EP1265619A1

EP1265619A1 - Composition based on sphingolipid and beta-hydroxy-acid for skin care

Info

Publication number: EP1265619A1
Application number: EP01917176A
Authority: EP
Inventors: Cyril Estanove; Florence Clemenceau
Original assignee: Laboratoire D'evolution Dermatologique (led)
Current assignee: Laboratoire D'evolution Dermatologique (led)
Priority date: 2000-03-20
Filing date: 2001-03-19
Publication date: 2002-12-18
Also published as: WO2001070235A1; FR2806301A1; AU4426801A; FR2806301B1

Abstract

The invention concerns a dermatological composition. Said dermatological composition, capable of being topically applied, comprises in combination at least a beta-hydroxy-acid such as salicylic acid, or one of its acceptable salts and esters, and at least a sphingolipid or a sphingolipid precursor, for example sphingosine and phytosphingosine. The invention is applicable to dermatological compositions for skin treatment and care, in particular for treating acne.

Description

COMPOSITION BASED ON S PHINGOLI PIDE AND BETA-HYDROXY-ACID FOR SKIN CARE

The present invention relates to a pharmaceutical and cosmetic composition, and more particularly to a composition comprising in combination at least one beta-hydroxy acid and at least one sphingolipid or a sphingolipid precursor, usable by topical administration for treatments and skin care.

Sphingolipids are substances essentially comprising a fatty acid, a polar group and a chemical structure called sphingoid base, consisting of a long hydrocarbon chain derived from 2-amino-1,3-diol. It is known that certain sphingoid bases, in particular sphingosine and phytosphingosine, precursors of ceramides, are present in human skin, and studies have shown that these molecules have inhibitory properties of the protein inase C, and seem to be involved in differentiation. keratinocytes of the epidermis. It has also been observed that sphingosines present in the stratum corneum and other layers of the epidermis inhibit the growth of certain undesirable microorganisms. Sphingosine, or 2-amino-4-octadecene-1,3-diol, is the most important base of animal sphingolipids. Phytosphingosine, or 2-amino-1,3,4-octadecanetriol, is found naturally in the lipids of plants, where there are also some analogs to 16, 19 and 20 carbon atoms. According to the present invention, the names sphingosine and phytosphingosine used here also include these analogs.

Ceramides, amides of fatty acids and sphingid bases, are natural constituents of the surface layers of the skin, and in particular the stratum corneum, and play an essential role in the structure of the skin lipid barrier, but their content tends to decrease with age in significant proportions. This is why much research has been done in order to have available synthetic ceramides capable of being used in compositions which can be used in cosmetology, in particular for combating dryness of the skin, or in compositions for hair treatment. For example, patent applications FR-A-2,673,179 and FR-A-2,714,829 describe ceramides which can be used in cosmetic or dermatological compositions. Patent application FR-A-2,773,074 describes compositions based on ceramides associated with alpha-hydroxy acids, which can be used in dermatology.

Salicylic acid is known as one of the main beta-hydroxy acids. It has keratolytic, anti-inflammatory and antibacterial properties. However, depending on the concentration, it exerts an irritant effect on the skin which limits its use to a few external treatments.

Salicylic acid esters have been proposed in low doses, that is to say generally less than 1%, in cosmetic compositions, and for example phytosphingosine salicylate obtained by the action of methyl salicylate on phytosphingosine in the medium basic hot as in patent EP-A-919,226 or salicylates of base spheroids obtained enzymatically or chemically by means of a coupling agent such as 1 hydroxybenzotriazole in the presence of a carbodumide as in WO application. 98.40350.

The use of various alpha-hydroxy acids, including their salts and esters, is well known in compositions useful in therapy or in cosmetology. Thus, patent EP 273,202 describes the use of alpha-hydroxy acids as additives in compositions containing one or more active drug ingredients, in order to improve their activity topically. Patent EP 504,862 shows that certain derivatives of alpha-hydroxy acids can be used for the treatment of ment of the atrophy of the skin induced by the topical application of corticoids such as clobetasol propionate.

Patent EP 413,528 describes compositions which can be used for the treatment of various dermatological conditions such as acne, eczema or psoriasis, containing alpha-hydroxy acids in combination with an amphoteric agent having the effect of increasing the pH of the composition.

