CN1726017A - Aqueous-alcoholic depigmenting gel containing a phenolic derivative and a retinoid - Google Patents

Abstract

The invention relates to a depigmenting composition for cosmetic or pharmaceutical application, comprising a phenolic derivative, a retinoid, especially a dispersed retinoid, and optionally a sunscreen in the form of an aqueous-alcoholic gel, to the process for preparing it and to its use in cosmetics and dermatology.

Description

Hydroalcoholic depigmentation gel containing phenolic derivatives and retinoids

The present invention relates to a depigmenting composition for cosmetic or pharmaceutical applications comprising a phenolic derivative, a retinoid (in particular a dispersed retinoid) and optionally a sunscreen, being aqueous-alcoholic Gel form.

With this composition, the gel provides a stable and non-hazardous composition.

Among the therapeutic agents suggested in the treatment of skin hyperpigmentation, phenolic derivatives such as hydroquinone and its derivatives have been used for decades as the most effective active agents. The therapeutic use of these agents is derived from the observed depigmentation of the skin in the case of rubber industry operations, where some of these products are used as antioxidants. Therefore, many studies have confirmed their efficacy alone or in combination with other depigmenting agents [Jorge L. Sanchez, M.D. and Miguel Vazquez, M.D. International Journal of Dermatology Jan-Feb 1982 Vol. 21, pp. 55-58]. They have also been found to be virtually indispensable active agents in the treatment of hyperpigmentation and are therefore present in many industrial products. Hydroquinone has been the subject of various patent applications, notably US 3856934, in which hydroquinone is combined with retinoic acid and corticoids as a depigmenting composition.

However, the incorporation of phenolic derivatives such as hydroquinone in particular presents two major disadvantages.

First, formulations containing phenolic derivatives such as hydroquinone, alone or in combination with other actives, typically degrade. In particular, hydroquinone is known to be sensitive to oxidation and heat, leading to reduced potency, rapid browning of the ingredients and sometimes even stratification or phase separation of the ingredients.

This problem was found to be an obstacle to obtaining compositions containing several active agents, in particular phenolic derivatives and retinoids.

In the prior art, sulfites are commonly used to reduce this phenomenon, but they are not sufficient to overcome this disadvantage. They also impair the viscosity of electrolyte sensitive formulations, leading to deposition of active agents such as retinoids. In particular, carbomer, which is usually used to provide the least viscosity, is affected by the sulfite-based electrolyte and so is no longer sufficient alone to obtain good stability of retinoids.

Furthermore, in order to accelerate the dissolution of phenolic derivatives, phenolic derivatives such as hydroquinone are often subjected to the action of heat during the preparation of the composition, especially in standard emulsions, which initiates and accelerates the phenomenon of browning.

A second disadvantage arising from the presence of phenolic derivatives such as hydroquinone alone or in combination with other active agents is their high irritation.

High concentrations of hydroquinone can cause post-onset hypermelanosis and chloasma phenomena due to irritation.

Local irritation and dermatitis may occur after long-term use of high concentrations of hydroquinone ["N-acetyl 4Scysteaminylphenol as a new type of depigmenting agent" Jimbow K. Arch. Dermatol. 1991 Oct;127(10):1528-1534].

Treatment with hydroquinone may be accompanied by irritation, which may lead to post-onset hypermelanosis. The appearance of this irritation depends on the concentration of hydroquinone. For the 10% concentration, this stimulation was high, while at the 5% dose it was significantly reduced and was considered to be essentially absent at the 2% concentration ["Les agents chimiques depigmentants (Depigmenting Chemicals )" JP. Ortonne Ann. Dermatol. Venerol. 1986, 113:733-736].

The selected composition may thus play a major role in reducing these effects and improving the tolerability of compositions containing two potentially irritating actives.

Therefore, the problem posed here is to obtain a composition containing phenolic derivatives and retinoids which are physically stable over time, thus ensuring that the ingredients remain unchanged. The product must also have a good cosmetic effect and be minimally irritating.

The Applicant has surprisingly found that hydroalcoholic gels with suitable excipients give good results in terms of physical and chemical stability. The gel also offers an excellent balance between stability, especially to temperature and oxidation, potency, harmlessness and cosmeticity.

