US007999008B2

(12) United States Patent (10) Patent No.: US 7.999,008 B2 Bernard et al. (45) Date of Patent: * Aug. 16, 2011

(54) UREACOMPOUNDS THAT PROMOTE OTHER PUBLICATIONS DESQUAMATION National Starch online retrieved from: http://news.nationalstarch. com/NewsStory.asp?newsltemld=416 on Mar. 20, 2009. Dec. 3, (75) Inventors: Dominique Bernard, Paris (FR); Lucie 2003. 3 pages.* Simonetti, Vincennes (FR); Pascale Formulating with Hydrovance online retrieved from: http://www. Pelletier, Antony (FR) personalcarepolymers.com/PCP/Products/ProductOverview. htm?id=95 on Mar. 20, 2009. May 17, 2005. 7 pages.* English language machine translation of DE2703185; Aug. 1978; 7 (73) Assignee: L'Oreal, Paris (FR) pages. Derivative online merriam websters online dictionary retrieved (*) Notice: Subject to any disclaimer, the term of this from http://.merriam-Webster.com/cgi-bin/ patent is extended or adjusted under 35 dictionary?book=dictionary&va-derivative; Jul. 5, 2008; 1 page.* U.S.C. 154(b) by 481 days. Anonymous: “pH Stability of Hydroxyalkylurea in Combination Either with One or More of a Cyclic (lactone) and/or Acylic Ester.” This patent is Subject to a terminal dis Dec. 22, 2004, IP. Com Journal, IP. Com. Inc., West Henrietta, NY, claimer. US, XPO 13022595. M. Ponec, et al. “Lack of Desquamation—the Achilles Heel of the (21) Appl. No.: 11/485,506 Reconstructed Epidermis' International Journal of Cosmetic Sci ence, 2002, vol. 24, (pp. 263-272). Sebastien Niamke, et al., “Physico-Chemical and Immunological (22) Filed: Jul. 13, 2006 Properties and Partial Amino Acid Sequencing of a New Metal loprotease: Endoprotease Thr-N” Biochimica et Biophysica Acta, (65) Prior Publication Data vol. 1623 (2003), (pp. 21-28), www.sciencedirect.com. D. Bernard, et al. "Analysis of Proteins with Caseinolytic Activity in US 2007/OO 14748A1 Jan. 18, 2007 a Human Stratum Corneum Extract Revealed a Yet Unidentified Cysteine and Identified the So-Called “Stratum Corneum Related U.S. Application Data Thiol Protease” as L2” The Society for Investigative Der (60) Provisional application No. 60/724.951, filed on Oct. matology. Inc, vol. 120, No. 4 (Apr. 2003), (pp. 592-600). 11, 2005. * cited by examiner (30) Foreign Application Priority Data Primary Examiner — Ernst Arnold (74) Attorney, Agent, or Firm — Oblon, Spivak, Jul. 13, 2005 (FR) ...... O5521.89 McClelland, Maier & Neustadt, L.L.P. (51) Int. Cl. (57) ABSTRACT A6 IK 8/02 (2006.01) The invention relates to the use of at least one urea derivative A6 IK3I/7 (2006.01) of the following formula (I) AOIN 47/28 (2006.01) (52) U.S. Cl...... 514/588; 424/401 (I) (58) Field of Classification Search ...... None R1 R4 See application file for complete search history. M A N-CO-N A V (56) References Cited R2 R3 U.S. PATENT DOCUMENTS in a composition containing a physiologically acceptable 2003/0O21379 A1 2/2003 Fein 2004/O197299 A1 * 10, 2004 Delattire et al...... 424/78.02 medium, as agent intended for stimulating descquamation of 2005/0113268 A1* 5/2005 Landa et al...... 510/130 the skin and/or the mucous membranes. It also relates to a method of cosmetic treatment and cosmetic agents containing FOREIGN PATENT DOCUMENTS it. EP 1535 607 A1 6, 2005 FR 2816837 5, 2002 18 Claims, 1 Drawing Sheet U.S. Patent Aug. 16, 2011 US 7.999,008 B2 FIG. I.

Acid protease activity of SC in the presence of N-(2-hydroxyethyl)-urea dose effect

1O 5 time in hours

Acid protease activity of SC in the presence of urea dose effect

10 15 time in hours US 7,999,008 B2 1. 2 UREACOMPOUNDS THAT PROMOTE and an extracellular matrix predominantly composed of col DESQUAMATION lagen, elastin and a substance called ground Substance. Leu kocytes, mastocytes or tissue macrophages are also present. REFERENCE TO PRIORAPPLICATIONS Finally, the dermis is crossed by blood vessels and nerve fibres. This application claims priority to U.S. provisional appli The cohesion between the epidermis and the dermis is cation 60/724,951 filed Oct. 11, 2005, and to French patent provided by the dermoepidermal junction. application 0552189 filed Jul. 13, 2005, both incorporated The epidermal homeostasis corresponds to an equilibrium herein by reference. between the keratinocytes entering into differentiation in the 10 deep layers of the epidermis and corneocytes removed from FIELD OF THE INVENTION the Surface of the epidermis in a process called descquamation. Normally, descquamation occurs corneocyte by corneocyte The present invention relates to novel desquamation-pro moting agents, and to their use in cosmetic orpharmaceutical, and remains imperceptible. in particular, dermatological, compositions. It also relates to 15 Desquamation has in the past been associated with cosmetic methods for treating the skin or its annexes, and mechanical actions. This so-called bricks and mortar theory, compositions allowing their use. the bricks being the corneocytes linked to each other by a lipid Additional advantages and other features of the present mortar (P. Elias, 1984), was contradicted only by the discov invention will be set forth in part in the description that ery of cohesive structures derived from the desmosomes follows and in part will become apparent to those having called corneodesmosomes linked to the horny envelope and to ordinary skill in the art upon examination of the following or the intermediate filaments of keratins (Chapman, Walsh et al. may be learned from the practice of the present invention. The 1991; Serre, Mils et al. 1991; Walsh and Chapman 1991). The advantages of the present invention may be realized and proteins which constitute these structures are the substrates obtained as particularly pointed out in the appended claims. for the descquamation . Indeed, the gradual appear As will be realized, the present invention is capable of other 25 ance of fragments of desmosomal proteins during differen and different embodiments, and its several details are capable tiation and the apparent ultrastructural modifications of the of modifications in various obvious respects, all without desmosome have led researchers in the direction of enzymes departing from the present invention. The description is to be responsible for these changes. regarded as illustrative in nature, and not as restrictive. The first, T. Egelrud (Egelrud, Hofer et al. 1988; Egelrud 30 and Lundstrom 1990; Egelrud and Lundstrom 1991), has BACKGROUND OF THE INVENTION demonstrated in the stratum corneum (SC) the existence of protease activities of the "trypsin-like” and especially "chy The skin has two compartments, one which is Superficial, motrypsin-like type associated with descquamation. These the epidermis, and one which is deeper, the dermis, which studies by T. Egelrud are part of the basic studies of any interact. The natural human epidermis is mainly composed of 35 research relating to the bio-chemistry of desquamation. Sub three types of cell which are the keratinocytes, which form the sequently, several cysteine and aspartic acid were great majority, the melanocytes and the Langerhans' cells. implicated in this process, in particular the stratum corneum The epidermis is conventionally divided into a basal layer thiol protease (SCTP) or cathepsin L2, the stratum corneum of keratinocytes constituting the germinative layer of the -like (SCCL) and cathepsin D. epidermis, a so-called prickle cell layer consisting of several 40 In a number of situations, it may be desirable to stimulate layers of polyhedral cells arranged on the germinative layers, this desquamation mechanism in order to promote epidermal one to three so-called granular layers consisting of flattened renewal and improve the brightness of the complexion, cells containing distinct cytoplasmic inclusions, the kerato attenuate surface irregularities and Smoothe the skin, or to hyalin granules and finally the horny layer (or stratum cor promote the cleansing action and the removal of dead cells at neum), consisting of a set of layers of keratinocytes at the final 45 the Surface of the body. In physiological states, thickening of stage of their differentiation, called corneocytes. The corneo the horny layer is also observed which it is desired to limit, for cytes are anucleated cells mainly composed of a fibrous example in the case of callosites or after exposure to Sunlight. matrix containing cytokeratins, Surrounded by a very resis Moreover, in Some skin disorders, descquamation becomes tant structure 15 nm thick, called horny or hornified envelope. visible and it is large sized scales containing numerous cor The stacking of these corneocytes constitutes the horny layer 50 neocytes which are removed. Deregulations of descquamation which is responsible for the barrier function of the epidermis. are increasingly better described at the molecular level and During the normal desquamation process, the most Superfi associated with aspects of abnormal skin. cial corneocytes become detached from the surface of the Ichthyoses are generally examples of impaired epidermal epidermis. differentiation associated with abnormal descquamation. In Intercellular structures derived from desmosomes, called 55 psoriasis, an inflammatory skin disease, and atopic dermati corneosomes or corneodesmosomes, have been described in tis, it has also been possible to show disorders associated with the horny layer. They are of major importance in intercorneo abnormal descquamation. In the field of acne, the accumula cyte cohesion and in the descquamation process. In particular, tion of a keratin plug (which can be removed by protease a close correlation exists between cell dissociation and pro activities) obstructing the pores is one of the reasons for the teolysis of certain corneodesmosomal components such as 60 appearance of comedones. The appearance of dandruff is desmoglein I or corneodesmosin. another example of a descquamation defect where the scales Several trypsin or chymotrypsin type serine proteases are abnormally visible. The impaired descquamation which is appear to be involved in the proteolysis of the corneodesmo generally present in reconstructed epidermes (Vicanova, Somes, in particular the chymotryptic of the horny Mommaas et al. 1996) also represents a proteolytic defect. layer (stratum corneum chymotryptic enzyme). 