JP2894843B2 - Topical anti-inflammatory agent - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to an external anti-inflammatory agent containing nimesulide as an active ingredient, and more particularly, nimesulide as an active ingredient is compounded in a dispersed state in a base ingredient. The present invention relates to an external anti-inflammatory agent and a method for producing the same.

2. Description of the Related Art Nonsteroidal anti-inflammatory drugs, when taken as an oral preparation, cause gastrointestinal tract disorders, which is cited as a drawback.To avoid this, various studies have been made to develop an external preparation, Several products are already in clinical use. However, conventional non-steroidal anti-inflammatory drugs for external use have not been effective enough in clinical practice even though they are effective in basic tests.

On the other hand, one of the non-steroidal anti-inflammatory drugs is Nimesulide (Nimesulide: 4-nitro-2-phenoxymethanesulfonanilide), which was synthesized by Leica in the United States and then orally in Europe by Helsin in Switzerland. Developed as an agent. Unlike conventional acidic anti-inflammatory drugs, it is known to selectively suppress PGE2 (COX2), and thus this nimesulide is a new type of drug that is expected to have clinical effects.

As prior art related to nimesulide, a substance patent is disclosed in U.S. Pat. No. 3,480,597, and a manufacturing patent is disclosed in Japanese Patent Publication No. 58-359.
No. 89, JP-B-58-50984 and JP-B-59-443
No. 11 publication. In these prior art documents, although the dosage forms such as capsules, creams, gels, and tapes are mentioned for the time being, no description or examples relating to specific formulations are given.

On the other hand, as a literature on nimesulide preparations, there is JP-A-6-502842. This is because Nimesulide is made into an inclusion compound with cyclodextrin to improve solubility as a water-soluble substance and enhance absorption in the gastrointestinal tract, and is not intended for external use. As described above, there is no known document that specifically shows the use of nimesulide as an external preparation, and no actual use of nimesulide in a specific dosage form has been known so far.

This suggests that although nimesulide has a pharmacological effect equal to or better than that of indomethacin, which is a potent anti-inflammatory drug, there are some insurmountable challenges when topically applying it as an external preparation. It is thought to be due to holding. That is, nimesulide is very poorly soluble and hardly soluble in water or various organic solvents. In order to dissolve it, it is necessary to add a solvent having a strong dissolving power, but in that case, there is a problem of causing skin irritation, rough skin, itching or redness. Even if Nimesulide is forcibly dissolved, the preparation becomes dark yellow and has a poor appearance. The applied formulation stains the clothing that comes into contact with it.

For this reason, at present, it has been necessary to give up using nimesulide as an external preparation.

An object of the present invention is to provide a topical anti-inflammatory agent for external use which is a highly absorbable nimesulide external preparation and has no problems such as coloring property and skin safety.

Means for Solving the Problems The present inventors have conducted intensive studies in consideration of the above-mentioned drawbacks of nimesulide as a topical drug, and found that the above problems were caused by compounding nimesulide in a dispersed state in a base component. Found out that they could all be solved at once, and completed the present invention. That is, surprisingly, when Nimesulide is blended in a base component in a dispersed state, it exhibits a pharmacological effect equal to or higher than that of a formulation blended in a soluble form, and requires less blending of a solubilizer.
It has been found that the skin safety is enhanced, and unlike the complete dissolution type preparation, the preparation is no longer colored, and all the above problems can be solved as an external preparation.

More specifically, by mixing nimesulide as an active ingredient in a dispersed state in a base component containing an oily substance, a nonionic surfactant, a basic substance, water and / or an absorption promoter, The object of the present invention is achieved. More specifically, an external preparation such as a cream or an ointment is prepared by dispersing and mixing 0.1 to 5% by weight of nimesulide, which is an active ingredient, in the form of fine particles with a hydrophilic polymer or white petrolatum added as a base. I do.

Nimesulide, which is an active ingredient, can be used in any form as long as it exhibits a dispersed state in the base component. Is preferably 0.01 μm or more,
On the other hand, from the viewpoint of percutaneous absorbability, sensitivity at the time of application (graininess), it is 75 μm or less, that is, it is preferable to pass through a 200-mesh sieve, more preferably 0.5 to 50 μm,
More preferably, it is 1 to 30 μm.

