WO1995026709A1 - Topical retinal-based composition - Google Patents

Abstract

Skin-care or cosmetic retinal-containing composition, wherein the composition has a pH of 3 to 6 and contains a stabilising system substantially comprising one or more liposoluble antioxidants.

Description

 TOPICAL COMPOSITION BASED ON RETINAL

The present invention relates to new compositions for topical use containing retinal. It also relates to a process for the preparation of such stabilized compositions containing retinal.

The use of retinoid-type derivatives is the subject of numerous studies today.

Retinoic acid, also known as vitamin A acid or tretinoin, has been recognized as a product of great interest in the treatment of keratinization disorders.

First used in the treatment of acne, this molecule quickly became the subject of applications such as the treatment of age spots, various skin conditions and recently in the treatment of wrinkles, an area in which it has real activity.

The interest of this molecule has led to study various compounds related to acidic vitamin A and in particular retinol and its derivative retinal or retinaldehyde.

Various works described in patent FR-2,681,784 (Pierre Fabre (H. Cousse and G. Mouzin)) and J.H. Saurat have demonstrated that the retinal has properties identical to those of retinoic acid. In addition, this molecule, having no acid function, has a much better tolerance than acid vitamin A.

It has been shown that in the treatment of skin alterations due to aging and photoaging, the retinal has a remarkable action by topical use.

Ideally, the use of preparations to fight against skin aging uses emulsions rich in fatty substances, in emollients to be able to promote the nutrition of the skin and the maintenance of its hydration.

However, for the treatment of certain skin dermatoses, light emulsions without lipids may be used to have a non-oily appearance on the skin. The stability of the retinal in formulations containing such products is difficult to control. It is well known that retinol is very unstable in alcohol form and that in order to be able to maintain the integrity of this active principle, it is necessary to use it in the form of an ester of palmitic or acetic acid, which are its derivatives. the most famous.

The pharmacologically active retinaldelyde can be in 13-cis, 13-trans form or in the form of a mixture of these two isomers.

Naturally, the 13-trans form tends to partially transform into the 13-cis form when introduced into preparations. If it is the 13-cis form which is used, it is a transformation into 13-trans form which is noted.

These two pure or mixed forms can be used, since these two forms are pharmacologically active and their skin tolerance is identical. A 13-trans-cis equilibrium tends to be established anyway.

However, studies of the aging of several preparations have led to the conclusion that many other forms of retinaldelyde can form.

The Applicant has demonstrated, among other undesirable products, the formation of:. 9-cis retinal. 11-cis retinal and. even polymer-type condensation products.

It is important to keep the retinal in 13-trans and 13-cis form during storage of the preparations and to avoid its degradation into less active and less well tolerated forms.

Unexpectedly, compositions for dermatological and / or cosmetic use containing retinal may be stabilized by a system of specific antioxidants and the adjustment of the pH to acid values. This is why the present invention relates to a dermatological or cosmetic composition containing retinal, characterized in that the pH of the composition is between 3 and 6 and in that it contains a stabilizing system consisting essentially of one or several fat-soluble antioxidants.

Excellent results are obtained for retinal concentrations of between 0.01% and 5% by weight relative to the total weight of the composition. The retinal is preferably present in the compositions according to the invention in soluble form, which represents an advantage over the compositions in which the retinoids are dispersed, in micronized form; in the latter it is necessary to introduce adjuvants such as PVP to disperse the solubilized active. The compositions according to the invention are devoid of PVP and are specially suitable for the formulation of dissolved retinal, for example by the addition of ethyl alcohol.

Unlike the compositions described above, the composition according to the invention almost exclusively contains liposoluble antioxidants. These liposoluble antioxidants can be chosen from the group comprising: alpha-tocopherol and its esters, chemical antioxidants such as butylhydroxyanisole, butylhydroxytoluene, propyl gallate, nordihydroguaiaretic acid, palmitate and ascorbyl acetate , and mixtures thereof.

Preferably, the concentration of alpha tocopherol present in the composition is between 0.05 and 5% relative to the total weight of the composition.