65 Some pathological skins can benefit from prodesquamating The dermis provides the epidermis with a solid support. It treatment based on urea derivatives. Among these patholo is also its feeder component. It consists mainly of fibroblasts gies, there may be mentioned the Netherton syndrome, the US 7,999,008 B2 3 4 Papillon-Lefevre syndrome, more generally ichthyoses of BRIEF DESCRIPTION OF THE FIGURE genetic origin and psoriasis or atopic dermatitis and the like. Various methods have already been proposed for promot FIG. 1 shows the results of Example 3. ing descquamation, in particular by peeling or scrubbing. It is also possible to use in particular retinoic acid and its deriva 5 DETAILED DESCRIPTION OF THE PREFERRED tives, X-hydroxy acids, such as lactic acid or glycolic acid, or EMBODIMENTS B-hydroxy acids, Such as salicylic acid. The invention thus relates to the use, etc., of certain com However, the active agents proposed, although they give pounds derived from urea of the following formula (I) good results, often have a proteolytic and/or keratolytic activ 10 ity which may lead to irritation of the areas where they are applied. Moreover, the addition of exogenous protease to (I) R1 R4 compositions can pose problems of Stabilization, irritation V A and create an allergy risk for Subjects to whom they are N-CO-N applied. 15 M V The prodesquamating properties of urea are generally R2 R3 associated with its protein-denaturing properties (so-called “keratolytic' effect). Urea is thought to denature certain cor in which: neodesmosomal Substrates promoting, interalia, the action of R. R. R. and R each represent, independently of each certain proteases. On the other hand, this effect is not a lasting other, a hydrogen atom, a C-C alkyl group or a C-C, effect capable of Stimulating the natural desquamation pro hydroxyalkyl group which optionally contains from 1 to 5 cesses because urea in the end, especially at concentrations hydroxyl groups, where at least one of the radicals R to R. greater than 2M, becomes denaturing for the proteases them represents a hydroxyalkyl group, selves. It would therefore be advantageous to find a com and their salts, their solvates and their isomers in a composi pound capable of durably stimulating the proteolytic activi 25 tion containing a physiologically acceptable medium, as ties of the stratum corneum. agent intended for stimulating desquamation of the skin and/ Some cosmetic active agents are capable of stimulating the or the mucous membranes and/or the Superficial body degradation of the proteins of the corneodesmosome and growths. therefore descuamation. Patent application EP 852 949 30 Indeed, it has been discovered, in the context of the present (Shiseido) describes the use, as descquamating agent, of invention, that Such compounds have a remarkable effect on derivatives of alpha-amino acids of the glycine type, which several mechanisms involved in descquamation, thus allowing favour the degradation of desmoglein (corneodesmosome a complete and natural action of stimulating this process, and protein). the application in all cases where it is desirable to promote 35 and/or accelerate the removal of the dead layers of the epi OBJECTS OF THE INVENTION dermis. This use is cosmetic and non-therapeutic, and is aimed at A need therefore still exists to have available agents stimu improving the physical appearance and/or the aesthetic lating descquamation of the skin or the mucous membranes, appearance of the individual whose descquamation and/or endowed with good activity without having the disadvantages 40 exfoliation and/or cell renewal is being stimulated. of the compounds of the state of the art. A particular need For compounds of formula (I): exists to stimulate the natural descquamation processes, in Preferably, R denotes a C-C hydroxyl group, and R. R. particular by promoting the proteases associated with descua and Ra denote, independently of each other, a hydrogen mation and naturally present in the skin. atom or a C-C alkyl group; 45 Preferably, R denotes a C-C hydroxyalkyl group com prising from 1 to 5 hydroxyl groups, in particular 1 SUMMARY OF THE INVENTION hydroxyl group, and R. R. and R. denote a hydrogen atom; Unexpectedly, it has been discovered that these objects and More preferably, R denotes a C-C hydroxyalkyl group others are achieved by the use of certain compounds derived 50 comprising 1 hydroxyl group, and R. R. and Radenote from urea of the following formula (I) a hydrogen atom. Among the alkyl groups, there may be mentioned in par ticular methyl, ethyl, n-propyl, isopropyl. n-butyl, isobutyl (I) and tert-butyl groups. R1 R4 55 Among the hydroxyalkyl groups, those containing a single V A N-CO-N hydroxyl group are preferred, and in particular the hydroxy A V ethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl and R2 R3 hydroxyhexyl groups, are preferred. Among the salts, there may be mentioned in particular the 60 salts of inorganic acids, such as Sulphuric acid, hydrochloric in which: acid, hydrobromic acid, hydriodic acid, phosphoric acid and R. R. R. and R each represent, independently of each boric acid. There may also be mentioned the salts of organic other, a hydrogen atom, a C-C alkyl group or a C-C, acids, which may contain one or more carboxylic, Sulphonic hydroxyalkyl group which optionally contains from 1 to 5 or phosphonic acid groups. They may be linear, branched or hydroxyl groups, where at least one of the radicals R to R. 65 cyclic aliphatic acids or aromatic acids. These acids may represents a hydroxyalkyl group, additionally contain one or more heteroatoms chosen from O and their salts, their Solvates and their isomers. and N, for example in the form of hydroxyl groups. There may US 7,999,008 B2 5 6 be mentioned in particular propionic acid, acetic acid, tereph and the mucous membranes. It is preferably a cosmetically thalic acid, citric acid and tartaric acid. acceptable medium, that is to say which has a pleasant colour, The expression Solvate is understood to mean a stoichio odour and feel and which does not cause unacceptable dis metric mixture of the said compound of formula (I) with one comfort. or more molecules of water or of organic solvent, such a The compositions are preferably cosmetic compositions or mixture typically being obtained from the synthesis of the products. The expression "cosmetic ' is understood to compound of formula (I). meanin particular any Substance or preparation intended to be As preferred compounds of formula (I), there may be men brought into contact with the various superficial parts of the tioned N-(2-hydroxyethyl)urea; N-(2-hydroxypropyl)-urea; human body (epidermis, piliary and hair system, nails, lips N-(3-hydroxypropyl)urea; N-(2,3-dihydroxypropyl)-urea; 10 and external genital organs) or with the teeth and the buccal N-(2,3,4,5,6-pentahydroxyhexyl)urea; N-methyl-N-(1,3,4,5, mucous membranes, exclusively or mainly, to clean them, to 6-pentahydroxy-2-hexyl)urea; N-methyl-N'-(1-hydroxy-2- perfume them, to modify the appearance thereof and/or to methyl-2-propyl)urea; N-(1-hydroxy-2-methyl-2-propyl) correct the body odours and/or to protect them or to maintain urea; N-(1,3-dihydroxy-2-propyl)urea; N-(tris them in a good state (amended cosmetics directive 76/768/ hydroxymethylmethyl)urea; N-ethyl-N'-(2-hydroxyethyl) 15 EEC). urea; N,N-bis(2-hydroxyethyl)urea; N,N'-bis(2- Three properties were therefore studied: hydroxyethyl)urea; N,N-bis(2-hydroxypropyl)urea; N,N'-bis The prodesquamating power, by the test of degradation of (2-hydroxypropyl)urea; N,N-bis(2-hydroxyethyl)-N'- corneodesmosin in a controlled environment chamber propylurea; N,N-bis(2-hydroxypropyl)-N'-(2-hydroxy with formulated products containing 5% active agent. ethyl)urea; N-tert-butyl-N'-(2-hydroxyethyl)-N'-(2- This test makes it possible to evaluate the capacity of a hydroxypropyl)urea; N-(1,3-dihydroxy-2-propyl)-N'-(2- formulated active agent to modulate the proteolytic deg hydroxyethyl)urea; N,N-bis(2-hydroxyethyl)-N',N'- radation of corneodesmosin. dimethylurea; N.N.N',N'-tetrakis(2-hydroxyethyl)urea; The “keratolytic potential: The keratin solubilization N',N'-bis(2-hydroxyethyl)-N',N'-bis(2-hydroxypropyl)- (“keratolysis”) test: This test corresponds to demonstrat urea; salts and Solvates thereof, and mixtures thereof. 25 ing the denaturing capacities of urea and its derivatives. Preferably, the compound of formula (I) is N-(2-hydroxy The effect of the molecules on the solubilization of the ethyl)urea. keratins of the SC is monitored on an electrophoresis The compounds of formula (I) are known compounds gel. which are described in particular in application DE-A- The “activating” potential of the acid proteases of the SC: 2703185. Among these, N-(2-hydroxyethyl)urea is addition 30 This test makes it possible to show that under certain ally commercially available, in the form of a mixture at 50% conditions, the proteolytic potential of certain epidermal by weight in water, from the company NATIONAL STARCH proteases could be increased. under the trade name HydroVance(R). However, to the knowl According to one of the aspects of the invention, the said edge of the applicant, these compounds have never been compound of formula (I) has a corneodesmosin degrading proposed for Stimulating proteolytic activities and promoting 35 effect which it stimulates. descquamation. According to another aspect of the invention, the said com The quantity of N-(2-hydroxyethyl)urea and of any other pound of formula (I) has a keratolytic effect greater than that compound of formula (I) used according to the invention of urea. depends on the desired result and in particular on the depth of Finally, and advantageously, the compound of formula (I) the peeling or exfoliation which it is desired to obtain, which 40 as defined above stimulates the activity of proteases of the itself depends on the condition of the skinto be improved. The stratum corneum. These enzymes are chosen in particular compound of formula (I) may be present in particular in the from the group comprising: composition according to the invention in an amount ranging serine proteases of the kallikrein family. Such as kallikrein from 0.01% to 70% by weight and more, relative to the total 5, 7 or 14 weight of the composition, preferably greater than or equal to 45 aspartic acid proteases such as cathepsin D, E or SASPase 0.1% by weight, or even greater than or equal to 1%; the (Locuslink 151516), or the protease described in appli concentrations can, in some embodiments, vary from 0.1% to cation WO 04/007548: 20% by weight, and will in particular preferably be less than cysteine proteases such as . H. L. L2, or equal to 10% by weight, in particular for daily care appli or 14, cations. 