The Applicant has developed a process for the preparation of the composition of the invention which can be prepared under cold conditions without the need for heating, thus making it possible to avoid exposure of the phenolic derivatives to the effects of heat.

The present invention therefore relates to a depigmentation composition comprising a phenolic derivative, a retinoid, in particular a dispersed retinoid, and optionally a sunscreen in a physiologically acceptable medium, characterized in that It is in the form of a hydroalcoholic gel.

The term "hydroalcoholic gel" denotes an aqueous gel comprising alcohol, at least one gelling agent and optionally a small proportion (up to 15%) of a fatty phase.

All ratios are expressed herein as weight percent based on the total weight of the composition.

The compositions according to the invention preferably contain 1-30% alcohol, preferably 2-20%, more especially 4-15% alcohol.

Among the alcohols that may be mentioned are, without limitation, ethanol, isopropanol and butanol.

Compositions according to the invention may preferably contain one or more of the following components:

a) carbomer,

b) another gelling agent,

c) antioxidants,

d) Chelating agents.

The hydroalcoholic gel-type compositions according to the invention provide good skin tolerance. The composition is also easier to apply than viscous lotions and leaves a pleasant fresh feel.

More particularly, the present invention is a hydroalcoholic gel for depigmentation comprising one or more of the following components:

-0.01-10% of phenolic derivatives,

- 0.0001-5% retinoids,

- 0-30% sunscreen,

-0.01-10% of carbomer and/or other gelling agents,

- 0.01-2% antioxidants, and

- 0.01-1% chelating agent.

A preferred composition according to the invention comprises:

-4.00% phenol derivatives,

-0.10% retinoids,

-20.00% ethanol,

-0.40% carbomer,

-0.60% of another gelling agent,

-0.40% sulfites, and

-0.10% EDTA.

A particularly preferred composition according to the invention comprises:

-4.00% 4-Hydroxyanisole,

-0.10% retinoids,

-5.00% ethanol,

-0.60% carbomer,

-0.40% of another gelling agent,

-0.40% sulfites, and

-0.10% EDTA.

Among carbomers, non-limiting examples that may be mentioned include Carbopol 981 and Carbopol ETD 2020 marketed by the company BF Goodrich.

Among other possible gelling agents, non-limiting examples that may be mentioned include xanthan gum, such as Keltrol T, marketed by the company Kelco; acrylates/C10-C30 alkyl acrylate crosspolymers, such as BF Goodrich products marketed by companies as Pemulen TR1 or Carbopol 1382; hydroxypropyl cellulose such as that marketed by Aqualon as Natrosol HHX250; and acrylamide/sodium acryloyldimethyltaurate copolymer and isohexadecane and polyethylen Oxylether 80, sold as Simulgel 600 by the company SEPPIC.

Among antioxidants, non-limiting examples that may be mentioned include ascorbic acid and its salts, tocopherol and sulfites such as sodium metabisulfite or sodium sulfite.

Examples of chelating agents that may be mentioned include ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate and sodium edetate.

Non-limiting examples of phenol derivatives that may be mentioned include hydroquinone, 4-hydroxyanisole and hydroquinone monobenzyl ether.

The term "retinoid" denotes any compound that binds to the retinoic acid receptor (RAR) and/or to the retinoic X (retinoic X) receptor (RXR), as well as their precursors and derivatives.

Preferably, the retinoid is a compound selected from the benzonaphthalene-based retinoids described in patent application EP 0199636. Adapalene (6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid) and their precursors and/or derivatives are particularly preferred. Tretinoin and isotretinoin can also be used.

The term "pre-retinoid" denotes intermediate biological precursors or substrates thereof, as well as chemical precursors thereof.

The term "retinoid derivatives" denotes their metabolic and chemical derivatives.

The term "sunscreen" means a chemical or physical sunscreen and mixtures thereof, non-limiting examples that may be mentioned include physical sunscreens such as titanium dioxide and zinc oxide, and chemical sunscreens such as octocrylene, Ethylhexyl methoxycinnamate, octyl salicylate, avobenzone, oxybenzone, ecamsule, and drometrizole trisitoxane.

