US 200900 12172A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0012172 A1 Fredon et al. (43) Pub. Date: Jan. 8, 2009

(54) COSMETIC/PHARMACEUTICAL (30) Foreign Application Priority Data COMPOSITIONS COMPRISING RETNOIDS AND ANT-IRRITANTS AND TREATMENT OF Dec. 15, 2005 (FR) ...... O512761 KERATINIZATION DISORDERS Nov. 28, 2006 (FR) ...... PCTIFR2006/051239 THEREWITH Publication Classification (75) Inventors: Laurent Fredon, Roquefort Les (51) Int. Cl. Pins (FR): Claire Mallard, A63L/92 (2006.01) Mougins (FR); Eve Ferrara, A6II 3/19 (2006.01) Valbonne (FR) A6IP 700 (2006.01) A6IP 7/10 (2006.01) Correspondence Address: BUCHANAN, INGERSOLL & ROONEY PC (52) U.S. Cl...... 514/569; 514/557 POST OFFICE BOX 1404 (57) ABSTRACT ALEXANDRIA, VA 22313-1404 (US) Topically applicable cosmetic/pharmaceutical compositions (73) Assignee: GALDERMARESEARCH & contain at least one retinoid and at least one anti-irritant DEVELOPMENT, BIOT (FR) compound selected from among the salts of 183-glycyrrhe tinic acid and derivatives thereof, and are useful for the treat (21) Appl. No.: 12/213,153 ment and/or prevention of a dermatological condition or affliction related to a disorder of keratinization relating to cell (22) Filed: Jun. 16, 2008 differentiation and to cell proliferation, e.g. Vulgaris.

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Patent Application Publication Jan. 8, 2009 Sheet 2 of 3 US 2009/0012172 A1

Histogram of the AUC for edemas D2-D19

FIGURE 2 Patent Application Publication Jan. 8, 2009 Sheet 3 of 3 US 2009/0012172 A1

Number of Comedones

FIGURE 3 US 2009/0012 172 A1 Jan. 8, 2009

COSMETCAPHARMACEUTICAL 0017 Stage 4, or nodulocystic acne, is accompanied by COMPOSITIONS COMPRISING RETNOIDS numerous Scars. It exhibits nodules and also large painful AND ANT-IRRITANTS AND TREATMENT OF purplish pustules. KERATINIZATION DISORDERS 0018. The various forms of acne described above can be THEREWITH treated with active principles, such as anti-seborrheics and anti-infectives, for example benzoperoxide (in particular the CROSS-REFERENCE TO PRIORITYAPCT product Eclaran R) marketed by Pierre Fabre), with retinoids, APPLICATIONS Such as tretinoin (in particular the product Retacnyl(R) mar 0001. This application claims priority under 35 U.S.C. S keted by Galderma) or isotretinoin (product Roaccutane(R) 119 of FR 0512761, filed Dec. 15, 2005, and is a continuation marketed by Laboratoires Roche), or with naphthoic acid of PCT/FR 2006/051239, filed Nov. 28, 2006, and designat derivatives. Naphthoic acid derivatives, such as, in particular, ing the United States (published in the French language on 6-3-(1-adamantyl)-4-methoxyphenyl-2-naphthoic acid, Jun. 28, 2007, as WO 2007/071860 A2; the title and abstract commonly known as adapalene (the product Differin R) mar were also published in English), each hereby expressly incor keted by Galderma), are widely described and recognized as porated by reference in its entirety and each assigned to the active principles which are as effective as tretinoin in the assignee hereof. treatment of acne. 0019 Adapalene in particular exhibits an effectiveness CROSS-REFERENCE TO COMPANION which is accepted by all; however, it would be advantageous and useful for its tolerance by the topical route, although APPLICATION better than that of its competitors belonging to the same 0002 Copending U.S. patent application Ser. No. chemical category (tretinoin, tazarotene), to be improved. Attorney Docket No. 1034227-000925), filed concurrently herewith, hereby expressly incorporated by reference and SUMMARY OF THE INVENTION also assigned to the assignee hereof. 0020. It has now surprisingly been discovered that the BACKGROUND OF THE INVENTION combination of adapalene with certain specific anti-irritant compounds significantly improves the tolerance of this retin 0003 1. Technical Field of the Invention oid and thus overcomes the problem of irritation. This is 0004. The present invention relates to compositions for because, as shown in the Example 2 to follow, certain anti topical administration and to their applications as cosmetic or irritants reduce by up to more than 60% the edema caused by pharmaceutical products. Such compositions being useful, in adapalene. particular, for the treatment of acne. 0021. The present invention thus features compositions, in 0005 2. Description of Background and/or Related and/or particular pharmaceutical compositions and