Thus, the known properties of alpha-hydroxy acids make it possible to envisage their use in dermatology for the treatment of certain skin conditions. However, they should be used in relatively low concentrations, not exceeding 10% in free form, due to the side effects they may cause, for example increased sensitivity and skin irritation. The various known compositions described above which can be used for dermatological treatments are not always suitable for specific treatments such as that of acne. Acne is a pathological condition resulting from occlusion of the upper extremity as well as of the internal part of the pilosebaceous canal by the abnormal multiplication of keratinocytes. In addition, the androgenic hormonal hyperactivity generally appearing during puberty causes a significant increase in seborrhea in the sebaceous glands, and the obstruction of the pilosebaceous canal causes the formation of retentional lesions in the form of comedones or microcysts. . This results in a proliferation of Propionibacterium acnes bacteria in the obstructed pilosebaceous follicles, all the more important as it is anaerobic and lipophilic, and the presence of fat, such as sebum, promotes its growth.

This phenomenon triggers an inflammatory reaction of the skin, which may be in the form of papules or pustules

(papulopustular acne), particularly common in adolescents. These lesions are generally located in the superficial dermis. In some cases there is a intense inflammatory reaction accompanying deep lesions reaching the deep dermis, forming nodules and macrocysts (nodulocystic acne) requiring appropriate treatment.

Conventional treatments use benzoyl peroxide and / or erythromycin, and isotret noine for nodulocystic acnes. However, the use of erythromycin in topical form for many years has resulted in the emergence of strains resistant to this antibiotic.

The work undertaken by the applicant has made it possible to show that the combined use of certain beta-hydroxy acids with certain sphingolipids or sphingolipid precursors, such as sphingosine and phytosphingosine, makes it possible to restore the natural defenses of the skin, and effectively fight against certain skin conditions, more particularly in the case of acne, thus offering an alternative to treatment with antibiotics such as erythromycin. The present invention relates to a composition based on beta-hydroxy acid and sphingolipid or sphingolipid precursor, such as sphingosine, sphinganine and phytosphingosine, usable in therapy and in cosmetics by topical application. The subject of the invention is also a composition comprising at least one beta-hydroxy acid in combination with a sphingolipid or a sphingolipid precursor, such as sphingosine, sphinganine and phytosphingosine, as well as excipients suitable for application by topically, for the treatment of various dermatological conditions, and more particularly for the treatment of acne.

The composition according to the present invention comprises, in combination, at least one beta-hydroxy acid, or one of its salts and esters, and at least one sphingolipid. The sphingolipid or sphingolipid precursor used in the compositions according to the present invention can be chosen more particularly from sphmgosine, hydroxyphosphmgosme, sphinganine, N, N-dimethylsphingosme, oleoyl-sphingosme and phytosphingosine.

The beta-hydroxy acid of the invention and its salts and esters can be represented by the general formulas (I) or (I ') below:

Ri - CH - - CH - COOR

1 1 OH R ₂

Ri - CC == = CC - CCOOOORR (I '

II OH R ₂ in which R _x and R ₂ , identical or different, represent a hydrogen atom or a linear or branched alkyl group comprising 1 to 5 carbon atoms, or a phenyl group, or

Ri and R ₂ together form a 5- or 6-membered ring, and R is a hydrogen atom, an alkyl group of 1 to 12 carbon atoms, an alkyl-silyl group, an ammonium group or an alkali or alkalo- earthy.

The beta-hydroxy acid used in the invention has keratolytic and antiseptic properties. According to a preferred form of the invention, the beta-hydroxy acid is salicylic acid, or an alkyl or alkali metal salicylate, for example isodecyl salicylate or tnmethylsilyl salicylate, or alternatively acid beta-hydroxybutyric. The compositions according to the present invention may also contain one or more alpha-hydroxy acids as well as their salts and esters, represented by the following general formula (II):

R ₃

HO - C - COOR ₅ m;

I wherein R ₃ and R ₄ , identical or different, represent a hydrogen atom, a linear or branched alkyl group comprising 1 to 5 carbon atoms optionally substituted by a carboxyl group, or a phenyl group, and R ₅ is an atom hydrogen, an alkyl group, an ammonium group or an alkali or alkaline earth metal.