When chemical antioxidants are used as stabilizers, their concentration is advantageously between 0.005 and 0.1% relative to the total weight of the composition. The pH of the composition is adjusted using bases or acids, organic or mineral, therapeutically and / or cosmetologically acceptable, to values between 3 and 6, preferably between 4 and 5.

The choice of pH regulation system depends in part on the other components, which may have an intrinsic acidic or basic character. If an acid is necessary, it can be chosen in particular from hydrochloric acid, sulfuric acid, sorbic acid, lactic acid, citric acid or tartaric acid.

The organic or inorganic bases suitable for implementing the invention can be chosen in particular from sodium hydroxide, potassium hydroxide, ammonium hydroxide, a primary, secondary or tertiary alkylamine, an alkanolamine, a diamine, a dialkylamine, a dialcanolamine, an alkylalkanolamine, a trialkylamine, a trialkanolamine, a dialkylalkanolamine or an alkyldialcanolamine in which the alkyl or alkanol radicals contain 1 to 8 carbon atoms.

The compositions according to the invention also contain all the cosmetologically or pharmaceutically acceptable excipients, which are known to those skilled in the art such as, for example, anti-bacterial or anti-fungal preservatives, perfumes, dyes or emollient agents for give skin comfort to this preparation. In certain cases, the compositions of the invention can also usefully contain a buffer, for example a phosphate and / or acetate buffer. Advantageously, PEG can be introduced to promote the dissolution of the retinal in the compositions.

The compositions formulated according to the invention having improved stability characteristics can be prepared in the form of a cream, or a fluid emulsion with an aqueous continuous phase, the fatty phase content of which can vary from 2 to 60%. Water / oil emulsions can also be prepared in accordance with the characteristics of the invention.

Aqueous or hydroalcoholic solutions containing retinal and stabilized by adjustment to an acidic pH and the presence of at least one fat-soluble antioxidant are included in the invention. The compositions according to the invention, according to another aspect can be formulated in aqueous, hydroalcoholic or oily gels. The subject of the invention is also a process for preparing a dermatological or cosmetic composition which comprises the following steps: a) the retinal is mixed with at least one lipid-soluble antioxidant and pharmaceutically or cosmetologically acceptable excipients, b) it is adjusted the pH with a base or a mineral or organic acid to obtain a mixture of pH between 3 and 6, c) the mixture obtained at the end of step b) is placed under vacuum, d) the vacuum is broken with an inert gas or a rare gas in order to recover a deaerated composition.

Indeed, it is preferable to completely deaerate the preparation by putting it under high vacuum to completely eliminate the air from the formula. The solubility of atmospheric gases being inevitable because there will always be a gas phase-liquid phase balance (atmosphere-preparation), it will be necessary to passivate the preparation by breaking the vacuum with an inert gas such as highly purified nitrogen or a rare gas like argon, krypton or radon.

To promote the stability of the retinal, avoid exposure to heat and light. The process will therefore advantageously be carried out at a temperature less than or equal to 15 ° C, protected from light.

The examples which follow are intended to illustrate the invention without in any way limiting its scope.

Example 1

Retinal 0.050 g

Ethanol at 95 ° 3 g Polyethylene glycol 600 p 5 g

Tocopherol acetate 0.5 g

Butylhydroxy toluene 0.02 g

Thick vaseline oil 5 g

Castor oil ethoxylated 2 g Vinyl carboxy polymer 1 g

Sorbic acid 0.05 g

Methyl parahydroxy benzoate 0.15 g

Triethanolamine 0.15 g

Water 100 g

In this formula, triethanolamine partially neutralizes the vinyl carboxy polymer, which gives an acid pH of 4.5 in the final preparation.