The production of the anti-inflammatory agent for external use of the present invention is, for example, in a cream, an oil phase obtained by heating and dissolving an oil component and an aqueous phase dissolving a water-soluble component are mixed and stirred, and the finely divided nimesulide is further added thereto. It is manufactured by stirring and cooling. In the cartilage,
While stirring and cooling the oil component dissolved by heating, finely divided nimesulide is added and the mixture is further stirred and cooled to produce the oil component.

The pH of the preparation is preferably adjusted to 4 to 8 from the viewpoints of coating irritation and transdermal absorption, more preferably 5 to 8.
~ 7.

Examples of the base for producing the topical anti-inflammatory agent of the present invention include a hydrophilic polymer, an oily substance, a nonionic surfactant, a basic substance, a so-called gel cream composed of water,
Vanishing type cream made from higher alcohols, hydrocarbons, fatty acid esters, polyhydric alcohols, bases, preservatives, water, etc., white petrolatum, surfactants, higher alcohols, hydrocarbons, fatty acid esters, polyhydric alcohols, preservatives Cream and hydrophilic ointment or absorption ointment of the Japanese Pharmacopoeia manufactured from water and water, and FAPG bases composed of higher alcohols and polyhydric alcohols, among others. So-called gel-like cream base consisting of 0.2 to 3% by weight of a functional polymer, 2 to 20% by weight of an oily substance, 0.5 to 7% by weight of a nonionic surfactant, 0.01 to 5% by weight of a basic substance, and 50 to 90% by weight of water A formulation containing 0.1 to 5% by weight of nimesulide is most suitable from the viewpoint of a transdermal absorption agent. The ointment was formulated by mixing 0.1 to 5% by weight of nimesulide with a vaseline ointment comprising 35 to 80% by weight of white petrolatum, 2 to 20% by weight of an oily substance, and 0.5 to 7% by weight of a nonionic surfactant. Formulations are most preferred.

Next, the base component of the present invention will be described more specifically.

Examples of the hydrophilic polymer include carboxyvinyl polymers (Carbopol 940,941, manufactured by BF Goodrich Co., Ltd., Hibiswako 104, 105 manufactured by Wako Pure Chemical Industries, Ltd.), hydroxypropyl cellulose (HPC-L, HPC-M manufactured by Nippon Soda Co., Ltd.)
And polyoisethylene polyoxypropylene block polymer (such as Lutrol F68 manufactured by BASF). These hydrophilic polymers are used singly or in combination of two or more, and preferably 0.2 to 3% by weight, more preferably 0.5 to 2% by weight, in consideration of the viscosity of the cream and the sticky tube.

Oily substances include diisopropyl adipate, diisopropyl sebacate, diethyl sebacate, medium chain fatty acid triglyceride, medium chain fatty acid propylene glycol,
Fatty acid esters such as isopropyl myristate,
Fatty acids such as stearic acid, oleic acid and myristic acid; higher alcohols such as cetanol, stearyl alcohol, cetostearyl alcohol, octyl alcohol and behenyl alcohol; hydrocarbons such as white petrolatum, liquid paraffin and squalane; and olive oil. And vegetable oils such as jojoba oil and castor oil, and crotamiton and benzyl alcohol. In the case of a cream formulation, the amount of these oily substances may be 2 to 20 in consideration of cream elongation, transdermal absorbability, stickiness, plaque, or instability in the formulation such as liquid separation.
%, Preferably 5 to 15% by weight. In the case of an ointment, 2 to 20% by weight, preferably 3 to 7% by weight is blended.

