RU2711090C2 - Non-staining gel composition containing nimesulide, for topical application - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention relates to medicine. Disclosed is non-staining gel composition for topical application. Composition contains nimesulide, one or more non-aqueous solvents, one or more gelling agents which do not depend on pH, one or more acidifying agents and, if necessary, one or more pharmaceutically acceptable excipients. PH of said composition is 2–5.EFFECT: invention provides a composition, the use of which does not cause or mainly does not cause skin and/or clothes colouring, while ensuring rapid penetration of nimesulide into the upper skin layer.8 cl, 2 dwg, 4 tbl, 6 ex

Description

FIELD OF THE INVENTION

This invention relates to non-staining gel compositions containing nimesulide for topical application. Also provided is a method for producing such compositions. The present invention also relates to the use of these compositions for relieving pain and inflammation symptoms associated with the musculoskeletal system, osteoarthritis and rheumatoid arthritis.

State of the art

Nimesulide is a non-steroidal anti-inflammatory agent (NSAID) from the sulfonanilide group that has low solubility. It is practically insoluble in water, readily soluble in acetone and slightly in ethyl alcohol. This substance has an antipyretic, analgesic and anti-inflammatory effect. Nimesulide is used to treat osteoarthritis, extra-articular rheumatism, post-traumatic and postoperative inflammatory processes and pain, fever fever and primary dysmenorrhea.

The chemical name of nimesulide is N- (4-nitro-2-phenoxyphenyl) methanesulfonamide; its structure is presented below (1).

(1)

(1)

In most cases, nimesulide is taken orally through the mouth (oral). One of the disadvantages of oral administration of compositions containing nimesulide is that the patient is likely to have negative side effects, including irritation of the gastrointestinal tract. This irritation can lead to chronic dyspepsia, and in some cases it manifests itself quickly spontaneous gastric bleeding, which is a life-threatening condition. Therefore, the use of nimesulide for the relief of local pain and inflammation is problematic - especially for those individuals who have disorders of the gastrointestinal tract. To avoid systemic side effects, it is necessary to develop various forms of nimesulide for topical administration, administered locally.

In the case of compositions containing nimesulide, for topical application, the main difficulty is the need for the drug to penetrate the skin. Nimesulide does not pass well through the skin, and its penetration requires a relatively long period of time after application to the surface of the body. In acute disorders, there is a need to increase the rate of absorption of nimesulide at the injection site.

It is known that surfactants and excipients are used to solve this problem, but the use of these agents has its limitations. In particular, agents that enhance penetration through the skin can cause irritation at the site of primary administration.

Since nimesulide is poorly soluble in water, it was included in pharmaceutical compositions at various concentrations in the form of a suspension in media containing the active ingredient, together with pharmaceutically acceptable excipients. These media usually consist of an aqueous gel containing 1% nimesulide. The therapeutic activity of nimesulide in suspension is limited, since absorption through the skin is insufficient due to the difficulty in releasing the active substance molecules from the suspension. And solubilized nimesulide has the advantage of immediate access of free molecules of the active substance to its place of exposure, and gel preparations containing solubilized nimesulide have been obtained using various pharmaceutical solvents. However, gel products containing solubilized nimesulide, when applied topically, cause unpleasant yellow staining of the skin and / or clothing. A number of patent documents known from the prior art describe non-staining gel compositions containing nimesulide for topical application.

Indian Patent No. 204642 describes a gel composition containing nimesulide for topical application, which includes monoolein (glycerol monooleate) in an amount of 17-59% (weight / weight) of the total weight of the composition. Indian Patent No. 230959 describes a gel composition containing nimesulide for topical application, which includes carbopol as a gelling agent. European Patent No. 2514409 describes a gel composition containing nimesulide for topical application, which includes methylsulfonylmethane. All the works mentioned above claim to offer a non-staining gel composition containing nimesulide, but so far no results or data have been reported in any of the patents in the art that demonstrate the lack of staining.

In an effort to develop a new composition containing nimesulide for topical use, the inventors of the present invention found that the use of one or more non-aqueous solvents, a pH-independent gelling agent and an acidifying agent, allows a therapeutically effective composition containing nimesulide to be produced which, when applied topically, does not or basically does not cause staining of the skin and / or clothes. The composition according to this invention provides the rapid penetration of nimesulide into the upper layer of the skin (stratum corneum of the epidermis). Once in this layer, nimesulide can then go into the deeper layers of the skin already more slowly, which is favorable in the treatment of conditions in which nimesulide is used.

