Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
  • C07C69/587—Monocarboxylic acid esters having at least two carbon-to-carbon double bonds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
  • A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
  • A61K8/8105—Compositions of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Compositions of derivatives of such polymers
  • A61K8/8111—Homopolymers or copolymers of aliphatic olefines, e.g. polyethylene, polyisobutene; Compositions of derivatives of such polymers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/08—Antiseborrheics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/10—Anti-acne agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to esters of alkane diol and polyunsaturated fatty acid, more particularly omega 3 and omega 6, as well as pharmaceutical and cosmetic compositions containing them, their method of preparation and their use, in particular in the treatment of acne or seborrheic dermatitis.
• Alkanes diol are compounds used in many fields such as cosmetology or agribusiness. In particular, their uses as a preservative can be cited because of their bacteriostatic properties. Thus, alkanes diol are a means of combating fungal and bacterial colonization and contribute to the protection of many cosmetic or agri-food products (Faergemann J, Fredriksson T. Sabouraudia: 1980; 18, 287-293). These diols have a broad spectrum of activity and are particularly effective against gram-like fungal and bacterial species (Harb NA, Toama MA, Drug Cosmet Ind .: 1976, 118, 40).
• 1,2-alkanediol have bacteriostatic activities, which are widely used as preservatives (JP-A-51091327) or in the treatment of pathologies such as acne where the microbial component plays a key role in the etiology (US 6123953).
• Other applications of 1,2 alkane diol are also described as protective properties with respect to body odors by virtue of their anti-septic effect (US 5516510; WO 2003/000220) or antimycotic agents (WO 2003/069994). ).
• 1,2-alkanediol combinations with other compounds are described with the resultant antimicrobial effect. synergistic.
• C3 PUFAs would be negative regulators of the inflammatory response, by inhibiting the NF-KB activation pathway, through the induction of the expression of IKBCC, the major inhibitor of the NF-KB pathway.
• PUFAs C11 have an inhibitory action on the synthesis of arachidonic acid in favor of the synthesis of docosahexanoic and eicosapentaenoic acids (Calder PC, Lipids: 2001; 36, 1007-24).
• P. acnes induces innate immunity receptors, producing pro-inflammatory NF-KB dependent cytokines such as IL-8. Then these mediators will influence the migration of neutrophils to the inflammatory site where they will be responsible for killing the bacteria. This inflammatory response is a normal and necessary phenomenon for the elimination of the pathogen in the infected tissue. However, excessive and unregulated activation leads to inflammatory acne lesions. Thus, it has been shown that the level of IL-8 correlates with the number of neutrophils mobilized in the inflammatory acne lesion (Abd El AIl HS et al., Diagn Pathol 2007: 2: 4).
• Bacterial colonization in an acne patient is most often associated with the appearance of inflammatory acne lesions: for example, there are more neutrophils, but also higher levels of IL-8 in the follicular canals. colonized compared to weakly colonized channels in non-acne subjects. The levels of these inflammatory markers seem to correlate with the bacterial burden. But many questions remain unanswered as the cause of colonization, or the way of proceeding leading to the formation of lesions. Be that as it may, the role of bacterial colonization as a factor in the progression of the disease is proven.
• the current treatment for minor to moderate acne or inflammatory acne corresponds to a topical application of anti-bacterial active agents acting against colonization, in particular by P. acnes in combination with anti-inflammatories (Shalita A., J. Eur Acad. Dermatol, Venereol 2001, 15: 43).
• Treatments are usually initiated after the onset of a number of inflammatory acne lesions.
• esters of alkane diol and of polyunsaturated fatty acid, and more particularly of omega 3 or 6, made it possible to have an antibacterial and anti-inflammatory action as early as the first colonization with P. acnes in the follicular canal, this action being moreover proportional to the colonization.
• esters of alkane diol and PUFA are recognized and specifically cleaved by the bacterial lipase (P. acnes), thus allowing, by cleavage of the ester bond, the release of two assets with complementary activities. , namely the antibacterial diol, able to fight against colonization by P. acnes, and anti-inflammatory PUFA, which blocks the recruitment of neutrophils and thus the inflammatory cascade characteristic of acne.
• the release of these two active agents induces an adapted response, that is to say, proportional to the colonization by P. acnes, from the first colonization and thus blocks the evolution of this pathology, which leads to the appearance of lesions inflammatory acne.
