FR2806301A1 - COMPOSITION BASED ON SPHINGOLIPID AND BETA-HYDROXY-ACID FOR TOPICAL USE FOR SKIN CARE - Google Patents

Abstract

The invention relates to a dermatological composition. The dermatological composition, which can be administered topically, comprises in combination at least one beta-hydroxy acid such as salicylic acid, or one of its acceptable salts and esters, and at least one sphingolipid or a sphingolipid precursor, for example sphingosine and phytosphingosine. Application to dermatological compositions intended for the treatment and care of the skin, in particular the treatment of acne.

Description

The present invention relates to a pharmaceutical composition.

  tick and cosmetic, and more particularly 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 comprising essen-

  tly 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. We know 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 protein kinase C inhibiting properties, 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

unwanted microorganisms.

  Sphingosine, or 2-amino-4-octadecene-1,3-diol, is the

  most important base of animal sphingolipids. The phyto-

  sphingosine, or 2-amino-1,3,4-octadecanetriol, is found naturally in the lipids of plants, where we find

  also some analogs to 16, 19 and 20 carbon atoms.

  According to the present invention, the sphingosine and phytosphingosine derivatives used here also include these analogs.

  Ceramides, amides of fatty acids and of sphin- bases

  goides, are natural constituents of the super-

  skin, especially 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 a lot of research has been done to obtain ceramides.

  synthetics capable of being used in compounds

  Sections usable 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, usable in dermatology.

  Salicylic acid is known as one of the main beta-hydroxy acids. It has keratolytic properties,

  anti-inflammatory and antibacterial. However, depending on

  tion of the concentration, it exerts an irritant effect on the skin which limits its uses to a few external treatments. 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 principles

  active drug cipes, to improve topical activity. Patent EP 504,862 shows that certain derivatives

  alpha-hydroxy acids can be used to treat

  the application of the atrophy of the skin

  topical corticosteroids 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 the internal part of the pilosebaceous canal by abnormal multiplication

  keratinocytes. In addition, androgenic hormonal hyperactivity

  This usually occurring during puberty causes a significant increase in seborrhea in the sebaceous glands, and 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 pilo- follicles

  obstructed sebaceous, all the more important as it is anaes-

  robie and lipophilic, and the presence of fat, like 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, an intense inflammatory reaction is observed, 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 isotretinoin for

  Nodulocystic acnes. However, the use of erythro-

  mycine in topical form for many years has

  caused the appearance of strains -resistant to this anti-

  biotic. 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 precursors of sphingo-

  lipid, such as sphingosine and phytosphingosine, allows to restore the natural defenses of the skin, and to fight effectively against certain skin conditions, more particularly in the case of acne, thus offering an alternative to treatment with antibiotics such as erythromycin. The subject of the present invention is a composition based on beta-hydroxy acid and sphingolipid or sphingolipid precursor, such as sphingosine, sphinganine and phytosphingosine, usable in therapeutics and in cosmetics

by topical application.

  The subject of the invention is also a composition comprising

  containing 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 topical application, for the treatment of various conditions dermatological, and more

  especially 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 sphingosine, hydroxy-

  sphingosine, sphinganine, N, N-dimethylsphingosine,

  oleoyl-sphingosine 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:

R1 - CH - CH- COOR (I)

He

OH R2

R1 - C = C -COOR (I ')

I I

OH R2

  wherein R1 and R2, 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 R1 and R2 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 a

alkali or alkaline earth metal.

  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 metal salicylate

  alkaline, for example isodecyl salicylate or sali-

  trimethylsilyl cylate, or beta-hydroxy acid

  butyric. 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): R3 HO - C COORs (II) R4 in which R3 and R4, 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 Rs is a hydrogen atom, an alkyl group, a group ammonium or a

alkali or alkaline earth metal.

  In formula (II) above, R3 is preferably a methyl or ethyl group and R4 is a hydrogen atom, or R3 and R4 both represent a group -CH2COOH. Rs is preferably a hydrogen atom, an ammonium group or an ion

  sodium, magnesium, potassium or calcium.

  When R5 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 R5 is a

  hydrogen atom, formula (II) represents an alpha-

  hydroxy acid which may preferably be glycolic acid, lactic acid, malic acid, ascorbic acid, mandelic acid, citric acid or 2-hydroxybutanoic acid. The salts and esters represented by the general formula (II) o Rs is an ammonium group or an alkali metal atom

  or alkaline earth, can be obtained by a simple reaction

  acid-base tion, by reacting the acid represented by the same formula (II) o Rs is a hydrogen atom, with a base constituted for example by a hydroxide, such as magnesium or calcium hydroxide, or a hydroxide of

alkali or alkaline earth metal.

  According to a preferred embodiment of

  the invention, an alpha-hydroxy acid ester is used.

  represented by the general formula (II) o R5 is an alkyl group such as an ethyl, propyl, butyl, octyl, decyl or dodecyl group, and more preferably ethyl lactate, tri-C12C13-citrate alkyl, lactate of C12-C13 alkyl, the

bis (trimethylsilyl) glycolate.