Disclosure of Invention

The present description relates to a non-staining gel composition containing nimesulide, for topical application, which includes one or more non-aqueous solvents, one or more pH independent gelling agents and one or more acidifying agents.

In one aspect of the invention, the present disclosure relates to a non-staining topical gel composition comprising

(i) nimesulide:

(ii) one or more non-aqueous solvents;

(iii) one or more pH independent gelling agents;

(iv) one or more acidifying agents; and

(v) optionally one or more pharmaceutically acceptable excipients.

In another aspect of the present invention, the present disclosure relates to a non-staining topical gel composition comprising

(i) nimesulide;

(ii) dimethyl sulfoxide;

(iii) a copolymer of acrylamide and sodium acryloyl dimethyl taurate / isohexadecane / polysorbate-80;

(iv) one or more acidifying agents; and

(v) optionally one or more pharmaceutically acceptable excipients.

In another aspect of the present invention, the present disclosure relates to a non-staining topical gel composition comprising

(i) nimesulide;

(ii) dimethyl sulfoxide;

(iii) a copolymer of acrylamide and sodium acryloyl dimethyl taurate / isohexadecane / polysorbate-80;

(iv) citric acid; and

(v) optionally one or more pharmaceutically acceptable excipients.

In another aspect of the present invention, there is provided a stable, transparent gel composition containing nimesulide without a warming effect for topical application.

In yet another aspect, the invention can be used to relieve pain and inflammation symptoms associated with the musculoskeletal system, osteoarthritis, and rheumatoid arthritis.

Brief Description of the Figures

Figure 1. The photographs presented allow us to compare the effect of dyeing a fabric with a commercially available product (A) and the product of this invention (B).

Figure 2. The photographs presented make it possible to compare the staining effect when a person uses a commercially available product (A) and the product of this invention (B).

The implementation of the invention

The present description relates to a non-staining gel composition containing nimesulide, for topical application, which includes one or more non-aqueous solvents, one or more pH independent gelling agents and one or more acidifying agents.

In one aspect of the invention, the present disclosure relates to a non-staining topical gel composition comprising

(i) nimesulide:

(ii) one or more non-aqueous solvents;

(iii) one or more pH independent gelling agents;

(iv) one or more acidifying agents; and

(v) optionally one or more pharmaceutically acceptable excipients.

In another aspect of the present invention, the present disclosure relates to a non-staining topical gel composition comprising

(i) nimesulide;

(ii) one or more non-aqueous solvents;

(iii) one or more pH independent gelling agents;

(iv) one or more acidifying agents; and

(v) optionally one or more pharmaceutically acceptable excipients;

moreover, the pH of this composition is less than 6.5.

In another aspect of the present invention, the present disclosure relates to a non-staining topical gel composition comprising

(i) nimesulide;

(ii) dimethyl sulfoxide;

(iii) a copolymer of acrylamide and sodium acryloyl dimethyl taurate / isohexadecane / polysorbate-80;

(iv) one or more acidifying agents; and

(v) optionally one or more pharmaceutically acceptable excipients.

In another aspect of the present invention, the present disclosure relates to a non-staining topical gel composition comprising

(i) nimesulide;

(ii) dimethyl sulfoxide;

(iii) a copolymer of acrylamide and sodium acryloyl dimethyl taurate / isohexadecane / polysorbate-80;

(iv) citric acid; and

(v) optionally one or more pharmaceutically acceptable excipients.

In another aspect of the present invention, the present disclosure relates to a non-staining topical gel composition comprising

(i) 0.1-15% (w / w) nimesulide;

(ii) 10-95% (w / w) of one or more non-aqueous solvents;

(iii) 0.1-15% (w / w) of one or more pH independent gelling agents;

(iv) 0.1-10% (w / w) of one or more acidifying agents; and

(v) 0-20% (w / w) of one or more pharmaceutically acceptable excipients.