50 metaloproteases such as carboxypeptidases. Higher concentrations, in particular from about 30 to 50%, In particular, N-(2-hydroxyethyl)urea at a concentration of will be preferably used for peeling applications; these appli 0.5 to 2M, and in particular 1M, durably stimulates the deg cations will be more spaced apart over time, for example radation of a protein by the acid proteases of the SC, weekly or every 2 weeks, in which the compounds of formula Such as cathepsin D or cathepsin L2. (I) will be removed from the application surface after a con 55 The compositions according to the invention are in particu tact time, for example by rinsing the corresponding body lar exfoliating compositions Suitable for Scrubbing the rough Surface. The contact time may vary for example from 5 minto ness of the skin. They may be peeling compositions which 6 hours. make it possible to remove a larger thickness of the horny The compositions according to the invention may be cos layer Such as calluses. metic or pharmaceutical compositions, in particular derma 60 Compositions according to the invention are also compo tological compositions. sitions intended for cleansing the skin and/or the scalp, in A physiologically acceptable medium is, according to the which the action of the cleansing agents will be enhanced by invention, a cosmetically or pharmaceutically acceptable promoting the removal of the dead cells from the surface medium compatible with the skin, the mucous membranes, cleansed. the nails and/or the hair. 65 According to another aspect of the invention, the compo The compositions according to the invention may be sition containing the compound of formula (I) or its deriva applied to the nails, the hair and more particularly to the skin tives is a care composition intended to improve the Surface US 7,999,008 B2 7 8 state of the skin and/or the mucous membranes, in particular The quantities of the various constituents of the composi the lips; in particular the said composition will promote the tions according to the invention may be those conventionally removal of the roughness and/or of the dead skins present at used in the fields considered. the surface of the skin and/or the lips. In the cosmetic field, these compositions constitute in par The invention also relates to the use of at least one com ticular cleansing, protective, treatment or care creams for the pound of formula (I) or its derivatives as defined in the pre face, for the hands, for the feet, for the large anatomical folds ceding text, for the preparation of a composition intended for and for the body (for example day creams, night creams, the treatment of the signs associated with descquamation dis makeup-removing creams, foundation creams, anti-Sun orders. creams), fluid foundations, makeup-removing milks, protec 10 tive or care body milks, anti-Sun milks, lotions, gels or foams The subject of the invention is also the use of at least one for skincare, such as cleansing lotions, artificial tanning compound of formula (I) for the preparation of a composition lotions, bath compositions, deodorant compositions compris intended for the treatment of at least one skin disorder chosen ing a bactericidal agent, aftershave gels or lotions, composi from ichthyosis, hyperkeratosis, Xeroses, psoriasis, atopic tions against insect bites, compositions for treating certain dermatitis, acne and dandruff. 15 diseases of the skin Such as eczema, rosacea, psoriasis, Xeroses are skin disorders in which there is deregulation of lichens and severe pruritus. descuamation; there may be mentioned senile Xeroses, winter The compositions according to the invention may also Xeroses, Xeroses linked to the onset of menopause or to the use consist of Solid preparations constituting cleansing soaps or of certain detergents. cakes. In the field of acne, the accumulation of a keratin plug The compositions may also be packaged in the form of an obstructing the pores is one of the reasons for the appearance aerosol composition also comprising a pressurized propel of comedones; the latter can be more easily removed, or its lant. formation slowed or avoided, by the proteolytic and descqua A composition according to the invention may also be a mating activities of the compounds according to the inven composition for care of the scalp, and in particular a shampoo, tion. 25 a hair-setting lotion, a treatment lotion, a hair-styling cream The appearance of dandruff is another example of a or gel, restructuring lotions for the hair, an anti-hair-loss descuamation effect where the scales are abnormally visible. lotion or gel, an antiparasitic shampoo, an antidandruff sham According to one of the embodiments of the invention, the poo and the like. compositions are intended for promoting wound healing, by A composition may also be for buccodental use, for promoting the removal of debris and the like. 30 example a toothpaste. In this case, the composition may con According to another embodiment, the compounds of for tain customary adjuvants and additives for compositions for mula I or the compositions containing them, as defined above, oral use, and in particular surfactants, thickening agents, are useful for improving the appearance of the nails by humectants, polishing agents such as silica, various active removing the Surface irregularities and by preparing them for ingredients such as fluorides, in particular sodium fluoride, the application of a care or makeup product. The retention of 35 and optionally Sweetening agents such as sodium sacchari the varnish on the nail will in particular be promoted by the nate. prior application of a compound of formula I, which will have When the composition is an emulsion, the proportion of the a keratolytic and desquamating activity. The compounds of fatty phase may vary from about 5% to 80% by weight, and formula I or the compositions containing them will also pro preferably from about 5% to 50% by weight relative to the mote the removal of the cuticles which may be presentaround 40 total weight of the composition. The oils, waxes, emulsifiers the nail. The compounds of formula I may be applied in a base and coemulsifiers used in the composition in the form of an formulation during a 1st stage, and then after drying, the nail emulsion are chosen from those conventionally used in the varnish will be optionally applied. cosmetic field. The emulsifier and the coemulsifier are In general, any composition of the invention may be present in the composition in a proportion ranging from 0.3% ingested, injected or applied to the skin (on any skin area of 45 to 30% by weight, and preferably from 0.5% to 20% by the body) or to the mucous membranes (buccal, jugal, gingi weight relative to the total weight of the composition. The val, genital, conjuctival and the like). emulsion may additionally contain lipid vesicles. Preferably, a composition according to the invention is When the composition is an oily solution or gel, the fatty applied to the skin or the mucous membranes. phase may represent more than 90% of the total weight of the According to the mode of administration considered, it 50 composition. may be provided in any galenic form. Foratopical application In a known manner, the cosmetic composition may also to the skin or the mucous membranes, the composition may contain customary adjuvants in the cosmetic field, such as have the form, in particular, of aqueous or oily solutions or of hydrophilic or lipophilic gelling agents, hydrophilic or lipo lotion or serum type dispersions, of emulsions having a liquid philic additives, preservatives, antioxidants, solvents, per or semi-liquid consistency of the milk type, which are 55 fumes, fillers, screening agents, odour absorbers and colour obtained by dispersing a fatty phase in an aqueous phase ing matter. The quantities of these various adjuvants are those (O/W) or conversely (W/O), or of suspensions or emulsions conventionally used in the cosmetic field, and for example having a soft consistency of the cream or aqueous or anhy vary from about 0.01% to 10% of the total weight of the drous gel type, or alternatively of microcapsules or micropar composition. These adjuvants, according to their nature, may ticles, or of vesicular dispersions of the ionic and/or nonionic 60 be introduced into the fatty phase, into the aqueous phase type or of foams. These compositions are prepared according and/or into the lipid spherules. to the customary methods. As oils or waxes which can be used in the invention, there For injection, the composition may be provided in the form may be mentioned mineral oils (liquid paraffin), vegetable of aqueous or oily lotions or in serum form. For the eyes, it oils (liquid fraction of shea butter, sunflower oil), animal oils may be provided in the form of drops, and for ingestion, it 65 (perhydrosqualene), synthetic oils (Purcellin oil), silicone may be provided in the form of capsules, granules, syrups or oils or waxes (cyclomethicone) and fluorinated oils (perfluo tablets. ropolyethers), beeswax, carnauba wax or paraffin wax. It is US 7,999,008 B2 10 also possible to add fatty alcohols and fatty acids (Stearic EP199636, EP325540, EP402072, chestnut or prickly pear acid) to these oils. As emulsifiers that can be used in the extracts, in particular marketed by SILAB; reducing com invention, there may be mentioned glyceryl Stearate, polysor pounds such as cysteine or cysteine precursors. bate 60 and the PEG-6/PEG-32/Glycol Stearate mixture sold Desquamating agents which can be used are also nicotinic under the name TefoseR) 63 by the company Gattefosse. 