorbent cotton • · · * «Φ * Immediately thereafter, the foot paw was injected subcutaneously .t 25 saline containing 1% carrageenan (0.1 ml) Paw volume • · · ii! after 1 hour, and the degree of edema was calculated based on the volume of the paw φ · • t before the The experimental results are shown in Table 1.

• · · »1 • • • • • • • • • • •••••• 118953 14

Table 1 Sample (amount given: 100 mg / point) Number of animals. Swelling rate (%) (after 3 hours)

Comparison 8 77.6

The ointment preparation of Example 1 8 38.9

The cream preparation 8 of Example 2 35.1

The ointment preparation 8 of Example 5 45.6

The ointment preparation of Example 6 8 64.6

Ointment according to the reference example

Commercially available ointment containing indomethacin 8 68.6

From the results shown in Table 1, it is clear that the pharmaceutical formulations of Examples 1, 2, 5 and 6 achieved excellent anti-inflammatory activity compared to the commercially available indomethacin containing formulation, which is as good as or greater than that of the reference example. effect of the preparation containing mesulide in dissolved form.

. ·. ; Experimental Example 2: Dyeing Test • * «: 7: 10] · *** The ointment preparation of the present invention and the ointment according to the Reference Example were prepared and applied to a cotton cloth, and the intensity of the dyeing. . * * was found. The experimental results are shown in Table 2.

• · • · ♦ • • o * · ♦ 15 Table 2 Sample Appearance of Fabric * ·.!: * Dyeing at the time of manufacture • · _ ... .--- -____ a · —.......-... ... -------

Slightly yellowish According to example 1 Slightly yellowish: **: White ointment ointment: *** · Slightly yellowish Slightly yellowish according to example 2. ·. ointment white ointment • · · I —Il 1 * · * ·] In the reference example, ointment yellow *. **: compliant ointment yellow 118953 15

As clearly shown in Table 2, the fabric was leached in the case of the nimesulide dissolved ointment formulation of the Reference Example, while in the formulations of Examples 1 and 2 of the present invention, almost no leaching was observed.

Effect of the Invention The externally used, anti-inflammatory agent in admixture with nimesulide in dispersed form has pharmacological effects similar to or better than those of the reconstituted formulation, it does not irritate the skin, it is safe, and it does not stain the skin or clothes because it does not. not colored. Accordingly, the present invention is a very useful dermatological agent for treating dermatitis, dermatitis and the like, as well as an topically applied, anti-inflammatory preparation in the field of postural defects (orthosis) in chronic rheumatoid arthritis, peripheral arthritis, and to treat pain.

• * * · · • »· • · · · · · · · ······················································ • • • • • • • 4 4 44 44 · · 4 4 4 4 4 4 • 44 4 4 4 4 4 444 4 · 4 4 444 4 4 4 4 4 44 4 4 4 4 444 4 4 4 • 44 • 44 4 4 4 4 4 ·· • 4 · 4 4

Claims (3)

An exogenous anti-inflammatory agent comprising nimesulide as active ingredient and a basic component, characterized in that the nimesulide is in dispersed form in an amount of from 0.1 to 5% by weight mixed with a gelatinous ointment base comprising a hydrophilic polymer in the range of 0 , In an amount of 2 to 3% by weight, in an amount of 2 to 20% by weight of an oily substance, in an amount of 0.5 to 7% by weight of a nonionic surfactant, in the range of 0.01 to 5% by weight of an alkaline substance and water in an amount of 50 to 90% by weight in the range of 10. 2. An exogenous anti-inflammatory agent according to claim 1, characterized in that said basic substance is diisopropanolamine, megumumin, triethanolamine and / or 1- (2-hydroxyethyl) pyrrolidine. 15 3. An exogenous anti-inflammatory agent according to claim 1, characterized in that the average particle diameter of the nimesulide is 0.01 to 75 µm. • · ♦ 1 1 • · · • • • • • • • • • • • • • • • • •••••••••••••••••••••••••••••• ·••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 1 • ·· n 118953