Example 2

Retinal 0.05 g

Ethoxylated beeswax 12.5 g

Vaseline oil 9 g

Sweet almond oil 13 g

White petrolatum 7.3 g

Hydrogenated and ethoxylated palm oil 5 g

Silicone 3 g

Glycerol 10 g

0.2 g imidazolidine

Butyl hydroxy Toluene 0.01 g

Water 100 g

Lactic acid for pH 4.5

In this cream the pH is adjusted between 4.3 and 4.8 thanks to the addition of lactic acid. Example 3

Retinal 0.05 g

Vaseline oil 35 g

Beeswax 17 g

Lanolin 10 g

Sorbitan monostearate 2 g

Ethoxyl sorbitan monostearate 3 g

0.2 g imidazolidine

Propyl gallate 0.01 g

Water qs 100 g

Lactic acid for pH 4.5

EXAMPLE 4 Aqueous Lotion

Retinal 0.05 g

Propylene glycol 60 g

BHT 0.01 g

Water 100 g

Lactic acid for pH 4.5

EXAMPLE 5 Hydro-alcoholic gel

Retinal 0.05 g

BHT 0.01 g

Alcohol 95 60 g

Hydroxyethyl cellulose 1 g

Water 100 g

Lactic acid for pH 4.5

Hydroxyethyl cellulose makes it possible to gel the product and the pH is adjusted using lactic acid between 4.3 and 5. Example 6

: ^_ -

Example: Loss of Retinal at 12 months formulation

: pH 7: pH 4.5

1 - 14.1% - 2.2%

2 - 15.3% - 2%

3 - 16.1% - 2.3%

4 - 15.7% - 1.8%

5 - 14.3% - 1.9%

In the table above, the control compositions of the first column were modified by adding HCl (0.1 N) to bring their pH to 7.

Claims

1. Dermatological or cosmetic composition containing retinal, characterized in that the pH of the composition is between 3 and 6 and in that it contains a stabilizing system consisting essentially of one or more liposoluble antioxidants. 2. Composition according to claim 1, characterized in that the fat-soluble antioxidant is chosen from the group comprising: alpha-tocopherol and its esters, chemical antioxidants such as butylhydroxyanisole, butylhydroxytoluene, propyl gallate, nordihydroguaiaretic acid, palmitate and ascorbyl acetate, and mixtures thereof. 3. Composition according to one of claims 1 or 2, characterized in that the pH is between 4 and 5. 4. Composition according to one of claims 1 to 3, characterized in that the pH of the composition is adjusted using a mineral or organic acid chosen in particular from hydrochloric acid, sulfuric acid, sorbic acid, lactic acid, citric acid or tartaric acid. 5. Composition according to one of claims 1 to 3, characterized in that the pH of the composition is adjusted using an organic or mineral base chosen in particular from sodium hydroxide, potassium hydroxide, ammonium hydroxide, a primary, secondary or tertiary alkylamine, an alkanolamine, a diamine, a dialkylamine, a dialcanolamine, an alkylalkanolamine, a trialkylamine, a trialcanolamine, a dialkylalkanolamine or an alkyldialcanolamine of which the alkyl or alkanol radicals count 1 to 8 carbon atoms. 6. Composition according to one of claims 1 to 5, characterized in that the retinal concentration is between 0.01% and 5% by weight relative to the total weight of the composition. 7. Composition according to one of claims 2 to 6, characterized in that the concentration of alpha tocopherol is between 0.05 and 5% relative to the total weight of the composition. 8. Composition according to one of claims 2 to 7, characterized in that the concentration of chemical antioxidant is between 0.005 and 0.1% relative to the total weight of the composition. 9. Method for preparing a composition according to one of claims 1 to 8, characterized in that: a) at least the retinal is mixed with at least one lipid-soluble antioxidant and pharmaceutically or cosmetologically acceptable excipients, b) the pH is adjusted with a base or an inorganic or organic acid to obtain a mixture of pH between 3 and 6, c) the mixture obtained at the end of step b) is placed under vacuum, d) the vacuum with an inert gas or a rare gas in order to recover a deaerated composition. 10. Method according to claim 9, characterized in that the steps are carried out at a temperature less than or equal to 15 ° C. 11. Method according to claim 10, characterized in that the steps are carried out protected from light.