In another aspect of the present invention, the present disclosure relates to a non-staining topical gel composition comprising

(i) 0.1-15% (w / w) nimesulide;

(ii) 5-80% (w / w) dimethyl sulfoxide;

(iii) 1-15% (w / w) copolymer of acrylamide and sodium acryloyl dimethyl taurate / isohexadecane / polysorbate-80;

(iv) 1-10% (w / w) of citric acid; and

(v) 0-20% (w / w) of one or more pharmaceutically acceptable excipients.

In another aspect of the present invention, the present disclosure relates to a non-staining topical gel composition comprising

(i) 1% (w / w) nimesulide;

(ii) 10-40% (w / w) dimethyl sulfoxide; 10-40% (w / w) diethylene glycol monoethyl ether; 10-40% (w / w) propylene glycol;

(iii) 1-5% (w / w) copolymer of acrylamide and sodium acryloyl dimethyl taurate / isohexadecane / polysorbate-80;

(iv) 1-5% (w / w) of citric acid; and

(v) 0-20% (w / w) of one or more pharmaceutically acceptable excipients.

In another aspect of the present invention, the present disclosure relates to a non-staining topical gel composition comprising

(i) 1% (w / w) nimesulide;

(ii) 25% (w / w) dimethyl sulfoxide; 25% (w / w) diethylene glycol monoethyl ether; 30-35% (w / w) propylene glycol;

(iii) 1-5% (w / w) copolymer of acrylamide and sodium acryloyl dimethyl taurate / isohexadecane / polysorbate-80;

(iv) 1-5% (w / w) of citric acid; and

(v) 0-20% (w / w) of one or more pharmaceutically acceptable excipients;

wherein the pH of said composition is less than pKa of nimesulide.

As used herein, the term “nimesulide” means at least one form of nimesulide selected from the parent form having the properties of a base, its active metabolites, complexes, pharmaceutically acceptable salts or polymorphs. Any of these forms of nimesulide can be crystalline or amorphous. In the present invention, nimesulide is used in a concentration of 0.1-15% (w / w), for example 1-5% (w / w), relative to the total weight of the composition containing it.

As used herein, the term “non-stainable composition” or “substantially non-stainable composition” refers to a composition containing nimesulide, after the application of which there are no stained spots on the skin or clothing, or staining is weaker compared to conventional gel compositions containing nimesulide.

Suitable solvents of this invention are selected from purified water or non-aqueous solvents. The non-aqueous solvent is selected from dimethyl sulfoxide, propylene glycol, polyethylene glycol-400, diethylene glycol monoethyl ether, ethyl alcohol, isopropyl alcohol, N-methylpyrrolidone, acetone, cyclomethicone, dimethicone, or combinations thereof. Dimethyl sulfoxide gives the gel composition containing nimesulide, transparency, lack of feeling of greasy and sticky, as well as external homogeneity. Water ensures the absence of a warming effect after applying a gel composition containing nimesulide, since the heat of hydration is released. Purified water is used in the present description in an amount of from 1% to 20% (mass / mass). If one or more non-aqueous solvents are used according to this invention, then it is taken in an amount of 10-95% (mass / mass), for example 40-95% (mass / mass). Dimethyl sulfoxide according to the present description is used in an amount of 5-80% (mass / mass), for example 10-40% (mass / mass). Dimethyl sulfoxide may be contained in the composition of this invention at a concentration of 25% (w / w). The propylene glycol according to this invention is used in an amount of 5-80% (mass / mass), for example 10-40% (mass / mass). Propylene glycol may be present in the composition of this invention at a concentration of 30-35% (w / w). Polyethylene glycol-400 according to the present description is used in an amount of 5-80% (mass / mass), for example 10-40% (mass / mass). Polyethylene glycol-400 may be contained in the composition of this invention at a concentration of 25% (w / w). Diethylene glycol monoethyl ether according to the present description is used in an amount of 5-80% (mass / mass), for example 10-40% (mass / mass). Diethylene glycol monoethyl ether may be contained in the composition of this invention at a concentration of 25% (w / w).

As used herein, the term “pH independent gelling agent” refers to substances that increase the viscosity of a solution or liquid / suspension even when the pH changes. Do not depend on the pH of gelling agents used in the present invention may be represented by an individual polymer or combination of polymers selected (but not limited to those listed above) from polyacrylamide, hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, gelatin, hydrophilic fumed silica (Aerosil ^® 200) or combinations thereof.