preferably der Prior Art matological compositions, intended in particular for topical 0006 Acne is a common multifactor pathology which application, comprising, formulated into a physiologically affects skin rich in Sebaceous glands (face, Scapula region, acceptable medium, at least one retinoid compound, prefer arms and inter-triginous regions). It is the commonest form of ably selected from among the naphthoic acid derivatives of dermatosis. The following five pathogenic factors play a formula (I) below, their salts and their esters, and at least one determining role in the formation of acne: anti-irritant compound selected from among the salts of 18B 0007 1. genetic predisposition; glycyrrhetinic acid and derivatives thereof. 0008 2. Overproduction of sebum (seborrhea); 0022 Advantageously, the Subject compositions do not 0009. 3. androgens: comprise any depigmenting agent other than the retinoid 0010 4. follicular keratinization disorders (comedogen compound, in particular adapalene. esis); and 0023 The term “physiologically acceptable medium’ 0011 5. bacterial colonization and inflammatory factors. means a medium compatible with the skin, mucous mem 0012 Several forms of acne exist, all having in common branes and/or Superficial body growths. that the pilosebaceous follicles are attacked. Exemplary are , acne keloid on the back of the neck, acne BRIEF DESCRIPTION OF THE DRAWINGS medicamentosa, recurrent acne , acne necrotica, acne neonatorum, premenstrual acne, , acne 0024 FIG. 1 is a graph comparing the irritant power of , senile acne, Solar acne and acne Vulgaris. reference gels versus that according to the present invention; 0013 Acne Vulgaris, also known as polymorphous juve (0025 FIG. 2 is a histogram of the AUC for edemas nile acne, is the commonest. It comprises four stages: D2-D19; and 0014 Stage 1 corresponds to comedonal acne, character 0026 FIG.3 is a graph showing the number of comedones ized by a large number of open and/or closed comedones and on the back of Rhino mice after 18 days of topical treatment of microcysts. with the gels of FIG. 1. 0015 Stage 2, or papulopustular acne, is of mild to mod erate seriousness. It is characterized by the presence of open DETAILED DESCRIPTION OF BEST MODE and/or closed comedones and of microcysts but also of red AND SPECIFICAPREFERRED EMBODIMENTS papules and of pustules. It mainly affects the face and leaves OF THE INVENTION few scars. 0016 Stage 3, or papulocomedonal acne, is more serious 0027. The retinoid compounds according to the invention and extends to the back, to the thorax and to the shoulders. It can be selected from among all trans retinoic acid (or tretin is accompanied by a larger number of Scars. oin), isotretinoin or motretinide. US 2009/0012 172 A1 Jan. 8, 2009

0028. The retinoid compounds according to the invention 0039. The anti-irritants according to the present invention are preferably selected from among naphthoic acid deriva are salts of 18f3-glycyrrhetinic acid and derivatives thereof. tives of formula (I), the salts and the esters thereof: The inclusion of these specific anti-irritants makes it possible to reduce the irritation caused by retinoids, in particular ada palene. (I) 0040. The term "salts of 18f3-glycyrrhetinic acid means, in particular, the potassium salt of 183-glycyrrhetinic acid, the Sodium salt of 183-glycyrrhetinic acid, the monoammo OH nium salt of 183-glycyrrhetinic acid (ammonium glycyrrhe tinate), the disodium salt of 183-glycyrrhetinic acid Succinate or the dipotassium salt of 183-glycyrrhetinic acid. 0041. The term "derivatives of the salts of 18 B-glycyrrhe tinic acid means in particular the monoester of glycerol and of 18f3-glycyrrhetinic acid. 0042 Preferably, the anti-irritant is the potassium salt of 18B-glycyrrhetinic acid. 0043. In the compositions according to the invention, the concentration of retinoid compound is from 0.001% to 10% JC by weight, preferably from 0.01% to 5% by weight and more preferably from 0.05% to 2% by weight of the total weight of the composition. Herein, unless otherwise specified, it is wherein R is a hydrogen atom, a hydroxyl radical, a linear or understood that, when concentration intervals are given, they branched alkyl radical having from 1 to 4 carbon atoms, an include the upper and lower limits of said interval. alkoxy radical having from 1 to 10 carbon atoms or a 0044 Preferably, the concentration of retinoid compound