5 acid and its esters and nicotinamide, also called vitamin B3 or As solvents which can be used in the invention, there may vitamin PP, and ascorbic acid and its precursors, as described be mentioned lower alcohols, in particular ethanol and iso in particular in application EP1529522. propanol, and propylene glycol. The compositions according to the invention may also As hydrophilic gelling agents which can be used in the contain other enzymes and in particular exogenous proteases, invention, there may be mentioned carboxyvinyl polymers 10 (CarbomerR), acrylic copolymers such as copolymers of and/or glycosidases and/or lipases and/or amidases. acrylates/alkyl acrylates, polyacrylamides, polysaccharides Such compounds are conventionally used in compositions Such as hydroxypropylcellulose, natural gums and clays, and, intended for desquamating and/or accelerating the renewal of as lipophilic gelling agents, there may be mentioned modified the horny layer, and combination with at least one compound clays such as bentones, metal salts of fatty acids such as 15 of formula (I) as defined above will make it possible to aluminium Stearates, hydrophobic silica, ethylcellulose and strengthen and/or prolong their action. These enzymes, in polyethylene. particular proteases, will thus be effective at concentrations The compounds of formula (I) may be used alone or as a below those recommended when they are used in composi mixture in any proportion. tions without potentiating agent, which will limit the risks and According to one of the embodiments of the invention, they difficulties linked to their use. are used as Sole descquamating agents. These proteases may be of animal, plant or microbiological According to another embodiment of the invention, they origin, and are used in increasingly purified form. It is pos are used in combination with at least one other descquamating sible in particular to use proteases of microbiological origin, agent. The composition then contains at least one other such as subtillisin, marketed under the name Exfocellia from descuamation-stimulating agent different from the com 25 COLETICA and Prozimex HTB LS 9142 from LS, or those pounds of formula (I). commercially available under the trade names Neutrase(R) and The compounds of formula (I) promote the activity of other Esperase(R) sold by the company NovoNordisk; these pro agents, whose quantity may thus be less in the composition. teases may also be proteases present in plant extracts such as The expression "descquamating agent' is understood to pawpaw, melon, and in particular based on , such as the mean any compound capable of acting: 30 product Linked Papain C-PS from COLLABORATIVE either directly on descquamation by promoting exfoliation, LABS, papain and , such as the product Vegeles such as B-hydroxy acids, in particular salicylic acid and LS2938 from LS, or Mucor mehi extract, such as Acitzyme its derivatives (including 5-n-octanoylsalicylic acid); E3M-M from ACTIVE ORGANICS. C-hydroxy acids, such as glycolic, citric, lactic, tartaric, The concentrations of these enzymes will be adjusted malic or mandelic acids; urea; gentisic acid, oligofu 35 according to the degree of purity and the activity of the coses; cinnamic acid; extract of Saphora japonica; res product containing them. They are generally from 0.0001% to Veratrol and some derivatives of jasmonic acid; 5%, but may be reduced to concentrations of less than or equal or on the enzymes involved in the descquamation or the to 1%, or even less than or equal to 0.1%, in combination with degradation of the corneodesmosomes, glycosidases, compounds of formula I according to the invention. stratum corneum chymotryptic enzyme (SCCE) of even 40 Glycosidases may be all the enzymes capable of having, as other proteases (trypsin, chymotrypsin-like). There may Substrate, proteoglycans, glycolipids and in general glyco be mentioned agents chelating inorganic salts: EDTA; conjugates of the stratum corneum. Such enzymes are in N-acyl-N,N',N'-ethylenediaminetriacetic acid; amino particular heparanase, sialidases such as for example Sulphonic compounds and in particular (N-2-hydroxy neuraminidases, mannosidases, galactosidases, glucosidases, ethylpiperazine-N-2-ethane)sulphonic acid (HEPES); 45 N-acetylglucosaminidases, N-acetylgalactosaminidases, derivatives of 2-oxothiazolidine-4-carboxylic acid (pro chondroitinases, glucuronidases or hyaluronidases, but also cysteine); derivatives of alpha-amino acids of the gly cellulases, as described for example in application WO cine type (as described in EP-0 852 949, and sodium 02/38122; in particular, it is possible to use N-glycanase, methylglycine diacetate marketed by BASF under the cellulases, B-glucosidase, B-galactosidase, N-acetylglu trade name TRILONM); honey; sugar derivatives such 50 cosaminidase and/or N-acetylgalactosaminidase. The gly as O-octanoyl-6-D-maltose and N-acetylglucosamine; cosidases used in the compositions according to the invention chestnut extracts such as those marketed by the company may be purified from extracts of proteins synthesized by the SILAB under the name Recoverine(R), prickly pear cells of the stratum corneum or may be glycosidases naturally extracts such as those marketed under the name Exfolac synthesized by microorganisms. They may also be recombi tive(R) by the company SILAB, or Phytosphingosine 55 nant glycosidases produced in a heterologous system. SLCR (phytosphingosine grafted with a salicylic acid) Examples of glycosidases used are those marketed by Cal marketed by the company Degussa. biochem or by Roche. It is understood that these enzymes Desquamating agents suitable for the invention may be may be present in the compositions containing the compound chosen in particular from the group comprising Sulphonic of formula I alone or in combination, in particular combina acids, calcium chelators, C.-hydroxy acids such as glycolic, 60 tions of 2 or 3 glycosidases. citric, lactic, tartaric, malic or mandelic acids; ascorbic acid Examples of amidase or with amidase activity and its derivatives such as ascorbylglucoside and magnesium are the compounds EC 3.5.1.1 to EC 3.5.1.89 of the conven ascorbyl phosphate; nicotinamide: urea; (N-2-hydroxyeth tional nomenclature, among which areasparaginase, glutami ylpiperazine-N-2-ethane)sulphonic acid (HEPES), B-hy nase, amidase, , aminoacylase, , cerami droxy acids such as Salicylic acid and its derivatives, retinoids 65 dase, peptidylglutaminase, formamidase, pentanamidase, Such as retinol and its esters, retinal, retinoic acid and its AGA, described in application EP 1 derivatives, those described in the documents FR 257.0377, 43.8968. US 7,999,008 B2 11 12 As lipase which can be used, there may be mentioned, tion may for example be chosen from plant proteins or without limitation, the product SP144 marketed by the com polypeptides, extracted in particular from Soyabean (for pany NOVO. example a soyabean extract marketed by the company LSN The compositions according to the invention may addition under the name Eleseryl SH-VEG 8(R) or marketed by the ally contain at least one cosmetic active agent which is a company SILAB under the trade name Raffermine(R); and compound chosen from moisturizing agents, agents reducing plant hormones such as giberrelins and cytokinins. or inhibiting the activity of harmful proteases, agents stimu AS agents reducing or inhibiting the activity of harmful lating epidermal differentiation and antiseborrheic agents. proteases, there may be mentioned those acting The expression "moisturizing agent' is understood to either on the inhibition of metalloproteinases (matrix met Ca 10 alloproteinases or MMPs) such as more particularly either a compound acting on the barrier function, in order MMPs 1, 2, 3 and 9. There may be mentioned: retinoids to maintain moisturization of the stratum corneum, oran and derivatives, oligopeptides and lipopeptides, occlusive compound. There may be mentioned ceram lipoamino acids, malt extract marketed by the company ides, sphingoid-based compounds, lecithins, glycosph COLETICA under the trade name Collalift(R); bilberry ingolipids, phospholipids, cholesterol and its deriva 15 and rosemary extracts; lycopene; isoflavones, their tives, phytosterols (stigmasterol, B-sitosterol, derivatives or plant extracts containing them, in particu camposterol), essential fatty acids, 1,2-diacylglycerol, lar extracts of soyabean (marketed for example by the 4-chromanone, pentacyclic triterpenes such as ursolic company ICHIMARU PHARCOS under the trade name acid, petroleum jelly and lanolin; Flavosterone SBR), red clover (marketed for example or a compound directly increasing the water content of the by the company SEDERMA under the name “STERO stratum corneum, Such as threalose and its derivatives, CARE(R), FLAX, kakkon or sage: Cucurma longa hyaluronic acid and its derivatives, glycerol, pen extracts; Siegesbeckla extracts (marketed for example tanediol, Sodium pidolate, serine, Xylitol, Sodium lac by the company Sederma); tate, glyceryl polyacrylate, ectoin and its derivatives, or on the inhibition of certain serine proteases Such as chitosan, oligo- and polysaccharides, cyclic carbonates, 25 leukocyte elastase or cathepsin G. There may be men N-lauroylpyrrolidonecarboxylic acid, N-C-benzoyl-L- tioned: the peptide extract of legume (Pisum sativum) arginine; Hepes, or C-glycosidated derivatives, as seeds marketed by the Laboratoires Serobiologiques described in WO 02/051828: under the trade name Parelastyl(R); heparinoids; and or a compound activating the sebaceous glands such as pseudodipeptides such as {2-acetyl-(3-trifluorometh steroid derivatives (including DHEA, its 7-oxidized and/ 30 ylphenyl)aminol-3-methylbutyrylamino-acetic acid. or 17-alkylated derivatives and Sapogenins), methyl Other protease-inhibiting agents which may be added dihydrojasmonate, and vitamin D and its derivatives. according to the invention are plasminogen activation inhibi The latter category of compounds will be more particu tors such as for example tranexamic acid. larly Suitable for applications to mature, or even very Indeed, while certain protease activities may be advanta mature, skins, for example in individuals over 55 or 60 35 geously activated according to the invention, it is known that years. other enzymes have a deleterious effect on the constituents of These compounds may represent from 0.001% to 30%, the dermis or of the epidermis and their activity must be preferably from 0.01 to 20%, of the total weight of the com repressed in order to obtain an optimum effect on the appear position according to the invention. ance and radiance of the skin. The agents stimulating epidermal proliferation or differen 40 According to another aspect, the composition contains tiation which are useful in the compositions according to the antiseborrhoeic agents, and for example a 5C-reductase invention are more specifically active on the keratinocytes. inhibitor; they may be chosen in particular from: The agents stimulating proliferation of the keratinocytes, retinoids, and in particular retinol; which can be used in the composition according to the inven Sulphur and Sulphur-containing derivatives; tion, comprise in particular retinoids such as retinol and its 45 Zinc salts such as Zinc lactate, gluconate, pidolate, carboxy esters, including retinyl palmitate; adenosine: phlorogluci late, Salicylate and/or cysteate; nol; extracts of nut cakes marketed by the company GATTE selenium chloride; FOSSE; and extracts of Solanum tuberosum marketed by the vitamin B6 or pyridoxin; company SEDERMA. the mixture of caprylol glycine, sarcosine and extract of The agents stimulating the differentiation of the kerati 50 Cinnamomum zeylanicum marketed in particular by the nocytes comprise, for example, minerals such as calcium; a company SEPPIC under the trade name Sepicontrol lupin peptide extract such as that marketed by the company A5(R); SILAB under the trade name Structurin R; sodium beta-sito an extract of Laminaria saccharina marketed in particular sterylsulphate Such as that marketed by the company by the company Biotech Marine under the trade name SEPORGA under the trade name Phytocohesin(R); and a 55 Phlorogine(R); water-soluble maize extract such as that marketed by the an extract of Spiraea ulmaria marketed in particular by the company SOLABIA under the trade name Phytovity1R; a company SILAB under the trade name Sebonormine(R); peptide extract of Voandzeia substerranea such as that mar extracts of plants of the species Arnica montana, Cinchona keted by the company Laboratoires Serobiologiques under succirubra, Eugenia caryophyllata, Humulus lupulus, the trade name Filladyn LS9397(R); and lignans such as sec 60 Hypericum perforatum, Mentha piperita, Rosmarinus oisolariciresinol. officinalis, Salvia officinalis and Thymus vulgaris, all The composition may as Such also contain 8-hexadecene marketed for example by the company MARUZEN: 1, 16-dicarboxylic acid, ecdysteroids Such as ecdysterone and an extract of Serenoa repens marketed in particular by the its derivatives, or vitamin D derivatives, and/or PPAR ago company EUROMED: nists. 