Each sunscreen may be added at a concentration of 0.001-20% by weight based on the total weight of the composition.

Obviously, in the compositions according to the invention, the amount of active agent will depend on the combination chosen and thus in particular on the quality of treatment desired.

The composition may also contain additives commonly used in cosmetics or pharmaceuticals, such as neutralizers, wetting agents and/or solubilizers, emollients, sedatives, preservatives or pH correctors, or mixtures thereof.

Obviously, a person skilled in the art will know how to choose these additive compounds and/or their amounts so that the advantageous properties of the composition according to the invention are not or substantially not adversely affected.

These additives may be present in the compositions of the invention at 0.001 to 20% by weight, based on the total weight of the composition.

Examples of neutralizing agents that may be mentioned include amine bases such as triethanolamine, diethanolamine or trimethylamine.

An example of a pH corrector that may be mentioned is citric acid.

Examples of wetting agents and/or solubilizers that may be mentioned include glycerin, sorbitol, propylene glycol and polyethylene glycol 400.

The compositions according to the invention may also contain 0.01-15% of a fatty phase, essentially comprising softeners. Non-limiting examples of emollients that may be mentioned include mineral oils such as Primol 352, Marcol 82, Marcol 172 and Marcol 352 sold by the company Esso; vegetable oils such as sweet almond oil, palm oil, soybean oil, castor bean oil, Sunflower oil; esters, such as cetearyl isononanoate (cetearyl), such as the product sold as Ceitol SN by the company Cognis France, diisopropyl adipate, such as the product sold as Ceraphyl 230 by the company ISF , isopropyl palmitate, such as the product sold as Crodamol IPP by the company Croda, caprylic/capric triglycerides, such as the product sold as Miglyol 812 by the company Huls/Lambert Riviere; silicone oils, such as dimethicone, For example the product sold by the company Dow Corning as Dow Corning 200 Fluid, or cyclomethicone such as the product sold by the company Dow Corning as Dow Corning 244 Fluid.

Non-limiting examples of sedatives that may be mentioned include allantoin and talc.

Non-limiting examples of preservatives that may be mentioned include benzalkonium chloride, phenoxyethanol, benzyl alcohol, diazolidinyl ureas and parabens, or mixtures thereof.

The subject of the present invention is also the composition described above as a medicinal product.

The object of the present invention also relates to a process for the preparation of a composition in the form of an aqueous alcoholic gel, carried out at room temperature, comprising the following steps:

a) preparing a batch phase comprising water, gelling agent and optionally a chelating agent, which is kept stirring until the mixture is completely homogeneous;

b) optionally adding a neutralizer solution to the batch phase;

c) preparing a first active phase comprising a phenol derivative and an alcohol, which is kept stirring until complete dissolution;

d) preparing a second active phase comprising a retinoid and optionally a wetting agent, which is kept stirring until a smooth homogeneous dispersion is obtained;

e) Mix the above active phases independently into the ingredient phase and stir until completely mixed.

In a preferred embodiment, the subject of the present invention also relates to a process for the preparation of a composition in the form of an aqueous alcoholic gel, carried out at room temperature, comprising the following steps in sequence:

a) preparing a batch phase comprising water, chelating agent and gelling agent, which is kept stirring until the mixture is completely homogeneous;

b) adding the neutralizing agent solution into the batching phase;

c) preparing the first active phase comprising the phenol derivative and the alcohol in a separate beaker and stirring it magnetically until complete dissolution;

d) preparing the second active phase comprising the retinoid and the wetting agent in a separate beaker, stirring it until a smooth homogeneous dispersion is obtained;

e) Mix the above active phases independently into the ingredient phase and stir until completely mixed.

If necessary, the natural pH of the mixture can be checked and corrected with a neutralizer solution in one of the above-mentioned preparation steps, and optional additives can be added, depending on their chemical nature.

Thus, in a particular embodiment of the method according to the invention, the antioxidant predissolved in water is added to the fatty phase after step (b).

In a last particular embodiment of the process according to the invention, the fatty phase is added to the gel obtained after step (e).

Depending on the physicochemical properties of the sunscreen, a person skilled in the art will be able to introduce the sunscreen in one of the above steps.

The term "ingredient phase" means a mixture obtained by introducing a group of components together into a single phase.