  This alpha hydroxy acid ester is used in combination

  due to beta-hydroxy acid and the sphingolipid or shingolipid precursor, these three components can be

  themselves supplemented by usual excipients and carriers-

  Lely used in cosmetic and pharmaceutical compositions

  ceutiques. 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, mandelic acid and malic acid. Tests have shown that the combined presence of an ammonium salt and one or more hydroxy acids potentiates the effects of the salt

  ammonium by improving absorption and remanence.

  The compositions according to the invention can also

  contain an alpha-acetoxylated acid such as alpha-

  acetylmandelic, alpha-acetylbenzylic acid, alphaacetylglycolic acid and alpha-acetyl-lactic acid, or also an alphaaceto-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 shingolipid precursor relative to the total weight of the composition. According to a preferred embodiment,

  the compositions comprise one or more beta-hydroxy-

  acids from 0.2% to 10%, one or more alpha-

  hydroxy acids in an amount of 0.5% to 30% in total, and a sphingolipid in an amount of 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

  % of alpha-hydroxy acid, between 5 and 20% of ester of alpha-

  hydroxy acid and between 0.01% and 1% of sphingolipid, by

  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 above, usual excipients, additives and carriers acceptable from the pharmaceutical and cosmetic point of view. So you can use

  emulsifiers, preservatives, thickeners, colo-

  rants, antioxidants, moisturizers, perfumes and various additives intended to improve the properties of the composition. It is also possible to use known encapsulation systems, for example by means of liposomes or microcapsules consisting for example of gelatin and anionic polyelectrolyte. To improve the stability of the composition, it may be advantageous to encapsulate certain 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 keratinization disorders such as atopic dermatitis, xerosis, psoriasis, and pityriasis of the scalp. Studies have shown that the sphingolipids, and in particular the sphingoid bases, used in the compositions of the invention have antimicrobial activity

  important on different types of bacteria, and in particular

  culier on Propionibacterium acnes), and yeast (Candida albicans), and play an important role in the barrier

  played 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. acnes is very important, with bacteriostatic activity from the concentration of 200 mg / l and bactericidal activity beyond this concentration. This work shows that regulation of the proliferation of P. acnes can be obtained

  with a concentration of 0.2% in phytosphingosine.

  A monocentric clinical study on 60 subjects aged

  over 14 years has made it possible to assess the effectiveness of

  tions 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 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 receives an excipient.

  At the end of the study, there is a decrease

  significant of superficial inflammatory lesions (papu-

  les and pustules) in the group having received the composition of the invention by comparison with the excipient group. Moreover,

  tolerance was found to be generally good.

  The following examples illustrate the invention in more detail without limiting its scope. Unless otherwise stated,

  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, qs 100.00 The gel whose composition 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 solution is first solubilized

  phytosphingosine salicylic acid and alpha-hydroxy-

  acids in ethanol, then we add ethyl lactate,

  cyclopentasiloxane and transcutol, and finally hydroxy-

  propylcellulose, operating at room temperature.

Example 2

  By a conventional method analogous to that of Example 1, and by means of a usual apparatus, a gel is prepared having the following composition: Sphingosine 0.40 Salicylic acid 2.00 Alkyl lactate 15.00 Isononaoate isononyl 15.00 Mandelic acid 5.00 Tartaric acid 4.00 Ethanol, qs 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 Lactate ammonium (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, qs 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 individual weight composition is prepared.

  listed below: Encapsulated phytosphingosine 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 Decyl oleate 4.00 Sodium chloride 2.00 Perfume 0.30 Water qs 100.00

Example 5

  A cream is prepared having the following composition: Sphingosine 0.20 Salicylic acid 3.00 Linoleic acid 5.00 Mandelic acid 5.00 Ammonium lactate 5.00 Glyceryl stearate (and) PEG-100 stearate 1.20 Methacrylate polymethyl 2.50 Arachidyl alcohol (and) behenyl alcohol (and) arachidyl glucoside 3.00 Cyclomethicone 3.00 C12C15 benzoate-alkyl 7.00 Perfume 0.30 Water qs 100.00

Claims (11)

  1. Composition usable topically for the treatment of dermatological conditions, characterized in that   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 sphingolipid precursor. 2. Composition according to claim 1, characterized in that the sphingolipid or sphingolipid precursor is   chosen from sphingosine, hydroxysphingosine, sphin-   ganine, N, N-dimethylsphingosine, 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 '): R1 - CH - CH - COOR (I) I I OH R2 R1 - C = C -COOR (I ') I I OH R2   wherein R1 and R2, 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 R1 and R2 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 a 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 a alkali metal salicylate.   5. Composition according to any one of the claims   tions above, characterized in that it additionally contains an alpha-hydroxy acid represented by the general formula (II) R3 I HO - C - COORs (II) R4 in which R3 and R4, identical or different, represent an atom of hydrogen, a linear or branched alkyl group comprising 1 to 5 carbon atoms optionally substituted by a carboxyl group, or a phenyl group, and Rs is a hydrogen atom, an alkyl group, an ammonium group or a 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-C12C13-alkyl citrate, lactate   of C12-C1 alkyl, and bis (trimethylsilyl) glycolate.   8. Composition according to any one of the claims   tions above, 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 sphingol precursor   lipid, 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 , through   relative to the total weight of the composition.   11. Composition according to any one of the claims.   previous tions, characterized in that it is presented under   gel, cream, milk, lotion, mask or ointment.