FR2894828A1 - NEW COSMETOLOGICAL AND / OR DERMATOLOGICAL COMPOSITIONS BASED ON PROLINE DERIVATIVES AND USES THEREOF - Google Patents

Abstract

The present invention relates to the necessities of life and more particularly to the field of cosmetology and dermatology.It more particularly relates to new cosmetological and / or dermatological compositions, which cause a very significant increase in the deposition of collagen type III in the extracellular matrix, characterized in that they contain as active principle a combination of a fatty acid amidoester of 4-hydroxyproline, of formula I: wherein R1 and R'1 are aliphatic chains , identical or different, having from 10 to 24 carbon atoms in a straight or branched line and an extract of the epicarp of the fruit of Opuntia Ficus-indica (Barbary fig) in a non-toxic excipient or inert carrier suitable for topical use.Use as a gel or oily cream for increased collagen production, without amplifying that of pro-collagen III or the enzymes of the family metalloproteinases.

Description

NEW COSMETOLOGICAL AND / OR DERMATOLOGICAL COMPOSITIONS BASED ON

  The present invention relates to the necessities of life and more particularly to the fields of cosmetology and dermatology.

  Elie more particularly relates to new cosmetological and / or dermatological compositions which cause a very significant increase in the deposition of type III collagen in the extracellular matrix and which improve the transport of pro-collagen by chaperone proteins, in particular HSP 47, in fibroblasts of human dermis.

  The invention specifically relates to new cosmetic and dermatological compositions characterized in that they contain A. as active principle 15] the combination of a fatty acid amidoester of 4-hydroxyproline, of formula I: Wherein R 1 and R '1 are aliphatic chains, identical or different, having from 10 to 24 carbon atoms in a straight or branched line and an extract of the epicarp of the fruit of Opuntia Ficus-indica ( prickly pear), in an inert carrier or vehicle, non-toxic suitable for topical application.

  The extract of the epicarp of the fruit of Opuntia Ficus-indica is preferably that obtained by the method described in patent EP0948340 B1, which consists of a depletion by a polar solvent of the epicarp dehydrate, in dilution with water and then purification by exhaustion with hexane.

  The 4-hydroxyproline amidoesters are new substances, with the exception of dipalmitoyl 4-hydroxyproline, already described in the French patent 91/12597 (intracellular Vesicular Vectors and their application in cosmetics).

  The invention is based on the surprising finding that 4-hydroxyproline amidoesters do result in a dose-dependent increase in collagen expression in the fibroblast culture medium by stimulating the formation and cleavage of the fibroblasts. type III collagen in human skin fibroblasts (FpH) and by amplifying the activity of degradation enzymes MMPK1, or rune families of enzymes.

  The same amidoesters encapsulated in a vectorized form such as a liposome significantly amplify the synthesis of pro-collagen type III and, in addition, reduce the activity of MMPK1. Extracts of Opuntia Ficus-indica stimulate in a less important but statistically significant manner, the expression of HSP 47 which is one of the chaperone proteins of pro-collagen.

  On the other hand, it is found that the simultaneous presence of a fatty acid amidoester of 4-hydroxyproline and epicarp extract of the fruit of Opuntia Ficus-indica leads to a greater stimulation of the synthesis of HSP 47 than any one. constituents taken in isolation.

  The presence of Opuntia Ficus-indica extract potentiates in an important way the expression of HSP 47 by fibroblasts of the human dermis. This synergistic effect does not lead to overexpression of type III pro-collagen induced by a 4-hydroxyproline amido ester, but overexpression of type III collagen.

  The addition to cultured human skin fibroblasts in the presence of the human skin keratinocyte culture supernatant is performed as follows: a) Keratinocyte culture is simultaneously treated with the 4-hydroxyproline fatty acid amide ester encapsulates and Opuntia Ficus-indica extract overnight, 8 hours. B) The cells are rinsed three times in order to remove all traces of the 4-hydroxyproline ester or Opuntia Ficus-indica extract vectors. C) New medium without addition of fetal calf serum is added. and left standing for 24 hours. The supernatant of this medium conditioned by the keratinocytes is added at 50% in a fibroblast culture medium.

  In comparison with fibroblasts that have not undergone any treatment, we can see: 1. An amplification of the synthesis of pro-collagen type III. 2. Reduction of metallo-proteinases and collagen degradation enzymes. 3. An improvement in the synthesis of type III collagen.