As a surfactant, sorbitan monostearate,
Sorbitan fatty acid esters such as sorbitan sesquistearate, glycerin fatty acid esters such as glyceryl monostearate and diglyceryl monooleate, and polyoxyethylene (20) sorbitan monostearate and polyoxyethylene (20) sorbitan monooleate Polyethylene glycol fatty acid esters such as oxyethylene sorbitan fatty acid ester, polyoxyethylene (10) monostearate, polyoxyethylene (10) monolaurate, polyoxyethylene (9) lauryl ether, polyoxyethylene (23) cetyl ether, etc. Polyoxyethylene alkyl ethers, such as polyoxyethylene alkyl ethers, polyoxyethylene (10) nonyl phenyl ether, and polyoxyethylene (10) octyl phenyl ether Phenyl ether, polyoxyethylene (10) hardened castor oil, polyoxyethylene (60)
And polyoxyethylene hardened castor oil such as hardened castor oil. These surfactants are blended alone or in combination of two or more, and 0.5 to 7% by weight, preferably 1 to 5% by weight is blended.

Examples of the basic substance include an inorganic or organic base such as potassium hydroxide, sodium hydroxide, triethanolamine, diisopropanolamine, and monoethanolamine, and an organic base is preferable from the viewpoint of transdermal absorption.
These basic substances are contained in an amount of 0.01 to 5% by weight, preferably 0.1 to 5% by weight.
1 to 2% by weight is blended.

Further, for the purpose of enhancing the transdermal absorbability of nimesulide according to the type of the formulation, an absorption enhancer is blended in the above formulation. Examples thereof include organic bases, crotamiton, medium-chain fatty acid esters, 1-menthol, benzyl alcohol and the like. The organic base forms a salt with nimesulide, becomes water soluble and facilitates release of nimesulide from the base. Organic bases include diisopropanolamine, meglumine, triethanolamine, and 1
-(2-hydroxyethyl) pyrrolidine and the like, among which diisopropanolamine and 1- (2-
(Hydroxyethyl) pyrrolidine is most preferred. The compounding amount of the absorption promoter is 0.1 to 20% by weight, preferably 0.2 to 10% by weight, alone or in combination of two or more.

The above-mentioned basic substance or organic base as an absorption enhancer also functions as a pH adjusting agent of the preparation. That is, if the pH of the preparation is too low (for example, 3 or less), the skin irritation becomes too strong due to too strong acid, and if the pH is too high (for example, 9 or more), the transdermal absorbability of the drug becomes poor and the skin irritation also becomes As it becomes stronger, the formulation turns yellow. For this reason, the pH of the preparation is preferably adjusted to 4 to 8 depending on the amount of the basic substance or the absorption promoter.

Animal fats and oils, waxes, hydrocarbons,
Preservatives or wetting agents can be added and blended.
As animal fats and oils, beef tallow, lard, horse oil, etc., as waxes, microcrystalline wax, montan wax, beeswax, etc., as hydrocarbons, paraffin, ceresin, etc., as preservatives, methylparaben, propylparaben, Butyl paraben and the like are used, and polyhydric alcohols such as glycerin, 1,3-butylene glycol, propylene glycol and dipropylene glycol are used as a wetting agent. These additives are used in the amounts used for ordinary creams or ointments.

Examples Hereinafter, the present invention will be described in more detail with reference to Examples.

Example 1 Component Weight% (1) Nimesulide (particle size: 5 to 20 μm) 3 (2) Carboxyvinyl polymer 1 (3) Diisopropyl sebacate 5 (4) Isopropyl myristate 10 (5 Crotamiton 3 (6) Polyoxy Ethylene (20) sorbitan monostearate 5 (7) Methyl paraben 0.1 (8) Propyl paraben 0.1 (9) Diisopropanolamine 0.5 (10) Purified water 72.3 100.0 (3), (4), (5), (6) and (8) at 75 ° C
And dissolved by heating. Separately, about 90% at 75 ℃ (10) (7)
Was added and stirred to emulsify. (2) was gradually added thereto at 50 ° C., followed by sufficient stirring. Next, (1) was gradually added thereto, and the mixture was stirred and dispersed. Next, a solution prepared by dissolving (9) in the remainder of (10) was added thereto, and the mixture was stirred until it became uniform to obtain an anti-inflammatory cream containing Nimesulide.