Examples of the polyacrylamide used in the present invention (non-limiting) include a mixture of a copolymer of sodium acryloyl dimethyl laurate, isohexadecane and polysorbate 80 (trade name Sepineo P600); a mixture of polyacrylamide, isoparaffin C13-14 and laureth-7 (for example, a product with the trade name Sepigel 305); a group of acrylic polymers joined by hydrophobic chains, for example a mixture of polyethylene glycol-150, decyl alcohol and a methylene bis (4-cyclohexylisocyanate) copolymer (SMDI) under the trade name Aculyn 44 (polycondensate comprising at least components such as polyethylene glycol containing 150 or 180 moles of ethylene oxide, decyl alcohol and the above SMDI), in an amount of 35% (w / w) in a mixture of propylene glycol (39%) and water (26%)); a group of modified starches, for example modified potato starch under the trade name Structure Solanace, or combinations thereof. According to the present invention, preferably Sepineo P 600 or Aerosil 200, or mixtures thereof, are used as the pH-independent gelling agent. Sepineo P 600 is capable of swelling in the presence of one or more organic solvents without precipitation, forming a transparent gel. The pH-independent gelling agents described above are used according to the invention in a concentration of 0.1-15% (w / w), for example 0.5-10% (w / w). PH independent gelling agents may be contained in the composition of this invention in an amount of 1-5% (w / w).

As used herein, the term “acidifying agent” refers to substances that impart an acidic pH to the composition, more specifically, a pH lower than pKa of nimesulide (pKa of 6.5). Being a weak acid, nimesulide at acidic pH remains in a non-ionized form and emits in the ultraviolet region of the spectrum (not perceived by the human eye). Thus, if in the microenvironment of nimesulide the pH is maintained below its pKa, then there should be no staining. In the composition of this invention, the pH is less than 6.5 or in the range of 2-5. In the composition of this invention, the pH may be 3. The acidifying agent used in this invention is selected (not limited to the substances listed here) from citric acid, hydrochloric acid, oleic acid, malic acid, tartaric acid, fumaric acid, phosphoric acid, or combinations thereof . According to the present invention, it is preferable to use citric acid as the acidifying agent. Leather and clothing fabrics usually have some buffer capacity due to the presence of basic compounds in them. Therefore, an excess of an acidifying agent is required in the composition of this invention to provide the desired pH. An effective amount of an acidifying agent in topical formulations is 0.1-10% (w / w), for example 1-5% (w / w). The acidifying agent may be contained in the composition of this invention at a concentration of 3% (w / w).

If necessary, the compositions of this invention may include one or more permeability enhancers at a concentration of 0-20% (w / w), for example 2-6% (w / w), relative to the total weight of the composition. Permeability enhancers such as propylene glycol, dipropylene glycol, propylene glycol dipelargonate, lauroglycol (propylene glycol monolaurate), oleic acid, glyceryl monooleate and ethoxydiglycol (listed here is not restrictive) are preferably used in the present invention.

Preferably, the compositions of this invention optionally contain one or more surfactants in a concentration of from 0% to 10% (w / w), for example from 0.1% to 2% (w / w). Examples of surfactants used in this invention are hydrophilic lipophilic balance surfactants (HLBs) of 7 to 9 or non-ionic surfactants, for example polyoxyethylated and / or polyoxypropylene copolymers. Surfactants such as poloxamers, in particular poloxamer-124 and / or poloxamer-182 (preferably listed here are not restrictive) are preferably used according to this invention.

The composition of this invention optionally contains one or more pharmaceutically acceptable excipients used in the field of cosmetics and pharmaceuticals, for example, complexing agents, antioxidants, sunscreens, preservatives, fillers, electrolytes, water-retaining agents, colorants, inorganic or organic acids commonly used in pharmaceutical preparations or bases, flavorings, essential oils, moisturizing agents, vitamins, essential fatty acids, sphingolipids, substances, o espechivayuschie tanning effect (e.g., dihydroxyacetone (DHA)), agents, soothing and protecting the skin, such as allantoin. There is no need to emphasize that a person skilled in the art should carefully approach the selection of such excipients and / or their amount in the composition.

These excipients may be contained in the composition of this invention in an amount of 0-20% (mass / mass) of its total mass.