  Then, compared to cultured fibroblasts in the presence of amidosters of 4-hydroxyproline encapsulates (French patent 91/12597): 1. An amplification of the synthesis of pro-collagen type III. 2. An increase in pro-collagen chaperone molecules (including HSPs) 3. A reduction in metallo-proteinases and collagen degradation enzymes. 4. Considerable amplification of type III collagen deposition. It is noted that the conditioned media, derived from culturing keratinocytes (Kc) treated with the mixture according to the invention, applied to human skin fibroblast cultures (FpH), increase the conversion of pro-collagen type III to collagen. type III, Sun order factor 4 depending on cell type and / or age, to achieve a conversion rate close to 100% (80 to 90%). The cells used for control have a conversion rate of pro-collagen to collagen of the order of 25%. As a result, the cells treated with the mixture described above deposited twice as much collagen as the cells treated directly with the 4-hydroxyproline derivative.

  The 4-hydroxyproline fatty acid amidoesters are prepared generally by reacting a functional fatty acid derivative, such as an acyl chloride, with 4-hydroxyproline in a polar solvent. Symmetrical amidoesters are then obtained (R1 = R'1). Mixed amidoesters (R 1 R '1) can also be prepared from N-acetyl 4-hydroxyproline. One conceivable route of synthesis is the reaction with a functional derivative of the chosen R'1000H fatty acid, for example the esterification of the acid itself. The acetyl function will then be selectively cleaved, for example subjected to acid hydrolysis. The liberated amine function may then react with a functional derivative of the selected R, 000H fatty acid, such as acyl chloride, if necessary in the presence of base. A mixed amidoester will then be obtained. The fatty acids used are generally acids having 10 to 24 carbon atoms, such as undecylenic acid, lauric acid, myrystic acid, stearic acid, ricinoleic acid and behenic acid. Transterification of a fatty acid methyl ester is also possible.

  The fatty acids used may be mono- or polyunsaturated, such as oleic acid, linoleic acid, α- or γ-linolenic acid, eicosapentaenoic acid or nervonic acid.

  The fatty acids may be substituted, such as, for example, 3-hydroxymyristic acid or 12-hydroxystearic acid.

  4-hydroxyproline and its amidoesters have two centers of asymmetry; the optically active forms and the cis and trans diastereoisomers can be separated. The starting material can be cis or trans 4-hydroxyproline.

  A fatty acid amide ester of 4-hydroxyproline, dipalmitoyl amide ester, of formula II: ## STR1 ## is already known and its amplification properties of the synthesis of pro-collagen and collagen III The lipophilic structure of this lipophilic structure allows it to be distributed as liposomes in a phospholipid vesicular vector The lipophilic liposome wall contains the dipalmitoyl amphiphilic derivative.

  A liposome-type vector containing a 4-hydroxyproline fatty acid amidoester acts as a trigger for modulation of collagen expression by cell phenotypes. Among the changes observed, the increase in collagen III synthesis is probably the most important phenomenon. The dipalmitoyl amide ester of 4-hydroxyproline has already been described as a repair factor for the epidermis, especially as a healing agent. It has also been presented as an agent improving the appearance of human skin, especially in cases of aging, by increasing its thickness.

  Nothing was known about the effect of other 4-hydroxyproline amidoesters in pharmacological and clinical terms.

  The epicarp extracts of the fruits of Opuntia Ficus-indica were already known for their promoting action on the synthesis of HSPs, in particular HSP 70 and HSP 90. It has in particular been described as usable in the treatment of vascular ischemia. , fibrosis, shock or stress.

  The synergy observed between the effect of 4-hydroxyproline fatty acid amidoesters and Opuntia Ficus-indica fruit epicarp extract was quite unexpected. Elie brings increased expression of nearly 50% of HSP 47 by fibroblasts and doubles the amount of collagen produced without amplifying pro-collagen III or enzymes of the metalloproteinase family.

  The addition of Opuntia Ficus-indica extract is active at a very low dose. At a dose of 10 g, it is already significant for 400,000 fibroblasts in 1 ml of medium. It can thus be considered that the compositions according to the invention contain a dose of 4-hydroxyproline amino ester of between 0.1 and 1% of the total preparation and preferably 0.2 to 0.5% by weight of the preparation. total, as well as a quantity of Opuntia Ficus-indica extract varying from 0.1 to 100 g by weight to bring about such synergy. The ratio of the amino ester of 4-hydroxyproline to the extract of Opuntia Ficus-indica thus ranges from 1,000,000 to 10,000 to 1.