cycloaliphatic radical which is unsubstituted or substituted. is equal to 0.01%. Alternatively, the concentration of retinoid 0029. The term “linear or branched alkyl radical having compound is preferably equal to 0.3%. from 1 to 4 carbon atoms” means, preferably, the methyl, 0045. The concentration of anti-irritant compound is, for ethyl, propyl and butyl radicals. its part, from 0.01% to 10%, preferably from 0.1% to 7% by 0030 The term “alkoxy radical having from 1 to 10 carbon weight. atoms” means, preferably, the methoxy, ethoxy, propoxy, 0046. The compositions according to the present inven butoxy, hexyloxy and decyloxy radicals. tion can be provided in all the formulation forms normally 0031. The term “cycloaliphatic radical means, prefer employed for topical application, in particular in the form of ably, mono- or polycyclic radicals, such as the 1-methylcy aqueous, aqueous/alcoholic or oily dispersions, of disper clohexyl radical or the 1-adamantyl radical. sions of the lotion type, of aqueous, anhydrous or lipophilic 0032. The term "salts of the naphthoic acid derivatives' gels, of emulsions with a liquid or semi-liquid consistency of means salts formed with a pharmaceutically acceptable base, the milk type, obtained by dispersion of a fatty phase in an in particular an inorganic base. Such as sodium hydroxide, aqueous phase (O/W) or vice versa (W/O), or of suspensions potassium hydroxide and aqueous ammonia, or an organic or emulsions with a soft, semi-liquid or Solid consistency of base. Such as lysine, arginine or N-methylglucamine, but also the cream, cream gel, foam or ointment type, or of micro the salts formed with fatty amines, such as dioctylamine, emulsions, of microcapsules, of microparticles or of vesicular aminomethylpropanol and Stearylamine. dispersions of ionic and/or nonionic type, or in the form of 0033. The term “esters of the naphthoic acid derivatives” SprayS. means esters formed with pharmaceutically acceptable alco 0047 Preferably, the compositions are provided in the hols. form of a gel. 0034 Preferably, the selection will be made, among the 0048 One skilled in the art will take care to select the naphthoic acid derivatives included in the compositions excipients constituting the compositions according to the according to the invention, of 6-3-(1-adamantyl)-4-methox invention as a function of the formulation form desired and yphenyl-2-naphthoic acid (adapalene), 6-3-(1-adamantyl)- Such that the advantageous properties of the composition 4-hydroxyphenyl-2-naphthoic acid, 6-3-(1-adamantyl)-4- according to the invention are retained. decyloxyphenyl-2-naphthoic acid or 6-3-(1-adamantyl)-4- 0049. In addition, the compositions according to the hexyloxyphenyl-2-naphthoic acid. invention can, in particular, comprise one or more of the 0035 More preferably still, the retinoid compounds following ingredients: according to the invention are selected from among adapalene 0050 a) one or more gelling agents or Suspending agents, (6-3-(1-adamantyl)-4-methoxyphenyl-2-naphthoic acid), 0051 b) one or more chelating agents, its salts and its esters. 0.052 c) one or more wetting agents, 0036. The term “adapalene salts' means, in particular, the 0053 d) one or more preservatives. salts formed with a pharmaceutically acceptable base, in par 0054 Exemplary gelling agents or Suspending agents ticular inorganic bases, such as sodium hydroxide, potassium which can be included in the compositions according to the hydroxide and aqueous ammonia, or organic bases, such as invention are carbomers marketed under the generic name of lysine, arginine or N-methylglucamine. Carbopol(R), carbomers said to be insensitive to electrolytes 0037. The term “adapalene salts' also means the salts marketed under the trademark of Ultrez. 10R or of Carbopol formed with fatty amines, such as dioctylamine, aminometh ETD by BF Goodrich, polysaccharides, with, as non-limiting ylpropanol and Stearylamine. examples, Xanthan gum, Such as Keltron TR, marketed by 0038 Preferably, the retinoid compound is adapalene. Kelco, guar gum, chitosans, cellulose and its derivatives, such US 2009/0012 172 A1 Jan. 8, 2009 as hydroxyethylcellulose, in particular the product marketed compounds and/or their amounts such that the advantageous under the trademark of Natrosol HHX250R by Aqualon, and properties of the composition according to the invention are the copolymer of Sodium acrylamide and of acrylamido-2- not, or not substantially, detrimentally affected. methylpropanesulfonate as a 40% dispersion in isohexade 0065. These additives can be present in the composition in cane, and polysorbate 80, marketed under the trademark of a proportion of 0.001% to 20% by weight, with respect to the Simulgel 600R by Seppic. total weight of the composition. 