In formula (II) above, R ₃ is preferably a methyl or ethyl group and R is a hydrogen atom, or R ₃ and R ₄ both represent a group -CH ₂ COOH. R ₅ is preferably a hydrogen atom, an ammonium group or a sodium, magnesium, potassium or calcium ion.

When R ₅ is an alkyl group in formula (II), this group may contain 1 to 15 carbon atoms, and may for example be an octyl, decyl or dodecyl group. When R ₅ is a hydrogen atom, formula (II) represents an alpha-hydroxy acid which may preferably be glycolic acid, lactic acid, malic acid, ascorbic acid, acid mandelic, citric acid or 2-hydroxybutanoic acid.

The salts and esters represented by the general formula (II) where R ₅ is an ammonium group or an alkali or alkaline earth metal atom, can be obtained by a simple acid-base reaction, by reacting the acid represented by same formula (II) where R ₅ is a hydrogen atom, with a base constituted for example by a hydroxide, such as 1 magnesium or calcium hydroxide, or an alkali or alkaline earth metal hydroxide.

According to a preferred embodiment of the invention, an alpha-hydroxy acid ester is used represented by the general formula (II) where R5 is an alkyl group such as an ethyl, propyl, butyl, octyl, decyl group. or dodecyl, and more preferably ethyl lactate, tri-Cι ₂ Cι ₃ -alkyl citrate, Cι ₂ -Cι ₃ alkyl lactate, bis (trimethylsilyl) glycolate.

This alpha-hydroxy acid ester is used in conjunction with beta-hydroxy acid and the sphingolipid or shmgolipid precursor, these three components can themselves be supplemented with excipients and carriers usually used in cosmetic and pharmaceutical compositions. For example, it may be advantageous to use a composition comprising an ethyl lactate or glycolate, a sphingolipid, a beta-hydroxy acid and one or two alpha-hydroxy acids chosen from glycolic acid, acid mandelic and malic acid. The tests carried out have shown that the combined presence of an ammonium salt and one or more hydroxy acids potentiates the effects of the ammonium salt by improving the absorption and the persistence.

The compositions according to the invention may also contain an alpha-acetoxylated acid such as alpha-acetylmandelic acid, alpha-acetylbenzylic acid, alpha-acetylglycolic acid and alpha-acetyl-lactic acid, or alternatively an alpha -aceto-acid such as pyruvic acid or gluconolactone.

The compositions according to the invention preferably comprise between 0.1% and 15% by weight of beta-hydroxy acid and between 0.01% and 6% by weight of sphingolipid or shmgolipid precursor relative to the total weight of the composition. According to a preferred embodiment, the compositions comprise one or more beta-hydroxy acids in a proportion of 0.2% to 10%, one or more alpha-hydroxy acids in a proportion of 0.5% to 30% in total, and a sphingolipid is 0.01% to 5% by weight. A preferred composition according to the invention comprises between 0.1% and 6% by weight of beta-hydroxy acid, between 0.5% and 15% of alpha-hydroxy acid, between 5 and 20% of ester of alpha-hydroxy acid and between 0.01% and 1% of sphingolipid, relative to the total weight of the composition.

The compositions in accordance with the present invention are intended to be administered topically and therefore comprise, in addition to the essential components indicated below, usual excipients, additives and carriers acceptable on the market. pharmaceutical and cosmetic. Thus, emulsifiers, preservatives, thickeners, colorants, antioxidants, moisturizers, perfumes and various additives intended to improve the properties of the composition can be used. It is also possible to use known encapsulation systems, for example by means of liposomes or microcapsules consisting for example of gelatin and of polyaminoelectrolyte. To improve the stability of the composition, it may be advantageous to encapsulate certain

10 sphingolipids or sphingolipid precursors used in the invention, for example phytosphingosine.

The compositions may be in the form of creams, milks, gels, lotions, masks or ointments, and preferably in an anhydrous form, for example an alcoholic gel.

They can be used in particular for the treatment of dermatological conditions such as acne, but also certain keratmisation disorders such as atopic dermatitis, xerosis, psoriasis, and pityriasis of the leather.

20 long-haired.