  The excipient used for such compositions is a gelling agent such as an acrylic acid polymer or a cellulose ether in an aqueous or hydro-alcoholic vehicle. The compositions according to the invention may also be dispersed in a fluid lipid vehicle or semi-fluid to achieve fat or non-greasy creams. The following examples illustrate the invention without however limiting it.

  EXAMPLE I Pharmacological study of the combination according to the invention.

  Expression of HSP-47 by senescent fibroblasts: Effects of conditioned media by keratinocytes treated with dipalmitoyl amino ester of 4-hydroxyproline (Compose A) and epicarp extract of Opuntia fruit (Compose B) Value 1 Value 2 Value 3 Value 4 Mean Standard deviation Control 0.67 0.68 0.67 0.67 0.67 0.005 Control MC 1.01 1.04 1.02 1.02 1.02 0.013 Comp.A 0.2 % 1.92 1.94 1; 97 1.93 1.94 0.022 Comp.A 0.5% 2.39 2.42 2.43 2.36 2.40 0.032 Corn B 10 g / ml 1.5 1 , 59 1.57 1.57 1.56 0.039 A 0.2 + 10 g B 3.29 3.41 3.38 3.37 3.36 0.051 A 0.5 + 10 g B 2.47 2.59 2.58 2.54 2.55 0.054 Comment The above results show a very significant increase in the expression of HSP 47 by fibroblasts after the addition of compound A to the culture medium of keratinocytes. This increase is dose-dependent. Similarly there is a stimulation that is less important mats statistically significant in the presence of compound B alone. Moreover, when A is added to the culture medium of the keratinocytes, the concentration of 0.2% in association with the compound B, there is a greater stimulation of the expression of the HSP 47 than with A alone: the presence of compound B potentiates the effect of compound A on the expression of HSP 47 by human dermal fibroblasts.

  Figure 1 illustrates the results obtained. EXAMPLE II Preparation of a dermal gel based on dipalmitoyl-4-hydroxyproline and extract of the epicarp of the fruit of Opuntia Ficus-indica. Allantoine 0.20 g 50% Sorbitol 5.00 g Preservatives (Phenoxy ethanol) 0.30 g Carbomere (Carbopol 940 P Goodrich) 0.80 g Tris (hydroxy methyl) amino methane 1.80 g Amino ester Dipalmitoyl 4 -hydroxyproline 4.00 g Lecithin 0.60 g Opuntia fruit extract Ficus-indica 0.0005 g Water qs 100 g

  This gives a lightly yellow, opaque gel having a viscosity determined at 24 ° C. on the Brookfield RVT viscometer at 5 rpm of 60 ° C. 65,000 mPas as a function of the carbomer concentration.

  The pH of the gel, determined at 25 ° C., is close to 7.5.

Claims (7)

  1. New cosmetic and / or dermatological compositions characterized in that they contain, as active principle, the combination of a fatty acid amide ester of 4-hydroxyproline, of formula I: (I) wherein RI and R 'i are aliphatic chains, identical or different, having from 10 to 24 carbon atoms in a straight or branched line and in which the asterisks represent asymmetric carbons and an extract of the epicarp of the fruit of Opuntia Ficus -indica (prickly pear), in a vehicle or vehicle suitable for topical application.   2. New cosmetic and / or dermatological compositions characterized in that the fatty acid amide ester of 4-hydroxyproline is dipalmitoyl-4-hydroxyproline. Of formula II:   3. New cosmetic and / or dermatological compositions according to claim 1 or claim 2, characterized in that the fatty acid amido ester of   4-hydroxyproline is an amido ester of trans 4-hydroxyproline with fatty acids having from 10 to 24 carbon atoms. 4. New cosmetic and / or dermatological compositions according to claim 1, characterized in that the extract of Opuntia Ficus-indica fruit epicarp is that obtained with water and exhaustion with hexane. 25 30   5. New cosmetic and / or dermatological compositions according to claim 1, characterized in that the ratio of the fatty acid amidoester of 4-hydroxyproline to the extract of the fruit epicarp of Opuntia Ficus-indica is staggered. from 1,000,000 to 1 to 10,000 for 1.   6. New cosmetic and / or dermatological compositions according to claim 1, wherein the excipient is a gelating agent or a fat.   7. New cosmetic and / or dermatological compositions according to claim 10, wherein the vehicle is a liquid or semi-fluid fatty substance.