• esters would also prevent the aggravation of the acne lesion by acting from the formation of the comedone and by inhibiting the inflammatory cascade characteristic of the 'acne.
• esters have already been described in the literature (WO 98/18751, Sugiura et al., J. Biol Chem 1999, 274 (5), 2794-2801) but not for their biological properties.
• n an integer between 1 and 15, preferably between 1 and
• M represents 0, 1, 2 or 3
• R represents the hydrocarbon chain of a polyunsaturated fatty acid chosen from omega 3 and omega 6.
• hydrocarbon chain of a polyunsaturated fatty acid is intended to mean the hydrocarbon chain (R 1) linked to the acid function of the polyunsaturated fatty acid (R 1 CO 2 H).
• the hydrocarbon chain considered is the following chain:
• omega 3 means a polyunsaturated fatty acid, as defined above, for which the first double bond of the chain corresponds to the third carbon-carbon bond by counting from the opposite end to the carboxylic acid function, as illustrated in the case of ⁇ -linolenic acid below:
• the omega-3s may be in particular ⁇ -linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, tetracosapentaenoic acid and Tetracosahexaenoic acid, and preferably it is ⁇ -linolenic acid or stearidonic acid, which have anti-inflammatory properties.
• omega 6 means a polyunsaturated fatty acid, as defined above, for which the first double bond of the chain corresponds to the sixth carbon-carbon bond by counting from the opposite end to the carboxylic acid function, as illustrated in the case of linoleic acid below:
• the omega-6s can be in particular linoleic acid, gamma-linolenic acid, eicosadienoic acid, dihomo-gamma-linolenic acid, arachidonic acid, docosatetraenoic acid, docosapentaenoic acid, adrenic acid and the calendrical acid, and preferably it is linoleic acid, which has sebo-regulating properties.
• n may be 1, 2, 3, 4 or 5, and preferably 5.
• n is 0 or 1.
• the hydrocarbon chain comes from a polyunsaturated fatty acid chosen from ⁇ -linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid.
• a polyunsaturated fatty acid chosen from ⁇ -linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid.
• the polyunsaturated fatty acid will be chosen from ⁇ -linolenic acid, stearidonic acid and linoleic acid, and more preferably from ⁇ -linolenic acid and linoleic acid.
• the compounds of the invention may be chosen from the following molecules:
• the present invention also relates to a compound of formula (I) as defined above for use as a medicament, in particular for the treatment of acne or seborrheic dermatitis.
• the present invention also relates to the use of a compound of formula (I) as defined above, for the manufacture of a medicament, intended in particular for the treatment of acne or seborrheic dermatitis.
• the present invention also relates to a method of treating acne or seborrheic dermatitis comprising administering an effective amount of a compound of formula (I) as defined above to a person in need thereof.
• the subject of the present invention is also a pharmaceutical or cosmetic composition
• a pharmaceutical or cosmetic composition comprising at least one compound of formula (I) as defined above in association with at least one pharmaceutically or cosmetically acceptable excipient, particularly suitable for percutaneous administration.
• pharmaceutically or cosmetically acceptable is understood to mean that which is useful in the preparation of a pharmaceutical or cosmetic composition, which is generally safe, non-toxic and neither logically nor otherwise undesirable and which is acceptable for a therapeutic or cosmetic use, especially by topical application.
• the pharmaceutical or cosmetic compositions according to the invention may be in the forms which are usually known for topical administration, that is to say in particular lotions, foams, gels, dispersions, emulsions, shampoos, sprays.
• compositions generally contain, in addition to the compound or compounds according to the present invention, a physiologically acceptable medium, generally based on water or solvent, for example alcohols, ethers or glycols. They may also contain surfactants, complexing agents, preservatives, stabilizing agents, emulsifiers, thickeners, gelling agents, humectants, emollients, trace elements, essential oils, perfumes, dyes, matifying agents, chemical or mineral filters, moisturizing agents or thermal waters, etc.
• a physiologically acceptable medium generally based on water or solvent, for example alcohols, ethers or glycols.
• surfactants generally contain, complexing agents, preservatives, stabilizing agents, emulsifiers, thickeners, gelling agents, humectants, emollients, trace elements, essential oils, perfumes, dyes, matifying agents, chemical or mineral filters, moisturizing agents or thermal waters, etc.