65 extracts of plants of the genus Silybum; and The agents stimulating the proliferation of fibroblasts extracts of Eugenia caryophyllata containing eugenol and which can be used in the composition according to the inven eugenylglucoside. US 7,999,008 B2 13 14 The compositions containing Such agents will be more During step (ii), the descquamating agent(s) will be applied particularly intended for the treatment of oily or hypersebor at a total concentration greater than or equal to 10%, in rhoeic skins. particular of about 20 to 50%, and will be left in contact with The subject of the invention is also a method of cosmetic the skin for between 5 min and 6 hours, preferably for treatment for promoting desquamation or for promoting the between 5 min and 30 min. removal of the superficial layers of the skin and/or the super The method according to the invention comprises at least ficial body growths comprising a step during which at least one additional step for removing the descquamating agent, in one compound of formula (I), in particular N-(2-hydroxy particular the compound of formula (I) such as N-(2-hy ethyl)urea or a composition containing it, is applied to the droxyethyl)urea by rinsing with water or with the aid of a mild area to be treated. 10 detergent. Another subject of the invention is a method of cosmetic treatment for promoting the radiance of the complexion and/ According to a particular embodiment, the invention or reducing the Surface irregularities of the skin and/or the relates to a method for the cosmetic treatment of keratin materials which consists in the application of at least two mucous membranes, wherein at least one compound of for components: mula (I) or a composition as described in the preceding text is 15 applied to the skin or the mucous membranes. a first component comprising at least one compound of To carry out this method, the compound of formula (I) or formula (I) or a composition containing it, as defined the composition containing it may be applied to any area of above, the skin or of its annexes, in particular of the face, the neck a second component comprising at least one agent chosen and shoulders, the hands or to the lips, in order to smooth the from proteases, lipases and glycosidases, these two visible and/or tactile irregularities of the skin, for example in components being applied simultaneously, conjointly or order to tone down pigmented spots or Scars, to Smooth the sequentially to the skin, the mucous membranes or the Surface and/or remove dead skins in particular from the lips. Superficial body growths. The application times will vary according to the concen Advantageously, the second component will comprise at tration of the compound of formula (I) in the composition, 25 least one protease, involved in descquamation. and the desired effect. As a guide, the composition may Agents chosen from moisturizing agents, agents reducing remain in contact with the skin or the superficial body or inhibiting the activity of harmful proteases, agents stimu growths between 5 min and 12 h, and may or may not be lating epidermal differentiation and anti-seborrhoeic agents removed at the end of this contact time. The application may may advantageously be present in the first and/or the second be carried out daily or twice daily, or weekly, and repeated 30 component. during periods of 2 weeks to 6 months; it being possible to The first component may optionally contain at least one extend or renew this period with no difficulty. descuamating agent, such as those chosen from compounds According to another embodiment, the invention relates to directly promoting desquamation and compounds acting on a cosmetic method for promoting descquamation of the skin the enzymes involved in descquamation or the degradation of and/or the mucous membranes, comprising at least a step (i) 35 the corneodesmosomes, in particular cysteine or its precur of preparing the skin for peeling, consisting in applying to the SOS. areas to be treated at least one compound of formula (I) as A subject of the invention is therefore also a cosmetic defined in the preceding text, in particular N-(2-hydroxy composition or agent in the form of a kit comprising at least ethyl)urea, or its salts or its Solvates, at a concentration at least two components less than that causing descquamation, and (ii) a Subsequent 40 a first component comprising at least one compound of step comprising the application of at least one descquamating formula (I) as defined above, agent at a Suitable concentration to cause desquamation. A a second component comprising at least one agent chosen step for removing the descquamating agent(s) by rinsing will from proteases, lipases and glycosidases, these two then be carried out. components being intended to be applied simulta Advantageously, the step (i) may be repeated with increas 45 neously, conjointly or sequentially to the skin, the ing concentrations of compound of formula (I). These con mucous membranes or the Superficial body growths. centrations will be adjusted by persons skilled in the art The additional descquamating agents described above, Such according to the desired effect and the number of applications as Sulphonic acids, calcium chelators, C.-hydroxy acids Such envisaged, but will be generally less than 10%. It will be as glycolic, citric, lactic, tartaric, malic or mandelic acids; possible for example to use a first concentration of about 2%, 50 ascorbic acid and its derivatives such as ascorbyl glucoside and then one or more successive applications with a concen and magnesium ascorbyl phosphate; nicotinamide; urea; and tration of about 4%, and then 6 or 8% by weight. (N-2-hydroxyethylpiperazine-N-2-ethane)sulphonic acid Step (ii) comprises the application of at least one descqua (HEPES), B-hydroxy acids such as salicylic acid and its mating agent which may be chosen from the group compris derivatives, retinol and its esters, retinal, retinoic acid and its ing the compounds of formula (I) alone or as a mixture, in 55 derivatives, chestnut and prickly pear extracts, reducing com particular N-(2-hydroxyethyl)urea, but also Sulphonic acids, pounds such as cysteine or cysteine precursors, nicotinic acid calcium chelators, C.-hydroxy acids such as glycolic, citric, and its esters and nicotinamide, also called vitamin B3 or lactic, tartaric, malic or mandelic acids; ascorbic acid and its vitamin PP, 8-hexadecene-1,16-dicarboxylic acid may also derivatives such as ascorbylglucoside and magnesium ascor be present in the first and/or second component. byl phosphate, nicotinamide; urea; and (N-2-hydroxyeth 60 The first and/or second component may additionally com ylpiperazine-N-2-ethane)sulphonic acid (HEPES), B-hy prise at least one cosmetic active agent as described in the droxy acids such as Salicylic acid and its derivatives, retinol preceding text, for example moisturizing agents, agents and its esters, retinal, retinoic acid and its derivatives, chest reducing or inhibiting the activity of harmful proteases, nut or prickly pear extracts, reducing compounds such as agents stimulating epidermal differentiation and antisebor cysteine or cysteine precursors, nicotinic acid and its esters 65 rhoeic agents. and nicotinamide, also called vitamin B3 or vitamin PP, The Subject of the invention is also a cosmetic or derma 8-hexadecene-1,16-dicarboxylic acid. tological composition comprising at least one compound of US 7,999,008 B2 15 16 formula (I) and at least one descquamating agent different ticular with notches, or with a threaded rod, or with a helical from a compound of formula (I) as defined in the preceding ramp, and capable of moving a stick in the direction of the text. said opening. Such a mechanism is described for example in According to another aspect, the invention also relates to a patent FR 2806 273 or in patent FR 2775 566. Such a cosmetic set comprising: mechanism for a liquid product is described in patent FR 2 i) a container delimiting at least one compartment, the said 727 609. container being closed with a closing element; and The container may consist of a case with a base delimiting ii) a composition as described above and placed inside the at least one housing containing the composition, and a cover, said compartment. in particular articulated to the base, and capable of at least The container may be in any suitable form. It may be in 10 particular in the form of a bottle, a tube, a pot, a box, a pack, partially covering the said base. Such a case is described for a bag or a case. example in application WO 03/018423 or in patent FR 2791 The closing component may be in the form of a removable O42. stopper, a cover, a lid, a tear-off strip or a capsule, in particular The container may be equipped with a draining device in of the type comprising a body attached to the container and an 15 the vicinity of the container opening. Such a draining device articulated cap attached to the body. It may also be in the form makes it possible to wipe the applicator and optionally the rod of a component