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

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

The composition of the present invention is particularly suitable for the treatment and/or prevention of skin diseases associated with pigmentary disorders, such as melasma, melasma, moles, age spots, vitiligo, freckles, caused by abrasions, burns, scars, Post-onset hyperpigmentation due to dermatological or contact allergy; genetically determined hyperpigmentation, metabolic or medical hyperpigmentation, melanoma, or any other hyperpigmented injury.

The compositions according to the invention are also used in cosmetics, in particular for preventing and/or counteracting the harmful effects of the sun and/or against photoinduced or chronic aging of the skin and integument.

The compositions of the invention are also useful for body and hair hygiene.

The present invention also relates to a method of non-therapeutic cosmetic treatment for beautifying the skin and/or improving its surface appearance, characterized in that it will contain phenolic derivatives, retinoids (in particular dispersed retinoids) and optionally The hydroalcoholic gel of the sunscreen is applied to the skin and/or its epidermis.

The following formulation examples serve to illustrate the compositions of the present invention, but do not limit the scope thereof. Examples illustrating the stability of the compositions of the invention are also described.

Ingredients Example

In the following compositions (Examples 1-6), the proportions of various ingredients are percentages by weight based on the total weight of the composition.

Example 1: raw material % Hydroquinone 4.00 adapalene 0.10 ethanol 20.00 EDTA 0.10 Carbopol 980 0.40 Acrylates/C10-C30 Alkyl Acrylate Crosspolymer 0.60 Sodium metabisulfite 0.20 Sulfite 0.20 Propylene Glycol 5.00 glycerin 5.00 Phenoxyethanol 1.00 10% aqueous solution of trimethylamine 4.00 citric acid (Appropriate amount to pH5-7) purified water Appropriate amount to 100

Example 2: raw material % hydroquinone 4.00 adapalene 0.10 ethanol 20.00 EDTA 0.10 Carbopol 980 0.30 Carbopol 981 0.30 xanthan gum 0.40 Sodium metabisulfite 0.20 Sulfite 0.20 Phenoxyethanol 1.00 Propylene Glycol 5.00 glycerin 5.00 10% aqueous solution of trimethylamine 4.00 citric acid (Appropriate amount to pH 5-7) purified water Appropriate amount to 100

Example 3: raw material % Hydroquinone 4.00 adapalene 0.10 ethanol 20.00 EDTA 0.10 Carbopol 980 0.60 xanthan gum 0.40 Sodium metabisulfite 0.20 Sulfite 0.20 Phenoxyethanol 1.00 Propylene Glycol 5.00 glycerin 5.00 10% aqueous solution of trimethylamine 4.00 citric acid (Appropriate amount to pH5-7) purified water Appropriate amount to 100

Example 4: raw material % Hydroquinone 2.00 retinoic acid 0.10 ethanol 30.00 Sodium edetate 0.10 Carbopol 981 0.50 Carbopol 1382 0.50 Sodium metabisulfite 0.20 Sulfite 0.20 Propylene Glycol 5.00 glycerin 5.00 Triethanolamine (Appropriate amount to pH5-7) purified water Appropriate amount to 100

Example 5: raw material % 4-Hydroxyanisole 5.00 retinoic acid 0.10 ethanol 5.00 Disodium Calcium EDTA 0.10 Carbopol ETD 2020 0.40 Hydroxypropyl Cellulose 1.00 Sodium metabisulfite 0.20 Sulfite 0.20 Propylene Glycol 5.00 Polyethylene glycol E400 5.00 10% aqueous solution of trimethylamine 4.00 citric acid (Appropriate amount to pH5-7) purified water Appropriate amount to 100

Embodiment 6: raw material % hydroquinone 4.00 adapalene 0.10 ethanol 20.00 EDTA 0.10 Carbopol 981 0.60 xanthan gum 0.40 Sodium metabisulfite 0.20 Sulfite 0.20 liquid paraffin 10.00 Phenoxyethanol 1.00 Propylene Glycol 5.00 glycerin 5.00 10% aqueous solution of trimethylamine 4.00 citric acid (Appropriate amount to pH5-7) purified water Appropriate amount to 100