0055. A preferred gelling agent is hydroxyethylcellulose, 0066. The present invention also features administration of the Subject compositions as described above as medica marketed, in particular, under the trademark Natrosol HHX mentS. 250(R). 0067. In particular, this invention features the formulation 0056 Exemplary chelating agents include diethylenetri of the Subject compositions as described above into medica aminepentaacetic acid (DTPA), ethylenediaminedi(o-hy ments useful for the treatment and/or prevention of dermato droxyphenylacetic acid) (EDDHA), (2-hydroxyethyl)ethyl logical conditions or afflictions related to a disorder of kera enediaminetriacetic acid (H EDTA), ethylenediaminedi(o- tinization relating to cell differentiation and to cell hydroxy-p-methylphenylacetic acid) (EDDHMA), proliferation, in particular in treating acne Vulgaris, come ethylenediaminetetraacetic acid (EDTA) and ethylenedi donal acne, papulopustular acne, papulocomedonal acne, aminedi(5-carboxy-2-hydroxyphenylacetic acid) (ED nodulocystic acne, acne conglobata, acne keloid of the back DCHA). of the neck, recurrent acne miliaria, acne necrotica, acne 0057 Preferably, wetting agents are included, the role of neonatorum, occupational acne, acne rosacea, senile acne, which is to reduce the Surface tension and to make possible Solar acne and acne medicamentosa. greater spreading of the liquid, and exemplary thereof are 0068 Preferably, the present invention features formula compounds such as propylene glycol, dipropylene glycol, tion of a composition as described above into medicaments propylene glycol dipelargonate, lauroglycol and ethoxydig useful to prevent and/or treat acne Vulgaris, whether regime or lycol, alone or as a mixture. Also, compounds may be regimen. included known for their role as emulsifiers, such as Tween 0069 Preferably, said compositions according to the 80, glyceryl monostearate & POE stearate, marketed under invention are administered topically. the trademark Arlacel 165FL(R) by Uniquema, polyoxyethyl 0070. In addition, this invention also features the cosmetic ene (21) stearyl ether, marketed under the trademark Brij application of the Subject compositions in the treatment of 721(R) by Uniquema, or Symperonics, with in particular Syn skin having a tendency toward acne, in order to combat the peronic PE/L62 (poloxamer 182) or Symperonic PE/L44 greasy appearance of the skin or hair. (0071. In order to further illustrate the present invention (poloxamer 124). and the advantages thereof, the following specific examples 0058. A preferred wetting agent is propylene glycol, Syn are given, it being understood that same are intended only as peronic PE/L62 (poloxamer 182) or Symperonic PE/L44 illustrative and in nowise limitative. In said examples to fol (poloxamer 124). low, all parts and percentages are given by weight, unless 0059 Exemplary preservatives that can be included are otherwise indicated. benzoic acid and its derivatives with benzyl alcohol, benza Ikonium chloride, Sodium benzoate, bronopol, chlorhexidine, EXAMPLE 1. chlorocresol and its derivatives, ethyl alcohol, phenethyl Solutions of Anti-Irritants alcohol, phenoxyethanol, potassium Sorbate, diazolidiny 0072 The anti-irritants used are formulated, unless other lurea, parabens, such as propylparaben or methylparaben, wise indicated, in an ethanol/water (50:50) vehicle at the taken alone or as mixtures. concentrations shown in the table below. The latter also 0060 Preferred preservative are the parabens and phe shows, for each anti-irritant, the group treated in Example 2. noxyethanol or benzalkonium chloride, alone or as mixtures. 0061 The compositions according to the invention can also comprise one or more emulsifiers. 0062 Surface-active emulsifiers are amphiphilic com Content in 50:50 pounds which have a hydrophobic moiety possessing an aqueous alcoholic affinity for the oil and a hydrophilic moiety possessing an Group Anti-irritants solution (%) affinity for the water, thus creating a connection from the two 4 18f3-Glycyrrhetinic acid (enoxolone) 1.5 phases. Ionic or nonionic emulsifiers thus stabilize oil/water 5 Potassium salt of 18f3-glycyrrhetinic acid 1.5 emulsions by being adsorbed at the interface and by forming lamellar layers of liquid crystals. 