allowing selective closure of the container, in to which it may be integrally attached. Such a draining device particular a pump, a valve or a shutter. is described for example in patent FR 2792 618. The container may be combined with an applicator, in The composition may beat atmospheric pressure inside the particular in the form of a brush comprising an arrangement container (at room temperature) or pressurized, in particular of bristles held together by a twisted wire. Such a twisted by means of a propellant gas (aerosol). In the latter case, the brush is described in particular in U.S. Pat. No. 4,887,622. It container is equipped with a valve (such as those used for may also be in the form of a comb containing a plurality of aerosols). application components obtained in particular from mould In one particular embodiment, the cosmetic set comprises ing. Such combs are described for example in patent FR 2796 25 at least (i) a first compartment containing at least one com 529. The applicator may be in the form of a brush, as pound of formula (I) as defined above and (ii) a second described for example in patent FR 2722380. The applicator compartment comprising at least one protease. may be in the form of a foam or elastomer block, a felt, or a Another subject of the invention is the use of at least one spatula. The applicator may be free (powderpuff or sponge) compound of formula (I) as defined in the preceding text, for or integrally attached to a rod carried by the closing compo 30 the preparation of reconstructed skins. nent, as described for example in U.S. Pat. No. 5.492.426. The applicator may be integrally attached to the container, as The invention thus relates to a method for extending the life described for example in patent FR 276.1959. of reconstructed skins in vitro, and more particularly of The product may be contained directly in the container, or reconstructed epidermes. indirectly. By way of example, the product may be placed on 35 According to one of the embodiments, the reconstructed an impregnated Support, in particular in the form of a wipe or epidermis may be treated with low concentrations of com a Swab, and placed (individually or several of them) in a pack pounds of formula (I) such as N-(2-hydroxyethyl)urea and its or in a bag. Such a Support incorporating the product is derivatives, daily, in order to promote regular descquamation, described for example in application WO 01/03538. similar to that observed in a healthy skin in vivo. The closing component may be coupled to the container by 40 According to another aspect, the compound of formula (I), screwing on. Alternatively, the coupling between the closing in particular N-(2-hydroxyethyl)urea, is applied to the recon component and the container is otherwise carried out by structed epidermis locally, at a high dose similar to those for screwing on, in particular via a bayonet mechanism, by Snap peeling, that is about 20 to 40%, and then removed by rinsing: fitting, tightening, welding, adhesive bonding or by magnetic this method makes it possible to remove the constituted horny attraction. The expression 'Snap-fitting is understood to 45 layer or a portion thereof, whose accumulation can damage mean in particular any system involving passing over a flange the survival of the keratinocytes. or a cord of material by elastic deformation of a portion, in Another subject of the invention is a method for selecting particular of the closing component, and then by returning descuamating molecules, comprising a step of determining elastically to the stress-free position of the said portion after the activation of proteases, in particular acid proteases, by the passing over the flange or the cord. 50 test compound. The container may be at least partially made of thermo This test comprises the steps consisting in: plastic material. By way of example of thermoplastic mate a) preparing a stratum corneum extract containing acid rial, there may be mentioned polypropylene or polyethylene. proteases, Alternatively, the container is made of a non-thermoplastic b) mixing a labelled protein substrate with various concen material, in particular of glass or metal (or alloy). 55 trations of the test compound, and with a proteolytic The container may have rigid walls or deformable walls, in concentration of urea, in order to obtain mixtures com particular in the form of a tube or a tubulated bottle. prising either the test compound, or urea The container may comprise means intended to cause or c) bringing fractions of the extract obtained in step a) into facilitate the distribution of the composition. By way of contact with the various mixtures obtained at the end of example, the container may have deformable walls so as to 60 step b), in order to obtain reaction mixtures comprising cause the outflow of the composition in response to an over either the test compound, or urea, or with the labelled pressure inside the container, which over-pressure is caused casein Substrate in order to obtain a control, by elastic (or non-elastic) crushing of the walls of the con d) after an incubation time, comparing the proteolytic reac tainer. Alternatively, in particular when the product is in the tion in the various reaction mixtures with that of the form of a stick, the latter may be driven by a piston mecha 65 control, nism. Still in the case of a Stick, in particular for a makeup e) selecting the compound for which the intensity of pro product, the container may comprise a mechanism, in par teolysis is greater than that of the control. US 7,999,008 B2 17 18 Advantageously, the extract of step a) is obtained by grind ing of the stratum corneum, centrifuging and recovering the Supernatant. Mean of 2 experiments According to an advantageous embodiment, the protein Base Arlacel/Myr 79 substrate is a casein substrate. It may be labelled with a 5% Hydrovance 23 fluorescent group, which will be released during the proteoly 5% urea 30 sis. It is in particular Bodipyfl-casein, which releases a fluo rescence proportional to the proteolysis. HydroVance(R) has a slightly higher effect than urea.

Other advantages of the invention will appear on reading 10 the examples which follow. Example 2 “Keratolytic' Potential on the Proteins of the Example 1 Stratum Corneum

15 Degradation of Corneodesmosins in a Controlled Urea is known for its denaturing activity on keratolytic Environment Chamber proteins. Optimization was performed in order to demon strate a solubilization effect on keratins and proteins of the SC The molecules are formulated in a neutral base Arlacel/ which are difficult to solubilize with urea derivatives. Myri. The products are in contact with varnished Strippings Procedure: under defined temperature, humidity and incubation time 30 mg of acetone powders of stratum corneum of the bot conditions. The corneodesmosin is assayed by immunodetec tom of the legs of Volunteers are prepared and brought into tion after incubation. It is studied on an immunoblot after contact with 3 ml of water +2% CHAPS (Zwitterionic deter electrophoretic separation and transfer onto a membrane. gent) for 10 min at room temperature. The mixture is then After specific labelling with the antibody G3619, it is visual 25 ground in a potter device and centrifuged for 10 min at 15 000 ized by chemiluminescence. g.The Supernatant is removed. This method makes it possible The HydroVance R product, which is a mixture comprising to remove the very soluble keratins and proteins which would N-(2-hydroxyethyl)urea marketed by the company National interfere with the interpretation of the results. The pellet is Starch, is compared with urea and with a control. taken up in 300 ul of water--CHAPS and 20 l are distributed 30 into 10 Eppendorf tubes. Each molecule to be studied is prepared at 2M in water 2% CHAPS. Formulas Formula No. 200 ulofsolution are mixed with 20 ul of extract of acetone Base Arlacel/Myr 657236 powders. The assays are carried out in duplicate. A control Base + 5% Hydrovance (R) 658890 35 with no reagent is performed in parallel. The reaction mix Base +5% urea 658892 tures are incubated for 10 min at room temperature, they are ground in a potter device and then incubated for 50 min at room temperature. They are centrifuged for 10 min at 15 000 Procedure: g. The Supernatants are collected and diluted 4 in 1x Laem Rectangles of 3x3.5 cm are cut out in varnished strippings 40 mli buffer. Electrophoresis is performed on a 12.5% acryla made on the bottom of dry skin legs. They are treated with 42 mide gel followed by staining with silver nitrate. mg of product (4 mg/cm) each. Controls and assays are Results carried out in parallel. The assays are incubated at 37°C. and The N-(2-hydroxyethyl)urea composition (HydroVance(R) 70% relative humidity for 5 days. The controls are kept for 5 is distinguishable from urea by the appearance of low MW days at -20°C. For each of the samples, acetone powders are 45 bands; proteins that are better extracted or fragments gener made and weighed. The proteins are extracted with 100 ul of ated during incubation. complete Laemmli buffer. They are assayed according to the Bradford method. The protein level of each sample is adjusted Example 3 and will allow direct comparison of the various samples. The proteins are separated by SDS-Page electrophoresis on 50 Activating Potential on Acid Proteases 12% acrylamide gel. After transferring the proteins onto a PVDF membrane, the immunodetection is carried out with Activation of Acid Proteases the anti-corneodesmosin antibody G3619 (Guy Serre) at 1/12 The property of activating certain acid proteases of the SC 500 according to a conventional Western-blot technique. The (stratum corneum) is evaluated. The measurement of this 55 activity is carried out by fluorimetric assay with the aid of the visualization is performed by chemiluminescence. The bands Enzchek kit (Molecular Probes). This protocol uses a detected by fluorSmax (Biorad) are quantified with the soft Bodipyfl-casein substrate which, when hydrolysed, releases ware quantity-one. fluorescence. The fluorescence released is directly propor This experiment was repeated twice and during the second tional to the protease activity. It is read directly on a 96-well experiment, the immunoblots were performed in triplicate. 