This is why the present invention also relates to a method of cosmetic treatment of the skin, consisting in applying to the skin at least one beta-hydroxy acid, or one of its acceptable salts and esters, and at least one

Sphingolipid or a sphingolipid precursor, as well as the use of a beta-hydroxy acid, or a pharmaceutically acceptable salt and ester thereof, in combination with a sphingolipid or a sphingolipid precursor, for the preparation of a composition dermatological for

30 treatment of acne.

Studies have shown that the sphingolipids, and in particular the spheroid bases, used in the compositions of the invention have significant antimicrobial activity on different types of bacteria, and in particular

35 culier on Propionibacterium acnes), and yeast (Candida albicans), and play an important role in the barrier heard by the stratum corneum against microorganisms.

The work carried out has shown that in the case of phytosphingosine, the antibacterial activity vis-à-vis P ^ 5 acnes is very important, with bacteriostatic activity from the concentration of 200 mg / 1 and bactericidal activity beyond of this concentration. These studies show that regulation of the proliferation of P. acnes can be obtained with a concentration of 0.2% in phytosphingosine. 0 A monocentric clinical study on 60 subjects aged over 14 years made it possible to evaluate the effectiveness of the compositions in accordance with the present invention on inflammatory lesions of acne and to demonstrate its good tolerance for the epidermis. The study was carried out for two 5 months at the rate of two applications per day, a group of 30 people receiving the composition of the invention while a second group of 30 people receiving an excipient.

At the end of the study, there is a significant reduction in surface inflammatory lesions (papules and pustules) in the group having received the composition of the invention by comparison with the excipient group. In addition, tolerance was found to be generally good.

The following examples illustrate the invention in more detail without limiting its scope. Unless otherwise indicated, all parts and percentages are expressed by weight.

Example 1

A gel (lotion) having the following weight composition is prepared:

Phytosphingosine 0.20 "Salicylic acid 2.00

Mandelic acid 5.00

Citric acid 2.00

Ethyl lactate 10.00

Cyclopentasiloxane 20.00 Ethoxydiglycol oleate 3.00

Hydroxy-propylcellulose 0.90

Transcutol 6.00

Ethanol, q.s.p. 100.00 The gel, the composition of which is given above, can be applied to the areas to be treated once or twice a day.

It can be prepared by conventional techniques. For example, a gel having the above composition can be obtained by operating according to the method indicated below, without this being limiting: the phytosphingosine salicylic acid and the alpha-hydroxy- are first solubilized acids in ethanol, then ethyl lactate, cyclopentasiloxane and transcutol, and finally hydroxypropylcellulose, are added thereto, operating at room temperature.

Example 2

By a classic method analogous to that of Example

1, and using a conventional apparatus, a gel is prepared having the following composition:

Sphingosine 0.40 Salicylic acid 2.00

Alkyl lactate 15.00

Isononyl isononaoate 15.00

Mandelic acid 5.00

Tartπque acid 4.00 Ethanol, q.s.p. 100.00

Example 3

A milk having the composition by weight indicated below is prepared by a usual method: Phytosphingosine (encapsulated) 0.10

Salicylic acid 2.50

Malic acid 1.00

Glycolic acid 0.90 Sweet almond oil 1.00

Ammonium lactate (sol. 65% aqueous) 12.00

Cetyl lactate 0.50

Cetyl alcohol 0.50 C12-C15 benzoate 2.00

Glyceryl stearate (and) PEG-100 stearate 5.00

Cyclopentasiloxane 4.00

Perfume 0.20

Water, q.s.p. 100.00 This milk is used in application on the parts of the body to be treated once or twice a day.