• compositions may further contain other active ingredients leading to a complementary or possibly synergistic effect.
• compositions according to the present invention will comprise from 0.01 to 10% by weight, preferably from 0.1% to 1% by weight, of the compound (s) of formula (I) relative to the total weight of the composition.
• compositions are more particularly intended for the treatment of acne or seborrheic dermatitis.
• the present invention also relates to a method of cosmetic treatment of acne or seborrheic dermatitis comprising the application to the skin of a cosmetic composition as defined above.
• the subject of the present invention is also a process for the preparation of a compound of formula (I) as defined above by coupling of a polyunsaturated fatty acid chosen from omega 3 and omega 6, the carboxylic acid function of which is found in free or activated form, and a diol of formula (II) below:
• n represents an integer between 1 and 15, and preferably between 1 and 10, and m represents 0, 1, 2 or 3.
• n may be 1, 2, 3, 4 or 5, and preferably 5.
• m is 0 or 1.
• free form is meant, in the sense of the present invention, that the carboxylic acid function of the PUFA is not protected and therefore represents a CO 2 H group. The PUFA is therefore in a form R 1 CO 2 H as defined above.
• activated form is intended to mean a carboxylic acid function modified so as to render it more active with respect to nucleophiles.
• activated forms are well known to those skilled in the art and may in particular be an acid chloride (COCl).
• COCl acid chloride
• the activated PUFA in the form of an acid chloride then corresponds to the formula R1COCl.
• the polyunsaturated fatty acid is used in its free acid form.
• the coupling reaction will be carried out in the presence of a coupling agent, such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) carbonyldiimidazole (CDI), 2-H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
• DIC diisopropylcarbodiimide
• DCC dicyclohexylcarbodiimide
• EDC 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
• CDI 2-H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphat
• HBTU 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) or O- (7-azobenzotriazol-1-yl) -1,3,3, 3-tetramethyluronium hexafluorophosphate
• a coupling aid such as N-hydroxy succinimide (NHS), N-hydroxy benzotriazole (HOBt), 3,4-dihydro-3-hydroxy-4-oxo 1,2,3-benzotriazole (HOOBt), 1-hydroxy-7-azabenzotriazole (HOAt), dimethylaminopyridine (DMAP) or N-hydroxysylfosuccinimide (sulfo NHS).
• the coupling will be carried out in the presence of a carbodiimide (in particular DIC, DCC or EDC) and dimethylaminopyridine.
• a carbodiimide in particular DIC, DCC or EDC
• the coupling will be carried out in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or diisopropylcarbodiimide and dimethylaminopyridine.
• the polyunsaturated fatty acid is used in its activated form, and more particularly in the form an acid chloride.
• the coupling reaction will advantageously be carried out in the presence of pyridine and dimethylaminopyridine.
• Figure 1 Demonstration of P. acnes lipase (33 kDa) in inflammatory acne lesions (M corresponds to size markers, A corresponds to inflammatory acne lesions, B corresponds to comedones excluding inflammation).
• Figure 2 Study of the hydrolysis of the esters of the invention with the recombinant lipase of P. acnes after 2 hours of incubation.
• the light gray column represents the results obtained with 3-hydroxybutyl alpha-linolenate
• the dark gray column represents the results obtained with 2-hydroxypentyl alpha-linolenate
• the black column represents the results obtained with alpha-linolenate.
• 2-hydroxyoctyl linolenate the white column represents the results obtained with 3-hydroxynonyl alpha-linolenate and the hatched column represents the results obtained with glyceryl trilinolenate.
• Figure 3 PUFA activity on the release of interleukin 8 by human keratinocytes HaCaT stimulated by PMA / A23187 (pro-inflammatory agents).
• Figures 4A, 4B and 4C Effects of PUFAs on the production of eicosanoids (cyclooxygenated metabolites (CYCLO), lipoxygenated metabolites (LIPOX), arachidonic acid (AA)) during an inflammatory response induced by PMA / A23187.
• the white columns represent the control (i.e., a reaction medium without PUFA);
• the light gray columns correspond to the activity of PUFA at 2.3 ⁇ g / mL;
• the dark gray columns correspond to the PUFA activity at 11.5 ⁇ g / mL and the black columns correspond to the PUFA activity at 23 ⁇ g / mL.