60 plate in a spectrofluorimeter at 750V at an excitation of 485 The results are a mean of 2 experiments performed. nm and an emission of 535 nm. The results obtained with N-(2-hydroxyethyl)urea (com Results: pound according to the invention) are compared with those The results are expressed as percentages of residual cor for urea. neodesmosin relative to the control -80° C. 65 Procedure: The lower the percentage, the higher the degradation and The molecules are prepared at 0, 1, 2 and 4 M in 0.1M the higher the prodesquamating effect. acetic buffer; pH 5.0. An enzymatic extract is prepared from US 7,999,008 B2 19 20 acetone powders. 2 ml of PBS buffer +0.1% TritonX100 are brought into contact for 1 h in crushed ice with 200 mg of (I) R1 R4 stratum corneum acetone powders. The mixture is then V A ground in a potter device and then centrifuged for 10 min at 15 N-CO-N M V 000 g at 4°C. The supernatant is collected. The Enzchek R2 R3 Substrate diluted /200 is incorporated into each Solution con taining the molecules. The assays are repeated three times. The reaction mixture is prepared directly in a white plate. in which: 10 ul of enzymatic extract are added to 200 ul of solution R. R. R. and R each represent, independently of each containing the Substrate at 0, 1, 2 or 4M. The readings are 10 other, a hydrogen atom, a C-C alkyl group or a C-C, carried out at t0, 1 2 h, t 16 hand t 24 h. hydroxyalkyl group which may contain from 1 to 5 hydroxyl The results are represented in the appended FIGURE. groups, where at least one of the radicals R to Ra represents Urea at 1 and 2M has a slightly activating effect on acid a hydroxyalkyl group, and their salts, their Solvates and their isomers; in a compo proteases up to two hours after the start of incubation. 15 sition containing a physiologically acceptable medium, as On the other hand, for HydroVance(R) (N-(2-hydroxyethyl) agent intended for stimulating desquamation of the skin and/ urea), a large increase inactivity is noted for concentrations of or the mucous membranes. 1 and 2 M compared with the control. This increase is long Further, description and enablement is provided hereinfor lasting. At 4M, a marked decrease in activity is observed the following preferred embodiments of the invention: regardless of the time studied. 1. Cosmetic use of at least one compound of the following Example 4 formula (I) Compositions (I) 25 R1 R4 V A N-CO-N M V R2 R3 Care cream:

TRIETHANOLAMINE O.3300 30 in which: WATER (and) HYDROXYETHYLUREA 1.O.OOOO HYDROGENATED POLYISOBUTENE S.OOOO R. R. R. and R each represent, independently of each PROPYLPARABEN O.1OOO other, a hydrogen atom, a C-C alkyl group or a C-C, METHYLPARABEN O.2OOO hydroxyalkyl group which may contain from 1 to 5 hydroxyl CARBOMER O.3OOO groups, where at least one of the radicals R to Ra represents CYCLOPENTASILOXANE 1S.OOOO 35 WATER 62.O700 a hydroxyalkyl group, PEG-SO STEARATE 2.SOOO and their salts, their Solvates and their isomers; in a compo GLYCERYL STEARATE (and) PEG-100 STEARATE 2.SOOO sition containing a physiologically acceptable medium, as CETYLALCOHOL 1.OOOO agent intended for stimulating desquamation of the skin and/ STEARYLALCOHOL 1.OOOO or the mucous membranes. 40 2. Use of at least one compound of formula (I) according to The cream may be applied every night to the face and the Embodiment 1, characterized in that informula (I) R. denotes neck. a C-C hydroxyalkyl group and R. R. and Ra denote, inde pendently of each other, a hydrogen atom or a C-C alkyl group. 45 3. Use according to at least either of Embodiments 1 and 2. Formula with Sugar esters characterized in that in formula (I) R. denotes a C-C, WATER (and) HYDROXYETHYLUREA 1.O.OOOO hydroxyalkyl group comprising from 1 to 5 hydroxyl groups, SHOREA ROBUSTA SEED BUTTER 2.OOOO and R. R. and R. denote a hydrogen atom. PRUNUS ARMENIACA (APRICOT) KERNEL OIL 6.OOOO CHLOREHEXIDINE DIGLUCONATE O.3OOO 4. Use according to at least one of Embodiments 1 to 3, 50 PROPYLPARABEN O.1OOO characterized in that in formula (I) R. denotes a C-C, METHYLPARABEN O.2SOO hydroxyalkyl group comprising 1 hydroxyl group. XANTHAN GUM O.2SOO 5. Use according to at least one of Embodiments 1 to 4, POLYACRYLAMIDE (and) C13-14 ISOPARAFFIN (and) 1.OOOO characterized in that R denotes a C-C hydroxyalkyl group LAURETH-7 CYCLOHEXASILOXANE 1.O.OOOO comprising 1 hydroxyl group and R. R. and Ra denote a WATER 64.1OOO 55 hydrogen atom. METHYL GLUCOSE SESQUISTEARATE 2.OOOO 6. Use according to at least one of Embodiments 1 to 5, PEG-20 METHYL GLUCOSE SESQUISTEARATE 2.OOOO characterized in that the compound of formula (I) is chosen STEARYLALCOHOL (and) CEREARTH-20 2.OOOO from N-(2-hydroxyethyl)urea; N-(2-hydroxy-propyl)urea; N-(3-hydroxypropyl)urea; N-(2,3-dihydroxy-propyl)urea; The cream may be applied daily. 60 N-(2,3,4,5,6-pentahydroxyhexyl)urea; N-methyl-N-(1,3,4,5, The above written description of the invention provides a 6-pentahydroxy-2-hexyl)urea; N-methyl-N'-(1-hydroxy-2- manner and process of making and using it such that any methyl-2-propyl)urea; N-(1-hydroxy-2-methyl-2-propyl) person skilled in this art is enabled to make and use the same, urea; N-(1,3-dihydroxy-2-propyl)urea; N-(tris this enablement being provided in particular for the subject hydroxymethylmethyl)urea; N-ethyl-N'-(2-hydroxyethyl) matter of the appended claims, which make up a part of the 65 urea; N,N-bis(2-hydroxyethyl)urea; N,N'-bis(2- original description and including the use of at least one hydroxyethyl)urea; N,N-bis(2-hydroxypropyl)urea; N,N'-bis compound of the following formula (I) (2-hydroxypropyl)urea; N,N-bis(2-hydroxyethyl)-N'- US 7,999,008 B2 21 22 propylurea; N,N-bis(2-hydroxypropyl)-N'-(2-hydroxy 21. Use of at least one compound of formula (I) according ethyl)urea; N-tert-butyl-N'-(2-hydroxyethyl)-N'-(2-hydrox to any one of the preceding Embodiments, characterized in ypropyl)urea; N-(1,3-dihydroxy-2-propyl)-N'-(2-hydroxy that the composition additionally contains at least one com ethyl)urea; N,N-bis(2-hydroxyethyl)-N',N'-dimethylurea; pound chosen from moisturizing agents, agents reducing or N.N.N',N'-tetrakis(2-hydroxyethyl)urea; N',N'-bis(2-hy inhibiting the activity of harmful proteases, agents stimulat droxyethyl)-N',N'-bis(2-hydroxypropyl)-urea; and mixtures ing epidermal differentiation and antiseborrhoeic agents. thereof. 22. Method of cosmetic treatment for promoting the radi 7. Use according to at least one of Embodiments 1 to 6, ance of the complexion and/or reducing the Surface irregu characterized in that the compound of formula (I) is N-(2- larities of the skin and/or the mucous membranes, character hydroxyethyl)urea. 10 ized in that at least one compound of formula (I) or a 8. Use of at least one compound of formula (I) according to composition containing it according to any one of the preced at least one of Embodiments 1 to 7, characterized in that the ing Embodiments is applied to the skin or the mucous mem said compound stimulates the degradation of corneodesmo branes. S1. 9. Use according to at least one of Embodiments 1 to 8, 15 23. Method for the cosmetic treatment of keratin materials, characterized in that the compound of formula (I) has a kera characterized in that it comprises in the application of at least tolytic activity. two components: 10. Use according to any one of the preceding Embodi a first component comprising at least one compound of ments, characterized in that the compound of formula (I) formula (I) according to one of the preceding Embodi stimulates the activity of proteases of the stratum corneum, in ments, particular acid proteases. a second component comprising at least one agent chosen 11. Use of at least one compound of formula (I) according from proteases, lipases and glycosidases, these two to at least one of Embodiments 1 to 10, characterized in that components being applied simultaneously, conjointly or the composition is an exfoliating composition. sequentially to the skin, the mucous membranes or the 12. Use according to any one of the preceding Embodi 25 Superficial body growths. ments, characterized in that the composition is intended for 24. Method of cosmetic treatment according to the preced cleansing the skin and/or the scalp. ing Embodiment, characterized in that at least one compound 13. Use according to any one of the preceding Embodi chosen from moisturizing agents, agents reducing or inhibit ments, characterized in that the composition is intended to ing the activity of harmful proteases, agents stimulating epi improve the surface state of the skin and/or the lips. 30 dermal differentiation, antiseborrhoeic agents and descqua 14. Use of at least one compound of formula (I) as defined mating agents, is additionally present in the first and/or the in any one of Embodiments 1 to 7, for the preparation of a Second component. composition intended for the treatment of the signs associated 25. Cosmetic agent in the form of a kit comprising at least with desquamation disorders. two components 15. Use of at least one compound according to Embodi 35 a first component comprising at least one compound of ment 14, characterized in that the composition is intended for formula (I) according to one of the preceding Embodi the treatment of at least one skin disorder chosen from ich ments, thyosis, hyperkeratosis, Xeroses, psoriasis, atopic dermatitis, a second component comprising at least one agent chosen acne and dandruff. from proteases, lipases and glycosidases, these two 16. Use of at least one compound according to either of 40 components being applied simultaneously, conjointly or Embodiments 14 and 15, characterized in that the composi sequentially to the skin, the mucous membranes or the tion is intended for promoting wound healing. Superficial body growths. 