0073 Group 4 is used as a negative control in the studies 0063 Exemplary preferred emulsifiers include the emul which follow. This is because, as shown in the following sifiers mentioned above for their property of wetting agents or studies, although being known as an anti-irritant, enoXolone lipophilic emulsifiers of glucate SS and glucamate SSE type. does not have an effect on the irritation due to retinoids. 0064. The compositions of the invention can additionally comprise any additive normally used in the cosmetics or EXAMPLE 2 pharmaceutical field, Such as neutralizing agents, Sunscreens, Evaluation of the Effects of Various Anti-Irritants in antioxidants, fillers, electrolytes, colorants, normal inorganic Preventive Treatment Before Topical Application of or organic bases or acids, fragrances, essential oils, cosmetic DifferinR) Gel on the BALB/c Mouse; Tolerance active principles, moisturizing agents, vitamins, essential Study fatty acids, sphingolipids, self-tanning compounds, such as 0074 The goal of the present study is to compare the DHA, Soothing and skin-protecting agents, propenetrating irritant power of a reference gel, comprising 0.1% adapalene, agents or a mixture of these. Of course, one skilled in the art when this treatment is preceded or not preceded by treatment will take care to choose this or these optional additional with an anti-irritant. US 2009/0012 172 A1 Jan. 8, 2009

0075. The treatment consists of a daily topical application 0093. It should also be noted that no loss in weight is (20 Jul) of anti-irritant, formulated in an aqueous/alcoholic recorded during the study. vehicle (50% ethanol and 50% water by volume), on the internal face of the right ear of BALB/c mice divided into 15 EXAMPLE 3 groups (female mice approximately 9 weeks old), followed Evaluation of the Comedolytic Activity of DifferinR) by a topical application (20 ul) of DifferinR) gel (reference gel Gel Alone Compared with DifferinR) Gel in Combi comprising 0.1% adapalene) at the rate of one application of nation with a Placebo Comprising an Anti-Irritant on each formulation per day for 6 days. the Rhino Mouse 0076. The test products are: 0077 Group 1: Untreated (controls) 0094. The goal of the present study is to compare the 0078 Group 2: DifferinR) gel (reference gel) comedolytic activity of DifferinR) gel (reference gel compris 0079 Group 3: Ethanol/water solution (aqueous/alcoholic ing 0.1% adapalene) whether this treatment is preceded or not vehicle for the anti-irritants), followed by DifferinR) gel preceded by a treatment with an anti-irritant. 0080 Group 4: Enoxolone, followed by Differin(R) gel 0.095 The treatment consists of a daily topical application 0081 Group 5: Potassium salt of 18f3-glycyrrhetinic acid, of an aqueous/alcoholic vehicle (ethanol/water 50:50) com followed by Differin R gel prising the anti-irritant potassium salt of 183-glycyrrhetinic 0082 Evaluation is carried out by measurements of the acid, followed 30 minutes later by an application of DifferinR) thickness of the ear by means of the Oditest and by clinical gel, on the skin of the back of the RHINO FVB/N RJ-hr" observation of the animals from the 2" to 19" day. (Rhino) mouse for 18 days. 0083. The results are represented in the table below and in (0096. The test products are: FIG. 1: (0097 Group 1: DifferinR) gel alone 008.4 FIG. 1 is the kinetics of the mean thickness of the 0.098 Group 2: Aqueous/alcoholic vehicle, followed by mouse ears from the 2" and 19" days for groups 1 to 3 DifferinR) gel placebo (references) and 4 and 5. These kinetics show that the Dif (0099 Group 3: Aqueous/alcoholic vehicle, followed by ferin Rigel formulation alone is an irritant; the addition of the Differin(R) gel aqueous/alcoholic vehicle to this formulation does not 0100 Group 4: Potassium salt of 18f3-glycyrrhetinic acid, change the degree of irritation (group 3). followed by Differin R gel. 0085 Enoxolone (group 4) has virtually no effect on the 0101 FIG.3 shows the results of the counting of the num decrease in the irritation caused by DifferinR) gel. ber of comedones per centimeter cm on the back of the I0086 On the other hand, the application of the potassium Rhino mice after 18 days of topical treatment for the 4 groups salt of 183-glycyrrhetinic acid (group 5) significantly reduces mentioned above. the irritation caused by Differin Rigel; this decrease is greater 0102 The results of the study show that skin treated with than 60%. placebos (group 2) exhibits a high number of comedones per 0087 Summarizing table for the results of the areas under centimeter, of from 51 and 60. Skin treated with Differin Rigel the curve (AUC) for the kinetics of the ear thicknesses (cf. alone or preceded by a placebo (groups 1 and 3) exhibits a FIG. 2 for the histograms) comparable and low number of comedones percentimeter, of from 3 and 5. 