Embodiment 7: raw material % hydroquinone 4.00 adapalene 0.10 ethanol 20.00 EDTA 0.10 Carbopol 1382 0.60 xanthan gum 0.40 Sodium metabisulfite 0.20 Sulfite 0.20 liquid paraffin 10.00 Avobenzene 2.00 Titanium dioxide 2.00 Phenoxyethanol 1.00 Propylene Glycol 5.00 glycerin 5.00 10% aqueous solution of trimethylamine 4.00 citric acid (Appropriate amount to pH5-7) purified water Appropriate amount to 100

Embodiment 8: raw material % paramethoxyphene 5.00 retinoic acid 0.10 ethanol 15.00 Disodium Calcium EDTA 0.10 Carbopol ETD 2020 0.40 Hydroxypropyl Cellulose 1.00 Ecampus 1.00 Sodium metabisulfite 0.20 Sulfite 0.20 Propylene Glycol 5.00 Polyethylene glycol E400 5.00 citric acid (Appropriate amount to pH5-7) purified water Appropriate amount to 100

Ingredient Examples 1-8 can be used once or twice a day until a complete depigmentation effect is achieved, for the treatment of moles, chloasma or melasma.

Claims (17)

1. A depigmentation composition comprising a phenolic derivative, a retinoid, especially a dispersed retinoid, and optionally a sunscreen in a physiologically acceptable medium, characterized in that it is a hydroalcoholic gel glue. 2. Composition according to claim 1, characterized in that the hydroalcoholic gel contains 1-30% alcohol. 3. Composition according to claim 1 or 2, characterized in that the alcohol is ethanol. 4. Composition according to any one of claims 1-3, characterized in that the hydroalcoholic gel also contains one or more of the following components: a) carbomer, b) another gelling agent, c) antioxidants, d) Chelating agents. 5. Composition according to any one of claims 1-4, characterized in that the hydroalcoholic gel contains: -4.00% phenol derivatives, -0.10% retinoids, -20.00% ethanol, -0.40% carbomer, -0.60% of another gelling agent, -0.40% sulfites, and -0.10% EDTA. 6. Composition according to any one of claims 1-5, characterized in that the phenol derivative is hydroquinone. 7. Composition according to any one of claims 1-5, characterized in that the phenol derivative is 4-hydroxyanisole. 8. Composition according to claim 7, characterized in that the hydroalcoholic gel contains: -4.00% 4-Hydroxyanisole, -0.10% retinoids, -5.00% ethanol, -0.60% carbomer, -0.40% of another gelling agent, -0.40% sulfites, and -0.10% EDTA. 9. Composition according to any one of claims 1-8, characterized in that the retinoid is adapalene. 10. Composition according to any one of claims 1 to 9, characterized in that it contains a chemical sunscreen or a physical sunscreen substance. 11. Composition according to any one of claims 1-10 for use as a medicinal product. 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 carried out at room temperature: a) preparing a batch phase comprising water, gelling agent and optionally a chelating agent, which is kept stirring until the mixture is completely homogeneous; b) optionally adding a neutralizer solution to the batch phase; c) preparing a first active phase comprising a phenol derivative and an alcohol, which is kept stirring until complete dissolution; d) preparing a second active phase comprising a retinoid and optionally a wetting agent, which is kept stirring until a smooth homogeneous dispersion is obtained; e) Mix the above active phases independently into the ingredient phase and stir until completely mixed. 13. Process according to claim 12, characterized in that an antioxidant predissolved in water is added to the formulation phase after step (b). 14. Process according to claim 12 or 13, characterized in that after step (e) a fatty phase is added to the gel obtained. 15. Use of the composition according to any one of claims 1-10 for the preparation of a medicament for the treatment and/or prevention of skin diseases associated with pigmentation. 16. Cosmetic use of a composition according to any one of claims 1 to 10 for preventing and/or combating the harmful effects of sunlight and/or combating light-induced or chronic aging. 17. A method of non-therapeutic cosmetic treatment for beautifying the skin and/or improving its surface appearance, characterized in that it comprises a phenolic derivative, a retinoid, especially a dispersed retinoid, and optionally a sunscreen The hydroalcoholic gel is applied to the skin and/or its epidermis.