17. Use according to at least one of Embodiments 1 to 16, 26. Cosmetic set comprising: characterized in that the composition is a cosmetic and/or a) a container delimiting at least one compartment, the said dermatological composition for topical application to the skin 45 container being closed with a closing element; and and/or the mucous membranes and/or the Superficial body b) a composition placed inside the said compartment, the growths. composition conforming to any one of the preceding Embodi 18. Use of at least one compound of formula (I) according mentS. to any one of Embodiments 1 to 17, characterized in that the 27. Cosmetic set according to the preceding Embodiment, composition additionally contains at least one descquamation 50 characterized in that it comprises at least (i) a first compart stimulating agent different from the compounds of formula ment containing at least one compound of formula (I) accord (I). ing to one of Embodiments 1 to 7 and (ii) a second compart 19. Use according to Embodiment 18, characterized in that ment comprising at least one protease. the descquamation-stimulating agent different from the com 28. Use of at least one compound of formula (I) according pounds of formula (I) is chosen from the group comprising 55 to one of Embodiments 1 to 7, for the preparation of recon Sulphonic acids, calcium chelators, (X-hydroxy acids such as structed skins. glycolic, citric, lactic, tartaric, malic or mandelic acids; ascor 29. Method for selecting descquamating compounds com bic acid and its derivatives Such as ascorbyl glucoside and prising the steps comprising in: magnesium ascorbyl phosphate; nicotinamide; urea; (N-2- a) preparing a stratum corneum extract containing acid hydroxyethylpiperazine-N-2-ethane)sulphonic acid 60 proteases, (HEPES), B-hydroxy acids such as salicylic acid and its b) mixing a labelled protein substrate with various concen derivatives, retinoids chestnut or prickly pear extracts and trations of the test compound, and with a proteolytic reducing compounds such as cysteine or cysteine precursors. concentration of urea, in order to obtain mixtures com 20. Use of at least one compound of formula (I) according prising either the test compound, or urea to at least one of the preceding Embodiments, characterized 65 c) bringing fractions of the extract obtained in step a) into in that the composition additionally contains at least one contact with the various mixtures obtained at the end of compound chosen from proteases, glycosidases and lipases. step b), in order to obtain reaction mixtures comprising US 7,999,008 B2 23 24 either the test compound, or urea, or with the labelled applying to the skin Suffering from ichthyosis a composi casein Substrate in order to obtain a control, tion, comprising: d) after an incubation time, comparing the proteolytic reac a physiologically acceptable medium and tion in the various reaction mixtures with that of the a desquamation effective amount of at least one compound control, of the following formula (I) e) selecting the compound for which the intensity of pro teolysis is greater than that of the control. As used herein, the phrases “selected from the group con (I) R1 R4 sisting of “chosen from.” and the like include mixtures of V A the specified materials. Terms such as “contain(s) and the 10 N-CO-N like as used herein are open terms meaning including at least A V unless otherwise specifically noted. R2 R3 All references, patents, applications, tests, standards, documents, publications, brochures, texts, articles, etc. men wherein tioned herein are incorporated herein by reference. Where a 15 R. R. R. and Reach represent, independently of each numerical limit or range is stated, the endpoints are included. other, a hydrogen atom, a C-C alkyl group or a Also, all values and Subranges within a numerical limit or C-C hydroxyalkyl group which may contain from 1 range are specifically included as if explicitly written out. to 5 hydroxyl groups, where at least one of the radicals The invention method and composition is preferably used R to Ra represents a C-C hydroxyalkyl group, by subjects desirous of the benefits noted herein, subjects “in their salts, their solvates, and mixtures thereof; need of these benefits. Such subjects are typically suffering wherein from signs associated with descquamation disorders, such as the descquamation effective amount of the compound of by self diagnosis or cosmetician or medical diagnosis, or are formula (I) is from 1M to 4M, and is effective for stimu at recognized and appreciated risk of developing such condi lating the acid protease proteolytic activities of the stra tions and who use the invention methods and compositions to 25 tum COrneum. combat these effects. In this regard, the invention process can 2. The method according to claim 1, wherein informula (I) be viewed as one for delaying the onset of the appearance of R is a C-C hydroxyalkyl group and R. R. and Ra are, and/or for reducing signs associated with descquamation dis independently of each other, a hydrogenatom or a C-C alkyl orders. In this regard and for example, those interested in the group. invention use the compounds and compositions, etc. dis 30 3. The method according to claim 1, wherein informula (I) closed herein as agents intended for stimulating descquama R is a tion of the skin and/or the mucous membranes and/or the C-C hydroxyalkyl group comprising from 1 to 5 Superficial body growths and the application in all cases hydroxyl groups, and R. R. and Rare each a hydrogen where it is desirable to promote and/or accelerate the removal atOm. of the deadlayers of the epidermis. This use is typically aimed 35 4. The method according to claim 1, wherein informula (I) at improving the physical appearance and/or the aesthetic R is a C-C hydroxyalkyl group comprising 1 hydroxyl appearance of the individual whose desquamation and/or group. exfoliation and/or cell renewal is being stimulated. 5. The method according to claim 1, wherein R is a C-C Naturally, one using the invention as disclosed will use an hydroxyalkyl group comprising 1 hydroxyl group and R. R. amount of the invention composition effective to reduce signs 40 and Rare each a hydrogen atom. associated with descquamation disorders. Such amount is 6. The method according to claim 1, wherein the compound inclusive of an amount of the compositions described herein of formula (I) is selected from the group consisting of N-(2- at the disclosed concentrations of active ingredients sufficient hydroxyethyl)urea, N-(2-hydroxypropyl)urea, N-(3-hydrox to cover the area of the skin being treated in a single applica ypropyl)urea, N-(2,3-dihydroxypropyl)urea, N-(2,3,4,5,6- tion, and of course includes that amount applied upon 45 pentahydroxyhexyl)urea, N-methyl-N-(1,3,4,5,6- repeated application, for example on a daily basis over a pentahydroxy-2-hexyl)urea, N-methyl-N'-(1-hydroxy-2- course of days, weeks, etc. In a preferred embodiment the methyl-2-propyl)urea, N-(1-hydroxy-2-methyl-2-propyl) invention process includes multiple applications of the inven urea, N-(1,3-dihydroxy-2-propyl)urea, N-(tris tion composition to the area(s) of skin, etc. in need of atten hydroxymethylmethyl)urea, N-ethyl-N'-(2-hydroxyethyl) tion. All of such amounts are “effective amounts.” 50 urea, N,N-bis(2-hydroxyethyl)urea, N,N'-bis(2- The above description is presented to enable a person hydroxyethyl)urea, N.N-bis(2-hydroxypropyl)urea, N,N'-bis skilled in the art to make and use the invention, and is pro (2-hydroxypropyl)urea, N,N-bis(2-hydroxyethyl)-N'- vided in the context of a particular application and its require propylurea; N,N-bis(2-hydroxypropyl)-N'-(2-hydroxyethyl) ments. Various modifications to the preferred embodiments urea, N-tert-butyl-N'-(2-hydroxy-ethyl)-N'-(2- will be readily apparent to those skilled in the art, and the 55 hydroxypropyl)urea, N-(1,3-dihydroxy-2-propyl)-N'-(2- generic principles defined herein may be applied to other hydroxyethyl)urea, N,N-bis(2-hydroxyethyl)-N',N'- embodiments and applications without departing from the dimethylurea, N.N.N',N'-tetrakis(2-hydroxyethyl)urea, spirit and scope of the invention. Thus, this invention is not N',N'-bis(2-hydroxyethyl)-N',N'-bis(2-hydroxypropyl)urea, intended to be limited to the embodiments shown, but is to be salts thereof, solvates thereof, and mixtures thereof. accorded the widest scope consistent with the principles and 60 7. The method according to claim 1, wherein the at least features disclosed herein. one compound of formula (I) is N-(2-hydroxyethyl)urea. 8. The method according to claim 1, wherein the compound The invention claimed is: of formula (I) Stimulates the degradation of corneodesmosin. 1. A method for treatment of skin suffering from ichthyo 9. The method according to claim 1, wherein the compound sis, comprising: 65 of formula (I) has keratolytic activity. stimulating natural desquamation of the skin Suffering 10. The method according to claim 1, wherein the compo from ichthyosis by: sition is an exfoliating composition. US 7,999,008 B2 25 26 11. The method according to claim 1, wherein the compo 17. The method according to claim 1, wherein a weight% sition further comprises at least one descquamation-stimulat of the at least one compound of formula (I) is 20-40 wt.%. ing agent not a compound of formula (I). 18. A kit comprising at least two compositions, wherein 12. The method according to claim 11, wherein the descqua a first comprises: mation-stimulating agent not a compound of formula (I) is at a physiologically acceptable medium and least one selected from the group consisting of Sulphonic a descquamation effective amount of at least one compound of acids, calcium chelators, C.-hydroxy acids, ascorbic acid, ascorbyl glucoside, magnesium ascorbyl phosphate, nicoti formula (I) namide: urea; (N-2-hydroxyethylpiperazine-N-2-ethane)sul phonic acid (HEPES), B-hydroxy acids, retinoids, chestnut or prickly pear extracts, cysteine, cysteine precursors, and mix 10 (I) tures thereof. 13. The method according to claim 1, wherein the compo sition further comprises at least one compound chosen from proteases, glycosidases and lipases. 15 14. The method of claim 1, further comprising application wherein: to the skin suffering from ichthyosis: R. R. R. and R each represent, independently of each a second component comprising at least one agent chosen other, a hydrogen atom, a C-C alkyl group or a C-C, from proteases, lipases and glycosidases, hydroxyalkyl group which may contain from 1 to 5 these second component being applied simultaneously, con hydroxyl groups, where at least one of the radicals R to jointly or sequentially relative to compound of formula (I) to R represents a hydroxyalkyl group, their salts, their the skin Suffering from ichthyosis. solvates, and mixtures thereof, wherein 15. The method according to claim 1, further comprising the descquamation effective amount of the compound of applying to the skin Suffering from ichthyosis, a second com formula (I) is from 1M to 4M, and is effective for stimu position comprising a physiologically acceptable medium 25 lating the acid protease proteolytic activities of the stra and an increased concentration of at least one compound of tum corneum; and formula (I) relative to the first application. a second composition comprising at least one agent 16. The method according to claim 1, further comprising, Selected from the group consisting of proteases, lipases after applying the composition to the skin Suffering from and glycosidases. ichthyosis: removing the composition by rinsing with water or with a 30 mild detergent.