Examples of the flavorings used in this invention include plant extracts and essential oils from sources such as eucalyptus, lemon, orange, cinnamon, mint, tangerine, grapefruit, curly mint, peppermint, clover, rosemary, or synthetic flavors, for example, synthetic vanillin and Calm Valley.

Examples of the complexing agents used in this invention include ethylenediaminetetraacetic acid (EDTA), as well as its derivatives and salts, dihydroxyethyl glycine, or combinations thereof.

Examples of the preservatives used in this invention include benzalkonium chloride, phenoxyethanol, benzyl alcohol, diazolidinyl urea and parabens or combinations thereof.

Examples of water-retaining agents used in this invention include glycerin and sorbitol.

In yet another aspect of the invention, there is provided a method for preparing a nimesulide-containing gel composition for topical application. This preparation method may be any conventionally suitable method suitable for a given case. comprising mixing solvents with nimesulide and then with an acidifying agent and a gelling agent. pH independent.

In yet another aspect, the invention can be used to relieve pain and inflammation symptoms associated with the musculoskeletal system, osteoarthritis, and rheumatoid arthritis.

Examples

Example 1

Number in order Ingredient Concentration,
% (mass / mass) 1 Nimesulide 1 2 Dimethyl sulfoxide 10 3 Diethylene glycol monoethyl ether 25 4 Propylene glycol 20,4 5 Polyethylene glycol-400 20 6 Lemon acid 3 7 Purified water 10 8 Fine silica 10 9 Sodium Acrylamide / Acryloyl Dimethyl Taurate Copolymer / Isohexadecane / Polysorbate-80 0.6

Way

1. Nimesulide was dissolved in a mixture of solvents (dimethyl sulfoxide and diethylene glycol monoethyl ether) to give a clear solution.

2. Propylene glycol and polyethylene glycol-400 were added to the resulting solution, followed by a solution of citric acid in purified water.

3. To the solution obtained in step 2, finely dispersed silicon dioxide and a mixture of a copolymer of acrylamide and sodium acryloyl dimethyl taurate / isohexadecane / polysorbate-80 were slowly added and mixed until a homogeneous gel formed.

Example 2

Number in order Ingredient Concentration,
% (mass / mass) 1 Nimesulide 1 2 Dimethyl sulfoxide 35 3 Diethylene glycol monoethyl ether 25 4 Propylene glycol 22 5 Lemon acid 3 6 Purified water 10 7 Acrylamide copolymer and
sodium acryloyl dimethyl taurate / isohexadecane /
polysorbate-80 4

Way

1. Nimesulide was dissolved in a mixture of solvents (dimethyl sulfoxide and diethylene glycol monoethyl ether) to give a clear solution.

2. Propylene glycol was added to the resulting solution, followed by a solution of citric acid in purified water.

3. To the solution obtained in step 2, a mixture of a copolymer of acrylamide and sodium acryloyl dimethyl taurate / isohexadecane / polysorbate-80 was slowly added and stirred until a homogeneous gel formed.

Example 3

Nome in order Ingredient Concentration,
% (mass / mass) 1 Nimesulide 1 2 Dimethyl sulfoxide 10 3 Diethylene glycol monoethyl ether 25 4 Propylene glycol 21 5 Polyethylene glycol-400 20 6 Lemon acid 3 7 Purified water 10 8 Fine silica 10

Mix solvents (dimethyl sulfoxide and diethylene glycol monoethyl ether) and add nimesulide to this mixture. When a clear solution forms, add propylene glycol and polyethylene glycol-400, and then a solution of citric acid in purified water. Fine silica is slowly added to the resulting mixture and mixed until a homogeneous gel forms.

Example 4

Number in order Ingredient Concentration,
% (mass / mass) 1 Nimesulide 1 2 Dimethyl sulfoxide 25 3 Diethylene glycol monoethyl ether 25 4 Propylene glycol 29.5 5 Lemon acid 3 6 Purified water 10 7 Oleic acid 3 8 Acrylamide copolymer and
sodium acryloyl dimethyl taurate / isohexadecane /
polysorbate-80 3,5

Mix solvents (dimethyl sulfoxide and diethylene glycol monoethyl ether) and add nimesulide to this mixture. When a clear solution forms, add propylene glycol and oleic acid, and then a solution of citric acid in purified water. To the resulting mixture, slowly add the copolymer of acrylamide and sodium acryloyl dimethyl taurate / isohexadecane / polysorbate-80 and mix until a homogeneous gel forms.

Example 5

Number in order Ingredient Concentration,
% (mass / mass) 1 Nimesulide 1 2 Dimethyl sulfoxide 25 3 Diethylene glycol monoethyl ether 25 4 Propylene glycol 30.5 5 Lemon acid 3 6 Purified water 10 7 Glyceryl monooleate 2 8 Acrylamide copolymer
and sodium acryloyl dimethyl taurate / isohexadecane /
polysorbate-80 3,5

Mix solvents (dimethyl sulfoxide and diethylene glycol monoethyl ether) and add nimesulide to this mixture. When a clear solution is formed, propylene glycol and glyceryl monooleate are added to it, followed by a solution of citric acid in purified water. To the resulting mixture, slowly add the copolymer of acrylamide and sodium acryloyl dimethyl taurate / isohexadecane / polysorbate-80 and mix until a homogeneous gel forms.

Example 6

Number in order Ingredient Concentration,
% (mass / mass) 1 Nimesulide 1 2 Dimethyl sulfoxide 25 3 Diethylene glycol monoethyl ether 25 4 Propylene glycol 31.9 5 Lemon acid 3 6 Purified water 10 7 Acrylamide copolymer
and sodium acryloyl dimethyl taurate / isohexadecane /
polysorbate-80 4 8 Synthetic flavor Calm Valley 0.1

Way

1. Nimesulide was dissolved in a mixture of solvents (dimethyl sulfoxide and diethylene glycol monoethyl ether) to give a clear solution.

2. Propylene glycol was added to the resulting solution, followed by a solution of citric acid in purified water.

3. To the solution obtained in step 2, a mixture of a copolymer of acrylamide and sodium acryloyl dimethyl taurate / isohexadecane / polysorbate-80 was slowly added and stirred until a homogeneous gel formed.

4. To the resulting gel at room temperature was added the synthetic flavor “Calm valley” with stirring.

By the method of Example 6, three series of similar compositions were obtained having the composition of Example 6; their stability was determined under various conditions (temperature and humidity). All three compositions were stable under conditions of accelerated degradation. The results of this study are presented in table 1.

Table 1

Conditions Example 6a Example 6b Example 6c pH Determination result pH Determination result pH Determination result Originally 2.83 98.5 3.19 98 3.09 97.8 3M / 25 ° C;
60% RH 2.88 99,4 2.82 100.1 2.99 99.5 6M / 25 ° C;
60% RH 3.32 102.8 3.38 103.8 3.35 100.0 3M / 40 ° C;
75% RH 3.34 100.6 3.42 99.6 3.39 99.3 6M / 40 ° C;
75% RH 3.56 99.6 3.74 99.9 3.81 102,2

RH - relative humidity

A series of gel compositions according to this invention was obtained (see table 2) and the effect of the lack of staining was determined for them.

Table 2

Ingredient Etc. 7 Etc. 8 Etc. 9 Etc. 10 Etc. eleven Etc. 12 Etc. thirteen Etc. 14 Etc. fifteen Nimesulide 1 1 1 1 1 1 1 1 1 Dimethyl sulfoxide 25 25 25 25 25 25 25 25 25 Monoethyl ether
diethylene glycol 25 25 25 25 25 25 25 25 25 Propylene glycol 34,4 33,4 32,4 31,4 30,4 31.9 30.9 29.9 30.9 Lemon acid 1 2 3 4 5 3,5 4 4,5 3 Purified water 10 10 10 10 10 10 10 10 10 Sodium Acrylamide / Acryloyl Dimethyl Taurate Copolymer / Isohexadecane / Polysorbate-80 3,5 3,5 3,5 3,5 3,5 3,5 4 4,5 5 Synthetic flavor "Calm valley" 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1

* All given values have dimension% (mass / mass)

Etc. - example

The effect of the lack of staining was determined by applying the indicated gel compositions to two different sets of pieces of white tissue 4 x 4 cm in size: set A) the tissue itself; set B) a cloth soaked in a solution of a surfactant. The gel compositions were applied to the surface of a white cloth and allowed to dry for 24 hours. Any changes in the color of the tissue at the site of application of the gel composition were compared with the result of exposure to the tissue of a product commercially available (figure 1). The results of this study are presented in table 3.

Table 3

Composition Description / Color of the white fabric sample Description / Color of a sample of white cloth soaked in soapy water Product Description Commercially Available Product Yellow coloring Yellow coloring Yellow gel Example 7 No yellow staining No yellow staining The gel is pale yellow Example 8 No yellow staining No yellow staining The gel is pale yellow Example 9 No yellow staining No yellow staining Clear yellowish gel Example 10 No yellow staining No yellow staining Clear yellowish gel Example 11 No yellow staining No yellow staining Clear yellowish gel Example 12 No yellow staining No yellow staining Clear yellowish gel Example 13 No yellow staining No yellow staining Clear yellowish gel Example 14 No yellow staining No yellow staining Clear yellowish gel Example 15 No yellow staining No yellow staining Clear yellowish gel

All gel compositions obtained according to this invention did not cause staining. Optimal are compositions containing 3-5% citric acid - they are the most transparent and without color shades.

The gel compositions obtained according to this invention were also evaluated in terms of acceptability to humans. In this study, 16 individuals were asked to use the non-staining compositions of this invention and a commercially available product to evaluate their acceptability in scores of 1 to 5 depending on the intensity of staining (“1” - no staining; “5” - strong staining) . The results of this study are presented in table 4; in FIG. 2, staining can be compared when using volunteers using a commercially available product (A) and a product of this invention (B)

Table 4

Individuals
(number in order) Non-staining gel with nimesulide Gel with nimesulide
commercially available 1 1 5 2 1 4 3 1 5 4 1 4 5 2 4 6 2 5 7 3 5 8 1 5 9 3 5 10 1 5 eleven 1 5 12 1 5 thirteen 1 4 14 2 5 fifteen 1 5 16 1 5

Claims (24)

1. Non-staining gel composition for topical application, containing: (i) nimesulide, (ii) one or more non-aqueous solvents, (iii) one or more pH independent gelling agents, (iv) one or more acidifying agents selected from citric acid, hydrochloric acid, oleic acid, malic acid, tartaric acid, fumaric acid, phosphoric acid, or combinations thereof, and (v) optionally one or more pharmaceutically acceptable excipients, moreover, the pH of the composition is 2-5. 2. The non-staining gel composition according to claim 1, wherein the non-aqueous solvent is selected from dimethyl sulfoxide, propylene glycol, polyethylene glycol-400, diethylene glycol monoethyl ether, ethyl alcohol, isopropyl alcohol, N-methylpyrrolidone, acetone, cyclomethicone or a combination of them, dimethyl. 3. The non-staining gel composition according to claim 1, wherein the pH independent gelling agents are selected from polyacrylamide, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose, gelatin, hydrophilic highly dispersed silicon dioxide or them. 4. The non-staining gel composition of claim 3, wherein the pH independent gelling agent is polyacrylamide. 5. The non-staining gel composition of claim 4, wherein the pH independent gelling agent is a mixture of a copolymer of acrylamide and sodium acryloyl dimethyl taurate / isohexadecane / polysorbate-80. 6. The non-staining gel composition according to claim 1, wherein the acidifying agent is citric acid. 7. Non-staining gel composition according to claim 1, containing: (i) 1% (w / w) nimesulide, (ii) 10-40% (w / w) dimethyl sulfoxide, 10-40% (w / w) diethylene glycol monoethyl ether, 10-40% (w / w) propylene glycol, (iii) 1-5% (w / w) of a mixture of a copolymer of acrylamide and sodium acryloyl dimethyl taurate / isohexadecane / polysorbate-80, (iv) 1-5% (w / w) of citric acid, and (v) 0-20% (w / w) of one or more pharmaceutically acceptable excipients. 8. Non-staining gel composition according to claim 7, containing: (i) 1% (w / w) nimesulide, (ii) 25% (w / w) dimethyl sulfoxide, 25% (w / w) diethylene glycol monoethyl ether, 30-35% (w / w) propylene glycol, (iii) 1-5% (w / w) of a mixture of a copolymer of acrylamide and sodium acryloyl dimethyl taurate / isohexadecane / polysorbate-80, (iv) 1-5% (w / w) of citric acid, and (v) 0-20% (w / w) of one or more pharmaceutically acceptable excipients.

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