Example 2 Ingredient% by weight (1) Nimesulide (particle size: 20 to 40 μm) 3 (2) Carboxyvinyl polymer 1 (3) Diisopropyl sebacate 5 (4) Isopropyl myristate 10 (5) Crotamiton 3 (6) Poly Oxyethylene (20) sorbitan monostearate 5 (7) Methyl paraben 0.1 (8) Propyl paraben 0.1 (9) Diisopropanolamine 0.5 (10) Purified water 72.3 100.0 (3), (4), (5), (6) And (8) at 75 ° C
And dissolved by heating. Separately, about 90% at 75 ℃ (10) (7)
Was added and stirred to emulsify. (2) was gradually added thereto at 50 ° C., followed by sufficient stirring. Next, (1) was gradually added thereto, and the mixture was stirred and dispersed. Next, a solution prepared by dissolving (9) in the remainder of (10) was added thereto, and the mixture was stirred until it became uniform to obtain an anti-inflammatory cream containing Nimesulide.

Example 3 Component Weight% (1) Nimesulide (particle size: 5 to 20 μm) 3 (2) Carboxyvinyl polymer 1 (3) Diethyl sebacate 5 (4) Medium chain fatty acid triglyceride 8 (5) Crotamiton 3 (6) Polyoxyethylene (20) sorbitan monostearate 5 (7) Methyl paraben 0.1 (8) Propyl paraben 0.1 (9) 1- (2-hydroxyethyl) pyrrolidin 0.5 (10) Purified water 74.3 100.0 (3), (4) , (5), (6) and (8) at 75 ° C
And dissolved by heating. Separately, about 90% at 75 ℃ (10) (7)
Was added and stirred to emulsify. (2) was gradually added thereto at 50 ° C., followed by sufficient stirring. Next, (1) was gradually added thereto, and the mixture was stirred and dispersed. Next, a solution prepared by dissolving (9) in the remainder of (10) was added thereto, and the mixture was stirred until it became uniform to obtain an anti-inflammatory cream containing Nimesulide.

Example 4 Ingredient% by weight (1) Nimesulide (particle size: 5 to 20 μm) 5 (2) Carboxyvinyl polymer 1 (3) Diethyl sebacate 5 (4) Medium chain fatty acid triglyceride 8 (5) Crotamiton 3 (6) Polyoxyethylene (20) sorbitan monostearate 5 (7) Methyl paraben 0.1 (8) Propyl paraben 0.1 (9) 1- (2-hydroxyethyl) pyrrolidin 0.5 (10) Purified water 72.3 100.0 (3), (4) , (5), (6) and (8) at 75 ° C
And dissolved by heating. Separately, about 90% at 75 ℃ (10) (7)
Was added and stirred to emulsify. (2) was gradually added thereto at 50 ° C., followed by sufficient stirring. Next, (1) was gradually added thereto, and the mixture was stirred and dispersed. Next, a solution prepared by dissolving (9) in the remainder of (10) was added thereto, and the mixture was stirred until it became uniform to obtain an anti-inflammatory cream containing Nimesulide.

Example 5 Component Weight% (1) Nimesulide (particle size: 0.5 to 10 μm) 3 (2) Carboxyvinyl polymer 1 (3) Diisopropyl adipate 5 (4) Isopropyl myristate 10 (5) 1-Menthol 2 (6) ) Polyoxyethylene (20) sorbitan monostearate 5 (7) Methyl paraben 0.1 (8) Propyl paraben 0.1 (9) Diisopropanolamine 0.5 (10) Purified water 73.3 100.0 (3), (4), (5), ( 6) and (8) at 75 ° C
And dissolved by heating. Separately, about 90% at 75 ℃ (10) (7)
Was added and stirred to emulsify. (2) was gradually added thereto at 50 ° C., followed by sufficient stirring. Next, (1) was gradually added thereto, and the mixture was stirred and dispersed. Next, a solution prepared by dissolving (9) in the remainder of (10) was added thereto, and the mixture was stirred until it became uniform to obtain an anti-inflammatory cream containing Nimesulide.