Example 4

A cream having the composition by weight indicated below is prepared: Phytosphingosine encapsulated 0.20

Salicylic acid 2.50

Mandelic acid 5.00

Ammonium lactate 5.00

Cyclomethicone 6.00 Cyclomethicone (and) dimethicone copolyol 10.00

Propylene glycol 2.00

Nylon-12 3.00

Decyle oleate 4.00

Sodium chloride 2.00 Perfume 0.30

Water q.s.p. 100, 00

Example 5

A cream is prepared having the following composition:

Sph gosine 0.20 Salicylic acid 3.00

Lmoleic acid 5.00

Mandelic acid 5.00

Ammonium lactate 5.00 Glyceryl stearate (and) PEG-100 stearate • i,, 20 Polymethyl methacrylate 2, 50

Arachidyl alcohol (and) behenyl alcohol (and) arachidyl glucoside 3, 00 Cyclomethicone 3, 00 Czo benzoate ₂ Cι ₅ -alkyl 7, 00 Perfume 0, 30 Water qs 00, 00

Claims

RESELL I CAT I ON S

1. Composition usable topically for the treatment of dermatological conditions, characterized in that it comprises in combination at least one beta-hydroxy acid, or one of its acceptable salts and esters, and at least one sphingolipid or a precursor sphingolipid.

2. Composition according to claim 1, characterized in that the sphingolipid or sphingolipid precursor is chosen from sp gosin, 1 'hydroxysphmgos e, sphinganine, N, N-dimethylsphmgosme, 1 oleoyl-sphingosine and phytosphingosine.

3. Composition according to claim 1, characterized in that the beta-hydroxy acid is represented by the general formula (I) or (I '):

Ri - CH - CH - COOR (I) I I

OH R ₂

Ri - C = C - COOR (I ')

II OH R ₂ in which Ri and R ₂ , identical or different, represent a hydrogen atom or a linear or branched alkyl group comprising 1 to 5 carbon atoms, or a phenyl group, or Ri and R ₂ together form a ring with 5 or 6 members, and R is a hydrogen atom, an alkyl group of 1 to 12 carbon atoms, an alkyl-silyl group, an ammonium group or an alkali or alkaline earth metal.

4. Composition according to claim 3, characterized in that the beta-hydroxy acid or its salt or ester is chosen from salicylic acid, an alkyl salicylate or an alkali metal salicylate.

5. Composition according to any one of the preceding claims, characterized in that it also contains an alpha-hydroxy acid represented by the general formula (II) R ₃

I HO - C - COOR5 (I I)

IR ₄ in which R ₃ and R ₄ , identical or different, represent a hydrogen atom, a linear or branched alkyl group comprising 1 to 5 carbon atoms optionally substituted by a carboxyl group, or a phenyl group, and R ₅ is a hydrogen atom, an alkyl group, an ammonium group or an alkali or alkaline earth metal.

6. Composition according to claim 5, characterized in that it comprises a beta-hydroxy acid, an ester or an ammonium or sodium salt of alpha-hydroxy acid, and a sphingolipid or a sphingolipid precursor.

7. Composition according to Claim 6, characterized in that the alpha-hydroxy acid ester is chosen from ethyl lactate, tri-C ₁₂ citrate Cι ₃ -alkyl, Cι ₂ alkyl lactate -Cχ ₃ , and bis (trimethylsilyl) glycolate.

8. Composition according to any one of the preceding claims, characterized in that it comprises between 0.1% and 15% by weight of beta-hydroxy acid and between 0.01% and 6% by weight of sphingolipid or precursor of sphingolipid, relative to the total weight of the composition.

9. Composition according to claim 8, characterized in that it comprises one or more beta-hydroxy acids in an amount of 0.2% to 10%, one or more alpha-hydroxy acids in an amount of 0.5% to 30% in total, and a sphingolipid or a sphingolipid precursor in an amount of 0.01% to 5% by weight.

10. Composition according to claim 8, characterized in that it comprises between 0.1% and 6% by weight of beta-hydroxy acid, between 0.5% and 15% of alpha-hydroxy acid, between 5 and 20% of alpha-hydroxy acid ester and between 0.01% and 1% of sphingolipid or sphingolipid precursor, relative to the total weight of the composition.

11. Composition according to any one of the preceding claims, characterized in that it is in the form of gel, cream, milk, lotion, mask or ointment.

12. Cosmetic treatment method for the skin, characterized in that it consists in applying to the skin at least one beta-hydroxy acid, or one of its acceptable salts and esters, and at least one sphingolipid or a sphingolipid precursor. .

13. Use of a beta-hydroxy acid, or a pharmaceutically acceptable salt and ester thereof, in combination with a sphingolipid or a sphingolipid precursor, for the preparation of a dermatological composition for the treatment of acne .