0103 Skin treated beforehand with the anti-irritant potas AUC for % AUC sium salt of 183-glycyrrhetinic acid exhibits a number of edema inhibition Student's comedones per centimeter statistically equivalent to that of D2-D19 WS. p t-test WS. groups 1 and 3. Mean SEM Differin values Differin 0104. It thus emerges from FIG. 3 that the anti-irritant potassium salt of 18 B-glycyrrhetinic acid with DifferinR) gel Untreated Differin 158.6 24.4 in a split treatment does not reduce the comedolytic activity of Ethanol water + Differin 147.6 12.8 7.0 O.6989 NS DifferinR) gel alone. Enoxolone + Differin 159.O 23.8 -0.3 O.9909 NS 0105 Finally, after 18 days of topical treatment, it should Potassium salt of 18B- 58.2 17.5 6.3.3 O.O1O2 : be noted that the animals do not exhibit a loss in weight. glycyrrhetinic acid + 0106. This overall study demonstrates that the application Differin of the specific potassium salt of 183-glycyrrhetinic acid NS = Not Significant before the treatment with DifferinR) gel does not reduce the comedolytic activity of DifferinR) gel. 0088. The results of the study show that, after repeated topical applications of 20 Jul of an anti-irritant Solution, fol EXAMPLE 4 lowed by 20 ul of Differin(R) gel, from D1 to D6 on the ear of the BALB/c mouse: Formulations of Gel Type Comprising 0.1% Ada I0089 the Differin(R) gel formulation is an irritant: palene and Anti-Irritants 0090 enoxolone does not have an effect on the irritation 01.07 caused by DifferinR) gel; 0091 on the other hand, the anti-irritant potassium salt of 18f3-glycyrrhetinic acid reduces the edema by 63%. 0092. This example shows that potential anti-irritants do Ingredients Formula A not all have the same effect with regard to the edema caused Adapalene O.1% by DifferinR) gel and that only the potassium salt of 18f3 Purified water 80.0% glycyrrhetinic acid is effective in reducing the irritation due to Potassium salt of 18B-glycyrrhetinic acid 1.5 adapalene. US 2009/0012 172 A1 Jan. 8, 2009

-continued (I) Ingredients Formula A Titriplex III O.2% Natrosol 250 HEHX Pharm 2.0% OH Propylene glycol 4.0% Symperonic PE/L.62 O.2% Phenoxyethanol 1.0% Purified water q.S. for 100%

EXAMPLE 5 Study of Tolerance of the Formulations of Example 4 0108. A study of tolerance is carried out according to the protocol of Example 2 with the formulation of Example 4. However, the present case, in contrast to Example 2, relates to a treatment which is not split since the adapalene and the where R is a hydrogen atom, a hydroxyl radical, a linear or anti-irritant are present in the same formulation. branched alkyl radical having from 1 to 4 carbon atoms, an 0109. The results of the areas under the curve (AUC) for alkoxy radical having from 1 to 10 carbon atoms or a Substi the kinetics of ear thickness from days 2 and 19 are reported tuted or unsubstituted cycloaliphatic radical, and at least one in the following table: anti-irritant compound selected from the group consisting of salts of 18f3-glycyrrhetinic acid and derivatives thereof, for mulated into a topically applicable, physiologically accept able medium therefor. 2. The cosmetic/pharmaceutical composition as defined by AUC D2-D19 Increase Student's 96 Inhibition claim 1, wherein said at least one retinoid has the formula (I) Standard WS. t-test vs. Differin and R is a methyl, ethyl, propyl or butyl radical. Mean deviation placebo vs. placebo gel 3. The cosmetic/pharmaceutical composition as defined by Differin 358.0 3.8 claim 1, wherein said at least one retinoid has the formula (I) placebo and R is a methoxy, ethoxy, propoxy, butoxy, hexyloxy or Differingel, 519.5 25.8 45.1 ::::::::: decyloxy radical. O.1% 4. The cosmetic/pharmaceutical composition as defined by Formula A 402.4 17.0 12.1 : 22.5 claim 1, wherein said at least one retinoid has the formula (I) and R is the 1-methylcyclohexyl radical or the 1-adamanty1 0110 Conclusions of the study: radical. 