• Figure 4A corresponds to ⁇ -linolenic acid
• Figure 4B corresponds to stearidonic acid
• Figure 4C corresponds to linoleic acid.
• the unsaturated fatty acid is dissolved in 20 ml of anhydrous CH 2 Cl 2 under N 2 circulation.
• a carbodiimide (coupling agent) (1.1 eq.) And dimethylaminopyridine (0.5 eq.) are then added directly.
• the diol (5 eq) is added.
• the medium is stirred vigorously for 18 hours, under N 2 , protected from light.
• the organic phase is then extracted with CH 2 Cl 2 and then washed with saturated NaCl solution, dried over MgSO 4 , filtered and concentrated.
• the crude product is a yellow oil which is purified by open chromatography, silica gel (0: 22x3.5 cm), CHCI 3 conditioning.
• Linoleyl chloride (6.7 ⁇ 10 3 mol) and dimethylaminopyridine (DMAP) (0.1 eq) are added, under nitrogen circulation, to a solution of diol (5 eq.) In pyridine (20 ml). . After stirring vigorously for 18 hours under N 2 , at room temperature and protected from light, the reaction medium is brought to dryness. The organic phase is then extracted with AcOEt and then washed with H 2 O and NH 4 + CF, dried over MgSO 4 , filtered and concentrated.
• DMAP dimethylaminopyridine
• the crude product is a brown oil which is purified by open chromatography, silica gel (0: 22x3.5cm), CHCI 3 conditioning.
• a formulation according to the invention, in cream form, has the following composition (the amounts are given in percentages by weight relative to the total weight of the composition):
• the tests are carried out in 2 ml amber glass vials. A check is made by not putting any enzyme to follow the possible spontaneous hydrolysis of the substrate in the buffer. A test sample of 10 ⁇ l is made at each desired time during the kinetics and frozen to stop the reaction. The liberated linolenic acid is then derivatized with Antry-ldiazomethane (ADAM) which forms a fluorescent complex with the fatty acid. The product formed is then separated by HPLC and quantified using a standard range of commercial linolenic acid derivatized under the same conditions. As shown in Figure 2, we have been able to show that the compounds of the invention give rise to a hydrolysis reaction in the presence of P. acnes since the formation of CC-linolenic acid is observed.
• ADAM Antry-ldiazomethane
• the hydrolysis of the compounds of the invention by P. acnes makes it possible to release the diol on the one hand and the PUFA on the other hand.
• the expression of the lipase is therefore a necessary condition for observing the cleavage of the compounds of the invention and therefore for obtaining a therapeutic effect.
• P. acnes lipase is essentially present in acneic subjects as shown in FIG. 1, the compounds of the invention should allow a response adapted for each person.
• n is an integer from 0 to 15 and m is 0, 1, 2 or 3.
• Tests were performed with 8 microbial strains using the dilution method described below. MICs are determined by micromethod in a liquid medium. Successive dilutions of reason 2 of the test products in the culture broth (Trypcase Soy) are carried out in 96-well microplates in a final volume of 0.1 ml. The wells are inoculated with 0.01 ml of the bacterial suspensions titrated at about 10 ⁇ CFU / ml. The microplates are incubated under optimal growth conditions and the MIC is read visually.
• Table 1 below presents the results obtained with different diols.
• the "STASE” columns represent the bacteriostatic activity and the “CIDIE” columns represent the bactericidal activity of the diols (1% corresponds to a concentration of 10 mg / ml).
• Pseiidoruonas aeruginoisa 10% 20% 5% 10% 0.312% 0 312% 0 625% 0 625%
• 1,3-nonanediol and 1,2-octanediol are bacteriostatic and bactericidal (gram +, gram-, fungal) in a concentration range of from 6.25 to 0.78 mg.ml- 1 .
• the derivative nonane appears as the one having the most marked activity for the strain P. acnes including a bacteriostatic and bactericidal effect found at 1.56 mg.ml respectively "1 and 3.12 mg.ml" 1 .
• the bacterial strains used are: Staphylococcus aureus ATCC6538 and Propionibacterium acnes ATCC6919.
• the culture medium used for Staphylococcus aureus ATCC6538 is Trypcase Soy Agar whereas the culture medium used for Propionibacterium acnes ATCC6919 is Schaedler agar.
