US009060943B2

(12) United States Patent (10) Patent No.: US 9,060,943 B2 Vielhaber et al. (45) Date of Patent: Jun. 23, 2015

(54) COMPOSITIONS COMPRISING (58) Field of Classification Search TRANS-TERT BUTYL. CYCLOHEXANOLAS CPC ...... A61Q 19/02: A61Q 17/04; A61Q 15700; SKN RRITATION-REDUCINGAGENT A61Q 11/00; A61Q 19/004; A61O 19/005; A61Q 19/04; A61Q 19/06; A61Q 19/08; (75) Inventors: Gabriele Vielhaber, Paris (FR); