KR20070017553A - Hydroalcoholic depigmentation gel comprising mequinol and adapalene - Google Patents

Abstract

The present invention relates to bleaching compositions for cosmetic or pharmaceutical use in the form of hydroalcoholic cream gels or gels containing mequinol, adapalene and, optionally, sunscreen. The invention also relates to the formulation of the composition and its use in the cosmetic and dermatological fields.

Description

HYDROALCOHOLIC DEPIGMENTATION GEL COMPRISING MEQUINOL AND ADAPALENE}

The present invention relates to the preparation of mequinol (4-hydroxyanisole) and adapalene (6- [3- (1-adamantyl) -4-ethoxyphenyl] -2-naphthoic acid) in a physiologically acceptable medium. In particular it relates to a bleaching composition for cosmetic or pharmaceutical applications containing in dispersed form in the form of an aqueous-alcoholic gel or gel-cream.

Among the recommended therapeutics for the treatment of skin hyperpigmentation, phenolic derivatives such as mequinol and derivatives thereof have been one of the most effective active ingredients in the last decades. However, it is known that phenolic derivatives are sensitive to oxidation and heat, causing the formulation to brown quickly and in some cases phase separation to occur.

Moreover, since adapalene has low water solubility, the possibility of precipitation of the active substance is a major problem encountered when it must be dispersed in the composition of the formulation and thus included in the formulation. Thus, it is difficult to obtain a formulation containing adapalene in the suspension while being sufficiently fluid and at the same time having some viscosity to keep the material in the suspension and not flow.

In the present invention, adapalene has been successfully suspended thanks to the use of carbomer gels and surface-active wetting agents to overcome aqueous-alcoholic gel or gel-cream forms and precipitation problems.

In the prior art, sulfites have typically been used to reduce browning problems in formulations. However, this can alter the viscosity of formulations that are sensitive to electrolytes. In particular, sulfites are known to break carbomer gels, reducing the viscosity-strengthening power of the gelling agent, leading to precipitation of the active agent.

Thus, containing mequinol and adapalene having a formulation that is physically stable (without significant phase separation and significant drop in viscosity) and chemical (without modifying the stability of the active agent) and optimizes the penetration of adapalene and mequinol into the skin. There is a need for external pharmaceutical compositions.

Surprisingly, we have demonstrated that formulations in the form of an aqueous-alcoholic gel or gel-cream containing excipients as disclosed herein show good results with regard to the physical and chemical stability of the active compounds. It also provides an excellent balance between stability, in particular resistance to temperature and oxidation, utility, safety and cosmetic quality.

Indeed, due to its composition and especially the presence of 2 to 10% alcohol, an aqueous-alcoholic gel or gel-cream ensures the stability and safety of the composition and its components.

In addition, the stability monitor results of the formulations presented in the examples below show that browning of mequinol is significantly reduced by combining the active compounds with sulfites, in particular sodium metabisulphite and sodium sulfite, EDTA and alcohol (ethanol). In the absence of sulfite, browning is observed after one month of storage at 55 ° C., and browning occurs in only a few days at 55 ° C. without all of the above compounds.

For adapalene suspensions, a solution to the problem of lowering the viscosity-strength of carbomers by sulfites is to add other gelling agents to the formulation.

The gelling agents or gelling agents selected alone or in combination should have the following properties:

Gelation of the aqueous phase to form an aqueous gel with sufficient firmness such that the final product does not flow even if the container is turned upside down;

Providing sufficient viscosity to maintain the adapalene in the suspension;

Low sensitivity to the electrolyte, ie not to lose gel properties in the presence of the electrolyte;

Not destroyed over time or at various storage temperatures (4 ° C. − RT − 40 ° C.).

The formulations presented in the examples below show that, thanks to the formation of the net by the gelling agent and the addition of surface-active wetting agents, adapalene is easily dispersed and the dispersion remains homogeneous over time.

In particular, the stability of the active phase of the composition according to the invention accounts for the utility of the product.

In addition, Applicant has demonstrated that the decolorizing action of mequinol is synergistically increased due to the presence of adapalene in the composition. Thus, the results presented in the examples show that the combination advantageously provides a faster and more effective decolorizing effect.

In addition, the applicant has developed a process for the preparation of the composition according to the invention.

Accordingly, the present invention relates to a composition characterized in that it is an aqueous-alcoholic gel or gel-cream, which is a bleaching composition containing mequinol and adapalene in a physiologically acceptable medium.

"Physiologically acceptable medium" means a medium suitable for skin, mucous membranes and / or skin appendages.

"Bleaching composition" means any composition containing at least one active agent having skin bleaching activity. The activity is to reduce the pigment present in the skin.

"Aqueous-alcohol gel" means an aqueous gel containing alcohol, water and one or more gelling agents.

"Aqueous-alcohol gel-cream" means an aqueous phase, an aqueous gel containing a small amount (0-20%, preferably 10%) of oil and an alcohol, which aqueous phase confines oil droplets and holds them in suspension. It contains a gelling agent capable of forming a mesh.

Aqueous-alcoholic gel creams are formulations that combine the benefits of the gel (ease of application, rapid release of the active agent, fresh on application) with the benefits of the cream (no skin comfort due to a small proportion of oil phase, no skin drying) to be.

The composition according to the invention preferably contains 2 to 10% alcohol, more preferably 5% alcohol.

Among the alcohols, non-limiting examples may include ethanol, isopropanol, and butanol. Ethanol is particularly preferred.

Advantageously, the composition according to the invention also contains a chelating agent, a surface-active wetting agent and one or more gelling agents.

The composition according to the invention also contains one or more of the following components:

a) carbomer;

b) one or more other gelling agents;

c) antioxidants;

d) an oil phase;

e) moisturizer / softener;

f) anti-irritant;

g) pH neutralizing agent;

h) preservatives.

Preferably, the aqueous-alcoholic gel or gel-cream according to the invention contains a carbomer and at least one other gelling agent or said carbomer and at least one other carbomer. As mentioned above, in fact, these compounds provide a suitable viscosity to the composition while maintaining the adapalene in the suspension.

Among the carbomers and other possible gelling agents, mention may be made by way of non-limiting examples: acrylate / C10-C30 alkyl acrylics sold under the name Carbopol 1382 sold under the name Carbopol 1382 by the company BF Goodrich or under the name Pemulen TR1 under the name BF Goodrich. Latex crosspolymer, xanthan gum such as Keltrol T from Kelco, hydroxypropylcellulose such as the product sold under the trade name Natrosol HHX from Aqualon, carbopol 980, carbopol 981, carbopol Ultrez 10, carbopol EDT 2020, carbopol 974, and Seppic Polysorbate 80, acrylamide / sodium acryloyldimethyltaurate copolymer and isohexadecane sold as Simulgel 600.

Among the gelling agents, mention may be made of a combination of a carbomer / acrylate / C10-C3O alkyl acrylate crosspolymer with xanthan gum and hydroxyethylcellulose or alternatively with a combination of carbomer 1382 with xanthan gum and carbomer 981. have.

Among the antioxidants, the following may be mentioned by way of non-limiting example: ascorbic acid and salts thereof, tocopherol and sulfite such as sodium metabisulfite, sodium sulfite.

The oil phase according to the invention may contain, for example, vegetable, mineral, animal or synthetic oils, silicone oils, and mixtures thereof.

As examples of mineral oils, mention may be made of paraffin oils with various viscosities, such as Primol 352, Marcol 82, Marcol 152 from Esso. The following may be mentioned as examples of vegetable oils: sweet almond oil, palm oil, soybean oil, sesame oil, sunflower oil.

As animal oils, mention may be made of: lanolin, squalene, fish oil, mink oil.

As synthetic oils, esters such as cetearyl isononanoate such as the product sold under the trade name Cetiol SN by Cognis France, diisopropyl adipate such as the product sold under the trade name Ceraphyl 230 by ISF, and Crodamol IPP by Croda company Mention may be made of isopropyl palmitate, such as the product sold, and caprylic capric acid triglycerides such as Miglyol 812 from Huls / Lambert Riviere.

As silicone oils, mention may be made of cyclomethicone, such as the product sold by Dow Corning 244 fluid by Dow Corning, dimethicone, such as the product sold by Dow Corning 200 fluid, or by the product Mirasil CM5 from SACI-CFPA. Can be.

Solid fats such as natural or synthetic waxes may also be used. In this case, one skilled in the art can adjust the heating temperature of the preparation with respect to the presence of the solid.

In the bleaching composition of the aqueous-alcoholic gel-cream type according to the invention, paraffin oil, more particularly Marcol 152, is preferred.

For better dispersion of adapalene, the compositions according to the invention advantageously contain at least 0.01% to 10%, more preferably 0.1% to 5% of one or more surface-active wetting agents.

Preferably, it is a surfactant having a HLB (Hydrophilic Lipophilic Balance) of 7 to 9, or alternatively a nonionic surfactant such as polyoxyethylene and / or polyoxypropylene copolymer.

The following may be mentioned as non-limiting examples of surface-active wetting agents: compounds of the poloxamers, more particularly poloxamer 124 and poloxamer 182.

Particularly preferred surface-active wetting agent is poloxamer 124.

The following may be mentioned as examples of chelating agents: ethylenediamine tetraacetic acid (EDTA), calcium disodium edetate, sodium edetate, disodium edetate, preferably disodium edetate and EDTA.

The composition may further contain additives commonly used in the cosmetic or pharmaceutical arts, such as neutralizers, moisturizers and / or cosolvents, emollients, soothing agents, preservatives, pH correctors, or mixtures thereof.

Those skilled in the art will naturally select the optional additional compound (s), and amounts thereof, so as not to adversely or substantially adversely affect the advantageous properties of the compositions according to the invention.

The additive may be present in the composition in a proportion of 0.001 to 20% by weight relative to the total weight of the composition.

The following may be mentioned as examples of humectants / emollients: glycerol, sorbitol, propylene glycol.

Cosolvents may be mentioned macrogol 400.

Anti-irritants and / or “calm” agents such as strontium nitrate, shea butter, 18-beta-glyciletin acid, acid dipotassium glycyrizate, teatrioil, enoxolone, alpha-tocopherol acetate, allantoin, talc And the like can also be added to the formulation.

As examples of pH neutralizing agents to obtain a suitable pH, mention may be made of: amine bases such as triethanolamine, diethanolamine, tromethamine, tromethol or other bases such as sodium hydroxide.

As examples of preservatives, mention may be made of benzalkonium chloride, phenoxyethanol, benzyl alcohol, diazolidinyl urea, parabens, or mixtures thereof.

However, preferred compositions according to the invention advantageously contain no preservatives.

The active agents according to the invention are mequinol (4-hydroxyanisole) and precursors and / or derivatives thereof and adapalene (6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naph Tomic acid), especially in its dispersed form, and precursors and / or derivatives thereof, and other agents may be added thereto, as described above. By dispersed form is meant the dispersion of various granulometry solids in the liquid medium.

The amount of active agent in the composition according to the invention, of course, depends on the combination selected, and therefore in particular on the quality of the desired treatment. Preferably, the amount of adapalene is 0.0001 to 20%, more preferably 0.001 to 10%.

The composition of the aqueous-alcoholic gel or gel-cream type according to the present invention provides excellent cutaneous tolerance. Advantageously, it spreads more easily and leaves a fresh pleasure compared to viscous emulsions.

More specifically, the present invention is an aqueous-alcoholic bleaching gel or gel-cream containing one or more of the following components:

0.01-5% mequinol;

0.10 to 2% of adapalene;

2 to 10% ethanol;

0.01 to 2% of one or more gelling agents;

0 to 1% of an antioxidant;

0.01 to 20% of chelating agent;

0 to 20% oil phase.

Preferred compositions according to the invention contain:

2% mequinol;

0.10 to 2% of adapalene;

5% ethanol;

1 to 2% of one or more gelling agents;

0.1 to 0.5% antioxidant;

0.10% EDTA;

0 to 15% oil phase.

Particularly preferred compositions according to the invention contain:

2% mequinol;

0.10% of adapalene;

5% ethanol;

1 to 2% of one or more gelling agents;

0.1 to 0.4% of an antioxidant and more preferably sulfite;

0.10% EDTA;

5 to 15% oil phase.

The invention also relates to a composition as defined above containing a chemical or physical sun filter.

"Ultraviolet blocker" means chemical or physical sunscreens and mixtures thereof, and non-limiting examples may include the following: Physical sunscreens such as titanium dioxide, zinc oxide and chemical sunscreens, octocrylene, ethylhexyl memethyl Oxycinnamate, octyl salicylate, avobenzone, oxybenzone, ecampul, drometrizole trisiloxane.

Each sunscreen may be added at a concentration ranging from 0.001 to 20% by weight, preferably 0.001 to 5% by weight of the total weight of the composition.

The present invention also relates to the aforementioned composition as a medicament.

The invention also relates to a process for the preparation of an aqueous-alcoholic gel or gel-cream type composition comprising the following steps:

a) preparing a formulation phase with water and stirring in a Rayneri stirrer, then pouring into the chelating agent and stirring until dissolved;

b) heating the mixture of step a) to 60 ° C., injecting a gelling agent or gelling agents and stirring until homogenized;

c) leaving the mixture to room temperature with stirring in a Rayneri stirrer;

d) preparing a first active phase containing mequinol and alcohol in a separate beaker with magnetic stirring until complete dissolution;

e) adding the first active phase to the formulation after returning to room temperature and maintaining stirring;

f) preparing a second active phase containing adapalene, a surface-active wetting agent and a humectant in a separate beaker and stirring until a smooth homogeneous dispersion is obtained;

g) then adding the second active phase to the formulation after returning to room temperature and maintaining stirring;

h) neutralization with a neutralizer while stirring with a Rayneri stirrer to obtain the desired pH;

i) Add antioxidant to the formulation and stir.

The original pH of the mixture is variable and, if necessary, adjusted with a neutralizer solution.

Any optional additive may be added in connection with its chemical nature during one of the steps of the above-described preparation method.

According to certain embodiments of the invention, humectants and / or anti-irritants may optionally be added to step a) simultaneously with the chelating agent.

In another specific embodiment of the invention, the oil phase obtained by mixing the preservative, surfactant and oil heated to 60 ° C. in a water bath is added to the formulation obtained at the end of step b).

Depending on the physicochemical properties of the sunscreen, those skilled in the art can add it during one of the steps defined above.

"Formulation phase" means a mixture of groups of components introduced together in a single phase.

"Active phase" means a formulation phase containing one or more active agents.

The present invention also relates to the use of the novel compositions described above in the field of cosmetic and dermatology.

In particular, the present invention relates to the use of the above-described compositions in the manufacture of pharmaceutical preparations for the treatment and / or prevention of dermatological conditions associated with pigmentation disorders.

The composition of the present invention is characterized by blemishes, liver spots, surpluses, senile surpluses, vitiligo, freckles, abrasions, burns, scars, skin diseases, post-inflammatory hyperpigmentation due to contact allergy, spots, hyperpigmentation by genetic predisposition, metabolic or It is particularly suitable for the treatment and / or prevention of dermatological conditions associated with pigmentation disorders such as hyperpigmentation, melanoma or all other hyperpigmentation lesions by medicines.

In addition, the compositions according to the invention may find use in the cosmetic field, in particular in the prevention and / or retardation of the deleterious effects of sun and / or light-induced or chronological aging on the skin and its appendages.

The composition according to the invention is also applicable to the hygiene of the human body and hair.

In addition, the present invention is a non-therapeutic cosmetic treatment method for improving the skin's complexion and / or its surface appearance, the aqueous-alcoholic gel or gel cream according to the present invention containing mequinol and adapalene, and optionally a sunscreen. To a skin and / or adjuncts thereof.

Examples of the following formulations illustrate but do not limit the scope of the compositions according to the invention. Examples describing the stability of the compositions according to the invention are also described.

In the following compositions (Examples 1, 3, 5, 7, 9 and 11), the proportions of the various components are expressed as weight percentages relative to the total weight of the composition.

Example  1: gel Formulation

Purified Water Qsf 100%

EDTA 0.10

Glycerol 5.00

Xanthan Gum 0.40

Acrylate / C1O C30 Alkyl Acrylate

Crosspolymer 0.60

Ethanol 5.00

Mequinol 2.00

Phenoxyethanol 1.00

Propylene Glycol 5.00

Poloxamer 124 0.20

Adapalene 0.10

Triethanolamine 1.30

Purified Water 5.00

Sodium metabisulfite 0.20

Sodium sulfite 0.20

Gel formulations are prepared in the following way:

a) phase of formulation:

Add most of the water to the main beaker and stir with a Rayneri stirrer.

Add chelating agent, anti-irritant and glycerol, then continue stirring until dissolved.

Heating to 60 ° C. promotes dispersion of the gelling agent.

Spray the gelling agent or gelling agents onto the formulation and keep stirring until homogeneous.

Then it is left to return to room temperature (RT) with continued stirring.

b) active phase

Weigh the bleach and ethanol in separate beakers and stir with a magnetic stirrer until completely dissolved;

Finally adding to the formulation returned to room temperature (RT) with stirring with a Rayneri stirrer;

Weigh adapalene, propylene glycol and poloxamer 124 in separate beakers and stir for 15 minutes at 20500 rev / min with Ultraturax until a smooth homogeneous dispersion is obtained;

Final addition on the formulation returned to room temperature (RT) with stirring with a Rayneri stirrer.

c) neutralization with base while stirring with a Rayneri stirrer to obtain a pH of 6 +/- 0.3.

d) Finally adding antioxidant to the formulation while stirring with a Rayneri stirrer.

Example  2: Example  Gel according to 1 Formulation  Physical and chemical stability

The physical stability of the gel formulations according to Example 1 was measured for 3 months at room temperature (RT), 4 ° C., 40 ° C. and 55 ° C .:

Formulation of the formulation in the TO:

pH 5.93 Visual observation White fluid gel Centrifugation 3000 rev / min Matches Microscopic observation Homogenized Dispersion of Adapalene 10000 rev / min Matches

T1 months T2 months T3 months  RT pH 5.69 5.41 5.35 Centrifugation Matches Matches Matches Visual observation Matches Matches Matches 4 ℃ Visual observation Matches Matches Matches Microscopic observation Matches Matches Matches 40 ℃ Visual observation Matches Matches Matches Microscopic observation Matches Matches Matches 55 ℃ Visual observation Consistent, more fluid than at 4 ° C Consistent, more fluid than at 4 ° C Consistent, more fluid than at 4 ° C

By "matching" is meant that the properties of the composition measured at 1, 2 or 3 months follow that obtained at T0.

The chemical stability of the gel formulations according to Example 1 was determined over 3 months at RT and 40 ° C. by HPLC:

     Chemical stability  T0 RT Mequinol: 94.4% Adapalene: 92.6% 40 ℃ Mequinol: / Adapalene: /  T1 M RT Mequinol: 96.6% Adapalene: 91.7% 40 ℃ Mequinol: 93.9% Adapalene: 92.6%  T2 M RT Mequinol: 93.6% Adapalene: 93.0% 40 ° C Mequinol: 93.8% Adapalene: 93.%  T3 M RT Mequinol: 93.9% Adapalene: 92.8% 40 ℃ Mequinol: 93.5% Adapalene: 94.0%

The results show that the composition is physically and chemically stable at all temperatures for three months.

In addition, browning of the formulation was not observed at 40 ° C. after 3 months.

Example  3: gel-cream Formulation

Purified Water Qsf 100%

EDTA 0.10

Glycerol 5.00

Xanthan Gum 0.40

Acrylate / C1O C30 Alkyl Acrylate

Crosspolymer 0.60

Mineral Oil 10.00

Ceareareth 20 0.50

Phenoxyethanol 1.00

Ethanol 5.00

Mequinol 2.00

Propylene Glycol 5.00

Poloxamer 124 0.20

Adapalene 0.20

Triethanolamine 0.40

Purified Water 5.00

Sodium metabisulfite 0.20

Sodium sulfite 0.20

The gel-cream formulation was prepared by the following method:

a) in aqueous formulation phase:

Add most of the water to the main beaker and stir with a Rayneri stirrer.

Add chelating agent, anti-irritant and glycerol, then continue stirring until dissolved.

Heating to 60 ° C. promotes dispersion of the gelling agent.

Spray on gelling or gelling agents and continue stirring until homogenized.

b) oil phase:

Weigh mineral oils, surfactants and preservatives in separate beakers.

Heated to 60 ° C. in a water bath.

Then add to aqueous phase a) with sufficient stirring in a Rayneri stirrer.

Allow the emulsion to return to room temperature.

c) active phase

Mequinol and ethanol are weighed in separate beakers and then stirred with a magnetic stirrer until completely dissolved.

Final addition on the formulation returned to room temperature (RT), with stirring in a Rayneri stirrer;

Weigh adapalene, propylene glycol and poloxamer 124 in separate beakers and then stir for 15 minutes at 20500 rev / min with Ultra-turax until a smooth homogeneous dispersion is obtained;

Final addition on the formulation returned to room temperature (RT) with stirring with a Rayneri stirrer.

d) Neutralize with base while stirring with Rayneri stirrer to obtain the desired pH.

e) finally adding sulfite solution onto the formulation while stirring with a Rayneri stirrer.

Example  4: Example  Gel-creams according to 3 Formulation  Physical and chemical stability

The chemical stability of the gel-cream formulations according to example 3 was determined by HPLC at room temperature (RT) and 40 ° C. for 3 months:

From TO Formulation  characteristic

pH 5.80 Tau  θ 13 Visual observation Glossy White Gel-Cream Centrifugation 3000 rev / min Exudate Microscopic observation Homogeneous Dispersion of Adapalene 10000 rev / min Exudate

The yield point (tau θ) is the force (minimum shear stress) required to overcome and vane the van der Waals type cohesive force. The yield point is compared with the measured value at 4 s-1.

Chemical stability RT 40 ℃ T0 Mequinol: 100.5% Adapalene: 99.2% Mequinol: / Adapalene: / T1  M Mequinol: 99.8% Adapalene: 99.8% Mequinol: 98.3% Adapalene: 99.1% T2  M Mequinol: 99.7% Adapalene: 101.0% Mequinol: 99.4% Adapalene: 100.3% T3  M Mequinol: 100.0% Adapalene: 100.0% Mequinol: 99.6% Adapalene: 100.5%

The composition is chemically stable for 3 months at all temperatures.

Example  5: other gel-creams Formulation

Purified Water Qsf 100%

EDTA 0.10

Allantoin 0.20

Glycerol 5.00

Xanthan Gum 0.40

Hydroxyethylcellulose 0.70

Carbomer 1382 0.20

Mineral Oil 10.00

Sorbitan Monooleate 1.00

Ethanol 5.00

Mequinol 2.00

Propylene Glycol 5.00

Poloxamer 124 0.20

Adapalene 0.20

10% Trisamino Solution 1.30

Purified Water 5.00

Sodium metabisulfite 0.10

Sodium sulfite 0.10

The formulation was prepared according to the method described in Example 3.

Example  6: Example  Gel-creams according to 5 Formulation  Physical and chemical stability

The physical stability of the gel-cream formulations according to Example 5 was measured for 3 months at room temperature (RT), 4 ° C. and 40 ° C .:

From TO Formulation  characteristic

pH 5.97 Tau  θ 24 Visual observation Glossy oily white gel-cream Centrifugation 3000 rev / min lubricity Microscopic observation Fine emulsion, droplets of 2.5μ to 7.5μ. Homogeneous Dispersion of Adapalene 10000 rev / min lubricity

T1  month T2  month T3  month RT pH 5.57 5.39 5.27 Centrifugation Matches Matches Matches Visual observation Matches Matches Matches Microscopic observation Matches. Droplets of 2.5 microns to 12.5 microns. Matches. Droplets of 2.5 microns to 10 microns. Matches. Droplets of 2.5μ to 7.5μ. θ ₀  ( Tau ) 45 25 20 4 ℃ Visual observation Matches Matches Matches Microscopic observation Matches. Droplets of 2.5μ to 6μ. Matches. Droplets of 2.5 microns to 15 microns. Matches. Droplets of 2.5 microns to 10 microns. 40 ℃ pH 6.05 5.96 5.66 Visual observation Matches Matches Matches Microscopic observation Matches. Droplets of 2.5 microns to 12.5 microns. Matches. Droplets of 2.5 microns to 8 microns. Coincides with a droplet of 2.5μ to 7.5μ.

The chemical stability of the gel-cream formulations according to example 5 was measured by HPLC for 2 months at room temperature (RT) and 40 ° C .:

Chemical stability RT 40 ℃ T0 Mequinol: 99.8% Adapalene: 100.9% Mequinol: / Adapalene: / T1  M Mequinol: 100.2% Adapalene: 101.1% Mequinol: 107.0% Adapalene: 104.0% T2  M Mequinol: 102.9% Adapalene: 103.5% Mequinol: 101.0% Adapalene: 103.1%

The composition is physically and chemically stable at all temperatures.

Example  7: Other gel-creams Formulation

Purified Water Qsf 100%

EDTA 0.10

Allantoin 0.20

Glycerol 5.00

Xanthan Gum 0.40

Hydroxyethylcellulose 0.70

Acrylate / C10 C30 Alkyl Acrylate

Crosspolymer 0.20

Mineral Oil 10.00

Sorbitan Monooleate 1.00

Ethanol 5.00

Mequinol 2.00

Propylene Glycol 5.00

Poloxamer 124 0.20

Adapalene 0.20

10% Trisamino Solution 1.30

Purified Water 5.00

Sodium metabisulfite 0.05

Sodium sulfite 0.05

The formulation was prepared according to the method described in Example 3.

Example  8: Example  Gel-creams according to 7 Formulation  Physical and chemical stability castle

The physical stability of the gel-cream formulations according to example 7 was measured for 2 months at room temperature (RT), 4 ° C. and 40 ° C .:

From T0 Formulation  characteristic

pH 6.16 Tau  θ 65 Visual observation Glossy oily white gel-cream Centrifugation 3000 rev / min lubricity Microscopic observation Fine emulsion, droplets of 2.5μ to 7.5μ. Homogeneous Dispersion of Adapalene 10000 rev / min lubricity

T1  month T2  month T3  month RT pH 5.95 5.92 5.67 Centrifugation lubricity lubricity lubricity Visual observation Matches Matches Matches Microscopic observation Coincides with a droplet of 2.5μ to 5μ. Coincides with droplets of 2.5μ to 12.5μ. Coincides with droplets of 2.5μ to 12.5μ. θ ₀  ( Tau ) 52 41 54 4 ℃ Visual observation Matches Matches Matches Microscopic observation Coincides with a droplet of 2.5μ to 10μ. Coincides with droplets of 2.5μ to 12.5μ. Coincides with a droplet of 2.5μ. 40 ℃ pH 5.85 5.69 5.30 Visual observation Matches Matches Matches Microscopic observation Coincides with a droplet of 2.5μ to 5μ. Coincides with a droplet of 2.5μ to 7.5μ. Coincides with a droplet of 2.5μ to 7.5μ.

The chemical stability of the gel-cream formulations according to example 7 was measured by HPLC for 1 month at room temperature (RT) and 40 ° C .:

Chemical stability RT 40 ℃ T0 Mequinol: 100.6% Adapalene: 98.0% Mequinol: / Adapalene: / T1  M Mequinol: 100.7% Adapalene: 98.4% Mequinol: 106.2% Adapalene: 103.4%

The composition is physically and chemically stable at all temperatures.

Example  9: other gel-creams Formulation

Purified Water Qsf 100%

Methyl Paraben 0.20

Disodium Edetate 0.10

Glycerol 5.00

Allantoin 0.20

Carbomer 1382 0.60

Carbopol 9B1NF 0.20

Xanthan Gum 0.40

Mequinol 2.00

Butyl hydroxytoluene 0.10

Ethanol 95% 5.00

Liquid Paraffin 10.00

Sorbitan Monooleate 1.00

Poloxamer 124 0.20

Propylene Glycol 5.00

Adapalene 0.10

Sodium sulfite 0.05

Sodium bisulfite 0.05

Triethanolamine qs pH4.5

The formulation was prepared according to the method described in Example 3.

Example   10: Example  Gel-creams according to 9 Formulation  stability

The physical stability of the gel-cream formulations according to Example 9 was measured for 3 months at room temperature (RT), 45 ° C. and 55 ° C .:

At TO Formulation  characteristic

pH 4.56 Visual observation Glossy White Gel-Cream Microscopic observation Fine emulsion, droplets of 2.5μ to 15μ. Homogeneous Dispersion of Adapalene

T1  month T2  month T3  month RT pH 4.45 4.56 4.60 Visual observation Matches Matches Matches Microscopic observation Matches Matches Matches 45 ℃ Visual observation Matches Matches Matches Microscopic observation Matches Matches Matches 55 ℃ Visual observation Matches Matches Matches

The composition is physically stable (pH, viscosity) for 3 months at all temperatures.

Furthermore, no browning of the formulation is observed at 55 ° C. after 3 months.

Example  11: Other gel-creams with sunscreen Formulation

Purified Water Qsf 100%

EDTA 0.10

Glycerol 5.00

Ecampus 2.00

Xanthan Gum 0.40

Acrylate / C10 C3O Alkyl Acrylate

Crosspolymer `0.60

Mineral Oil 5.00

Octocrylene 5.00

Ceteares 20 0.50

Phenoxyethanol 1.00

Ethanol 5.00

Mequinol 2.00

Propylene Glycol 5.00

Poloxamer 124 0.20

Adapalene 0.20

Triethanolamine 0.40

Purified Water 5.00

Sodium metabisulfite 0.20

Sodium sulfite 0.20

The gel-cream formulation was prepared according to the method described in Example 3.

Sunscreen was added during step b).

Example  12: SKH2  In the mouse Adapalen  And Mequinol  Determination of Debinding Activity of Combinations

The objective of this study was to externally apply a composition containing (i) 2% mequinol, (ii) 0.1% adapalene or (iii) a combination thereof (composition according to the invention) to the tail skin of SKH2 mice. Four weeks later, the decolorizing activity of the composition is evaluated. The two formulations, gel and gel-cream, were also compared.

The two formulations (20 μl) were applied externally over 4 weeks at the rate of applying the two formulations (20 μl) once a day for 5 days to the tails of SKH2 mice divided into two groups (female mice, about 9 weeks old).

The assessment was based on various clinical observations:

Pigment formation was assessed once a week with scores ranging from 0 to 4. The rating was based on:

0: natural pigmentation

Decolorization index: rating -1 to -4

-1: a little discoloration

-2: moderate discoloration

-3: significant discoloration

-4: complete bleaching

The results are shown in FIGS. 1 and 2.

[Brief Description of Drawings]

FIG. 1 shows the kinetics of mouse skin depigmentation index as a function of treatment time for the following two formulations:

처리되지 않은 피부,-

Untreated skin,

위약으로 처리된 피부,

메퀴놀 2% 로 처리된 피부,

아다팔렌 0.1% 로 처리된 피부,

메퀴놀 2% + 아다팔렌 0.1% 의 조합 으로 처리된 피부;In gel formulations:

Placebo treated skin,

Skin treated with 2% mequinol,

Skin treated with 0.1% of adapalene,

Skin treated with a combination of mequinol 2% + adapalene 0.1%;

위약으로 처리된 피부,

메퀴놀 2% 로 처리된 피부,

아다팔렌 0.1% 로 처리된 피부,

메퀴놀 2% + 아다팔렌 0.1% 의 조합으로 처리된 피부.In gel-cream formulations:

Placebo treated skin,

Skin treated with 2% mequinol,

Skin treated with 0.1% of adapalene,

Skin treated with a combination of mequinol 2% + adapalene 0.1%.

2 shows the comparative bleaching index of the two formulations as follows:

처리되지 않은 피부-

Untreated skin

메퀴놀 2% + 아다팔렌 0.1% 의 조합으로 처리된 피부.In gel formulations:

Skin treated with a combination of mequinol 2% + adapalene 0.1%.

아다팔렌 0.1% 로 처리된 피부,

메퀴놀 2% + 아다팔렌 0.1% 의 조합으로 처리된 피부.In gel-cream formulations:

Skin treated with 0.1% of adapalene,

Skin treated with a combination of mequinol 2% + adapalene 0.1%.

The findings show that after 4 weeks the composition containing 2% mequinol has a significant decolorizing effect, which increases when applied in combination with 0.1% adapalene.

0.1% adapalene alone has no depigmentation effect because the bar chart shows that the rating is zero for gel formulations and gel-cream formulations.

The same score corresponding to zero was also recorded for the control (untreated mice and mice treated with placebo).

The bleaching effect was faster and more pronounced in the gel-cream formulations, especially for the combination of mequinol and adapalene.

The results show a synergistic effect on the decolorizing activity between mequinol and adapalene. In particular, the combination of 2% mequinol and 0.1% adapalene has a faster and more pronounced decolorizing effect than mequinol alone.

For the treatment of surpluses, hepatic or blemishes, the formulations according to Examples 1, 3, 5, 7 and 9 can be applied once or twice a day until complete bleaching.

Claims (17)

A decolorizing composition containing mequinol and adapalene in a physiologically acceptable medium, wherein the composition is an aqueous-alcoholic gel or gel-cream. The composition of claim 1 wherein the aqueous-alcoholic gel or gel-cream contains 2 to 10% alcohol. A composition according to claim 1 or 2, wherein the alcohol is ethanol, isopropanol or butanol. 4. A composition according to any one of claims 1 to 3, which also contains a chelating agent, a surface-active wetting agent and at least one gelling agent. The composition of claim 1, wherein the aqueous-alcoholic gel or gel-cream contains one or more of the following ingredients: a) carbomer; b) one or more other gelling agents; c) antioxidants; d) an oil phase; e) moisturizer / softener; f) anti-irritant; g) pH neutralizing agent; h) preservatives. 6. The composition of claim 1, wherein the aqueous-alcoholic gel or gel-cream contains a carbomer and at least one other gelling agent or said carbomer and at least one other carbomer. 7. The composition according to any one of claims 1 to 6, wherein the aqueous-alcoholic gel or gel-cream contains: 0.01-5% mequinol; 0.10 to 2% of adapalene; 2 to 10% ethanol; 0.01 to 2% of one or more gelling agents; 0 to 1% of an antioxidant; 0.01 to 20% of chelating agent; 0-20% oily liquid phase. 8. A composition according to any of claims 1 to 7, wherein the aqueous-alcoholic gel or gel-cream contains: 2% mequinol; 0.10% to 2% of adapalene; 5% ethanol; 1 to 2% of one or more gelling agents; 0.1 to 0.5% antioxidant; 0.10% EDTA; 0-15% oily liquid phase. The composition of claim 1, wherein the aqueous-alcoholic gel-cream contains: 2% mequinol; 0.10% of adapalene; 5% ethanol; 1 to 2% of one or more gelling agents; 0.1 to 0.4% antioxidant; 0.10% EDTA; 5 to 15% oily liquid phase. 10. A composition according to any one of the preceding claims containing a chemical or physical sunscreen. The composition according to any one of claims 1 to 10, as a medicament. 12. A process for the preparation of a composition according to any one of the preceding claims, characterized in that it comprises the following steps: a) preparing a formulation phase comprising water and chelating agent, stirring until dissolved, and optionally adding humectant and anti-irritant; b) heating the mixture of step a) to 60 ° C., injecting a gelling agent or gelling agents and stirring until homogenized; c) leaving the mixture to room temperature with stirring in a Rayneri stirrer; d) preparing a first active phase containing mequinol and alcohol in a separate beaker with magnetic stirring until complete dissolution; e) adding the first active phase to the formulation after returning to room temperature and maintaining stirring; f) preparing a second active phase containing adapalene, a surface-active wetting agent and a humectant in a separate beaker and stirring until a smooth homogeneous dispersion is obtained; g) then adding the second active phase to the formulation after returning to room temperature and maintaining stirring; h) neutralization with a neutralizer while stirring with a Rayneri stirrer to obtain the desired pH; i) Add antioxidant to the formulation and stir. 13. The process according to claim 12, wherein the oil phase obtained by mixing the preservative, the surfactant and the oil heated to 60 ° C. in a water bath is added to the formulation obtained at the end of step b). Use of a composition according to any one of claims 1 to 11 in the manufacture of a pharmaceutical formulation for the treatment and / or prevention of dermatological conditions associated with pigmentation disorders. 15. The post-inflammatory hyperpigmentation, spots, genetic predisposition according to claim 14, wherein the condition associated with pigmentation disorder is blemishes, liver spots, surpluses, senile surpluses, vitiligo, freckles, abrasions, burns, scars, skin diseases, contact allergies. Hyperpigmentation by, metabolic or hyperpigmentation by medicine, melanoma or any other hyperpigmentation lesion. Cosmetic use of a composition according to any one of claims 1 to 10 for preventing and / or preventing the harmful effects of sun and / or light-induced or chronological aging. A non-therapeutic cosmetic treatment method for improving the complexion of skin and / or its surface appearance, the method comprising: a mequinol and adapalene-containing aqueous-alcoholic gel or gel-cream according to any one of claims 1 to 10, and Optionally applying a sunscreen to the skin and / or the appendages thereof

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