Example 6 Ingredient Weight% (1) Nimesulide (particle size: 0.5 to 10 μm) 0.5 (2) Stearic acid 5 (3) Diisopropyl adipate 3 (4) Cetanol 5 (5) Medium chain fatty acid triglyceride 7 (6) Poly Oxyethylene (23) cetyl ether 3 (7) sorbitan monostearate 1 (8) 1,3-butylene glycol 5 (9) diisopropanolamine 1 (10) sodium benzoate 0.1 (11) purified water 69.4 100.0 (2) , (3), (4), (5), (6) and (7) were dissolved by heating at 75 ° C. Separately at 75 ° C (11)
A solution in which (8), (9) and (10) were dissolved was added and stirred to emulsify. (1) was gradually added thereto at 50 ° C. or lower, and the mixture was stirred until uniformly dispersed to obtain an anti-inflammatory cream containing Nimesulide.

Example 7 Ingredient Weight% (1) Nimesulide (particle size: 0.5 to 10 μm) 3 (2) Crotamiton 3 (3) Diethyl sebacate 5 (4) Microcrystalline wax 10 (5) Medium chain fatty acid triglyceride 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 (11) White petrolatum 43.8 100.00 (2), (3), (4) ), (5), (6), (7),
(8), (9), (10) and (11) were heated and dissolved at 80 ° C. (1) was gradually added thereto at 50 ° C., followed by stirring and dispersion to obtain an anti-inflammatory ointment containing nimesulide.

Example 8 (dispersed cream having a particle diameter of the active ingredient of 76 to 180 μm) Ingredient% by weight (1) Nimesulide (particle diameter: 75 to 180 μm 3 (2) Carboxyvinyl polymer 1 (3) Isopropyl myristate 15 (4) polyoxyethylene (20) sorbitan monostearate 5 (5) methyl paraben 0.1 (6) propyl paraben 0.1 (7) propylene glycol 3 (8) diethanolamine 0.5 (9) purified water 72.3 100.0 (3), (4) And (6) were dissolved by heating at 75 ° C. Separately, about 90% of a solution in which (9), (6) and (7) were dissolved was added at 75 ° C., and the mixture was stirred and emulsified. (2) was gradually added and stirred sufficiently, then (1) was slowly added and stirred to disperse, and then (8) dissolved in the remainder of (9) was added and stirred until uniform. Anti-inflammatory with Nimesulide A cream was obtained.

Reference example (active ingredient-soluble cream) Ingredient% by weight (1) Nimesulide 3 (2) Carboxyvinyl polymer 1 (3) Isopropyl myristate 15 (4) Polyoxyethylene (20) Sorbitan monoostearate 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 (3), (4) and (6) were heated and dissolved at 75 ° C. Separately, a solution in which (5) and (7) were dissolved in about 90% of (9) was added at 75 ° C., and the mixture was stirred and emulsified. (2) was gradually added thereto at 50 ° C., and the mixture was sufficiently stirred and dissolved. Next, (1) was gradually added thereto and dissolved by stirring. Next, a solution prepared by dissolving (8) in the remaining (9) was added thereto, and the mixture was stirred until the mixture became uniform to obtain an anti-inflammatory cream containing Nimesulide.

Test Example 1: Inhibition test of rat carrageenin paw edema Examples 1, 2, 5, 7, 8, Reference Example and a commercially available cream containing indomethacin were examined for their anti-inflammatory effect by suppressing rat carrageenin paw edema.

Test Method A test substance was applied to the right footpad of a male Wistar rat weighing 132 to 150 g, covered with a wrap film and fixed.
When applying the drug, give the animal a plastic neck skein,
Drugs were housed in individual gauges to prevent oral ingestion. Four hours after the application of the drug, the drug was completely removed with absorbent cotton soaked in warm water. Immediately thereafter, 1% carrageenan saline solution was subcutaneously injected (0.1 ml) into the footpad. Three hours later, the paw volume was measured, and the edema rate was determined from the paw volume before injection of the proinflammatory substance. The test results are shown in Table 1.