011 1 0.1% DifferinR) gel increases the area under the 5. The cosmetic/pharmaceutical composition as defined by curve by 45% with respect to the placebo gel. claim 1, wherein said at least one retinoid compound is 0112. The formulation with the anti-irritant increases the selected from the group consisting of adapalene, 6-3-(1- area under the curve with respect to the placebo gel by 12%. adamantyl)-4-hydroxyphenyl-2-naphthoic acid, 6-3-(1- 0113. With respect to 0.1% Differin(R) gel, formula A is adamantyl)-4-decyloxyphenyl-2-naphtholic acid and 6-3- less irritating by 20%. (1-adamantyl)-4-hexyloxyphenyl-2-naphthoic acid. 0114. The potassium salt of 18f3-glycyrrhetinic acid 6. The cosmetic/pharmaceutical composition as defined by appears to be an effective anti-irritant. These results confirm claim 1, wherein said at least one retinoid compound is ada those of Example 2, where the anti-irritant had been evaluated palene. in the split treatment, namely, before application of 0.1% 7. The cosmetic/pharmaceutical composition as defined by Differin(R) gel. claim 1, wherein said at least one anti-irritant compound is the 0115 Each patent, patent application, publication, text potassium salt of 183-glycyrrhetinic acid. and literature article/report cited or indicated herein is hereby 8. The cosmetic/pharmaceutical composition as defined by expressly incorporated by reference in its entirety. claim 1, formulated as a gel. 0116. While the invention has been described in terms of 9. The cosmetic/pharmaceutical composition as defined by various specific and preferred embodiments, the skilled arti claim 1, said at least one retinoid compound comprising from san will appreciate that various modifications, Substitutions, 0.001% to 10% by weight of the total weight thereof. omissions, and changes may be made without departing from 10. The cosmetic/pharmaceutical composition as defined the spirit thereof. Accordingly, it is intended that the scope of by claim 9, wherein the concentration of said at least one the present invention be limited solely by the scope of the retinoid compound is about 0.1%. following claims, including equivalents thereof. 11. The cosmetic/pharmaceutical composition as defined What is claimed is: by claim 9, wherein the concentration of said at least one 1. A topically applicable cosmetic/pharmaceutical compo retinoid compound is about 0.3%. sition comprising at least one retinoid compound selected 12. The cosmetic/pharmaceutical composition as defined from the group consisting of all trans retinoic acid, isotretin by claim 1, wherein the concentration of said at least one oin, motretinide, naphthoic acid compounds having the struc anti-irritant compound ranges from 0.01% to 10% by weight tural formula (I) and the salts and esters thereof: of the total weight thereof. US 2009/0012 172 A1 Jan. 8, 2009

13. The cosmetic/pharmaceutical composition as defined Solar acne or acne medicamentosa, comprising topically by claim 1, formulated as a medicament. applying onto the affected skin area of an individual in need 14. A regime or regimen for the treatment and/or preven of such treatment, a thus effective amount of the cosmetic? tion of a dermatological condition or affliction related to a pharmaceutical composition as defined by claim 1. disorder of keratinization relating to cell differentiation and to 16. The regime or regimen as defined by claim 15, com cell proliferation, comprising topically applying onto the prising the treatment and/or prevention of acne Vulgaris. affected skin area of an individual in need of such treatment, 17. A regime or regimen for the treatment of skin having a a thus effective amount of the cosmetic/pharmaceutical com tendency toward acne or for combating the greasy appearance position as defined by claim 1. of the skin or hair, comprising topically applying onto the 15. A regime or regimen for the treatment of acne Vulgaris, affected skin area of an individual in need of such treatment, comedonal acne, papulopustular acne, papulocomedonal a thus effective amount of the cosmetic/pharmaceutical com acne, nodulocystic acne, acne conglobata, acne keloid of the position as defined by claim 1. back of the neck, recurrent acne miliaria, acne necrotica, acne neonatorum, occupational acne, acne rosacea, senile acne, c c c c c