• Stock solutions containing 1% and 0.5% 1,2-octanediol are prepared extemporaneously in 1% Polysorbate 20 (qs water PPI) and then adjusted to pH 7 with 0.1N NaOH solution. A volume of 5 ml of each of the mother solutions is inoculated with 50 .mu.l of bacterial suspension titrating approximately 1.10 8 CFU / ml. After each contact time (contact time tested: 5mn, 15mn, 30mn and
• a count of residual bacteria is made by taking an aliquot of ImI neutralized with 9ml of Trypcase Soy Broth and 10% of Polysorbate 80.
• the enumeration is carried out by inclusion of 1 M of the neutralized mixture and 4 serial 1/10 dilutions in the corresponding culture agar plates.
• the agar plates are incubated at 36 ° C +/- 1 ° C in an aerobic atmosphere for S. aureus and anaerobic for P. acnes (Generbag Anaer, Biomérieux) for 72 hours then the
• R means "Reduction”. This is the ratio between the number of bacteria inoculated and the number of residual bacteria after contact of the test solution with the bacterial suspension.
• the bactericidal action of octane diol was examined on two bacterial species (P. acnes, S. aureus) at the following two concentrations: 0.5% and 1%. At physiological pH and at the lowest concentration (0.5%), a decrease greater than 99.9% of the population, in particular P. acnes, is observed after a contact time of 1 hour. 3.4. Study of the anti-inflammatory activity of PUFAs obtained after hydrolysis of the compounds of the invention
• the changes induced by these PUFAs are evaluated on the production of eicosanoids and an inflammatory cytokine, interleukin 8, during an inflammatory process triggered by PMA / A23187.
• Study of IL8 secretion (FIG. 3): The HaCaT cells are incubated on 96-well plates for 24 h in the presence of PUFAs, rinsed and then stimulated with PMA / A23187; the supernatants are recovered after 6 hours of stimulation and IL8 is quantified in ELISA OptEIA TM kit marketed by BD Pharmingen. Study of the metabolism of arachidonic acid (AA) (FIGS.
• HaCaT keratinocytes were incubated in a 24-well plate in the presence of 1 ⁇ Ci [ 3 H] AA for 18 hours under an atmosphere of 5% CO 2 .
• HaCaT [3 H] labeled are pretreated with PUFAs for 24 hours, rinsed and then stimulated with 500 nM PMA and 1 microM A23187 for 5 hours.
• the [ 3 H] AA and the metabolites released by HaCat in the culture medium are extracted by column chromatography. The eluate is evaporated under N 2 .
• the dry residue is taken up in methanol and deposited on thin-layer silica plates previously activated at 100 ° C. for 1 hour.
• the migration solvent is the organic phase of the ethyl acetate / water / isooctane / acetic acid mixture (110: 100: 50: 20, v / v).
• AA [3 H] and metabolites (6-keto-prostaglandin F l ⁇ , 6k-PGFI ⁇ prostaglandin (PG) F ⁇ E2D 2, thromboxane (TX) B2, Leukotrienes (LT) B 4, C 4, D 4 ) are identified by a BERTHOLD TLC scanner.
• Figure 3 shows the activity of some PUFAs on the release of interleukin-8 (IL-8) by human keratinocytes HaCaT stimulated by PMA / A23187.
• IL-8 interleukin-8
• the compounds according to the invention are therefore useful for the treatment of acne.
• the etiological schema of seborrheic dermatitis having similarities with that of acne, the compounds of the invention are also potentially useful for the treatment of seborrheic dermatitis.
• the microorganism at the origin of the inflammatory response in the context of this pathology Malassezia, secretes lipases (DeAngelis YM and J Invest Dermatol 2007: 127: 2138-46) at the level of the scalp which can also be used to release the two active ingredients, alkane diol with anti-fungal properties and PUFA such as ⁇ -linolenic acid with anti-inflammatory properties.
• fatty acids such as linoleic acid are activators of nuclear receptors PP ARa, which exert a marked seboregulatory effect (Downie MM et al., Br J Dermatol, 2004; 151: 766-75).
• diol-linoleic acid conjugates can be used in particular to limit seborrhea in various indications such as acne and seborrheic dermatitis.

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