As is clear from the results in Table 1, Examples 1, 2, 5,
Formulations 7 and 8 exhibited superior anti-inflammatory effects as compared with commercially available indomethacin cream formulations, and showed equivalent or better effects even when compared with the cream formulation in which nimesulide of the reference example was incorporated in a dissolved state. .

Test Example 2: Coloring test The cream preparation of the present invention and the cream preparation of the reference example were experimentally produced, thinly applied to a cotton cloth, and the degree of coloring was observed. The test results are shown in Table 2.

As is clear from Table 2, the cream formulation of the reference example in which nimesulide was blended in a dissolved state colored the cloth, but the cream lumbers of Examples 1 and 2 of the present invention were hardly colored.

The effect of the present invention, an external anti-inflammatory agent in which the nimesulide of the present invention is compounded in a dispersed state has a pharmacological effect equal to or higher than that of a soluble form,
And it is safe without skin irritation and does not stain skin or clothes because there is no coloring. Therefore, the present invention
Eczema, dermatitis, dermatological treatment, or rheumatoid arthritis, osteoarthritis, shoulder periarthritis, tenoscleritis,
It is very useful as an anti-inflammatory external treatment for orthopedic areas such as muscle pain and swelling and pain after trauma.

──────────────────────────────────────────────────続 き Continuing on the front page (51) Int.Cl. ⁶ Identification code FI A61K 47/18 A61K 47/18 47/22 47/22 (72) Inventor Yoichi Kawamura 408, Tadachimachi, Tashiro, Tosu City, Saga Prefecture Hisamitsu Pharmaceutical Co., Ltd. (58) Field surveyed (Int. Cl. ⁶ , DB name) A61K 31 / 18,9 / 10,9 / 16 A61K 47 / 10,47 / 16,47 / 18 A61K 47/22 CA ( STN) MEDLINE (STN)

Claims (14)

(57) [Claims] 1. An external anti-inflammatory agent comprising nimesulide as an active ingredient dispersed in a base component. 2. The topical anti-inflammatory agent according to claim 1, wherein 0.1 to 5% by weight of nimesulide is blended. 3. The external anti-inflammatory agent according to claim 1, wherein the pH is 4-8. 4. The method according to claim 1, wherein the base component contains a hydrophilic polymer, white petrolatum, an oily substance, a nonionic surfactant, water, a basic substance and / or an absorption promoter. Topical anti-inflammatory agent. 5. An absorption enhancer comprising an organic base, crotamiton,
The topical anti-inflammatory agent according to claim 4, which is a medium-chain fatty acid ester, 1-menthol and / or benzyl alcohol. 6. An organic base comprising diisopropanolamine, meglumine, triethanolamine and / or 1- (2-
The topical anti-inflammatory agent according to claim 5, which is (hydroxyethyl) pyrrolidine. 7. The external anti-inflammatory agent according to claim 1, wherein the dosage form is a cream. 8. A hydrophilic polymer of 0.2 to 3% by weight, an oily substance of 2 to 20% by weight, a nonionic surfactant of 0.5 to 7% by weight,
8. The external preparation according to claim 7, wherein nimesulide is incorporated in an amount of 0.1 to 5% by weight in a gel cream base component comprising 0.01 to 5% by weight of a basic substance and 50 to 90% by weight of water. Inflammatory agent. 9. The topical anti-inflammatory agent according to claim 1, wherein the dosage form is an ointment. 10. White petrolatum 35-80% by weight, oily substance 2
Nimesulide is contained in a petrolatum ointment base component consisting of -20% by weight and a nonionic surfactant 0.5-7% by weight.
The anti-inflammatory agent for external use according to claim 9, which is blended by weight. 11. A method for producing an external anti-inflammatory agent, characterized by gradually adding finely divided nimesulide as an active ingredient to a base component, and stirring and dispersing it. 12. The method according to claim 11, wherein an oil component heated and dissolved is used as the base component. 13. The method according to claim 11, wherein the base component is obtained by mixing and stirring an oil phase in which an oil component is dissolved by heating and an aqueous phase in which a water-soluble component is dissolved. 14. The method according to claim 11, wherein the finely divided nimesulide having an average particle diameter of 0.01 to 75 μm is used.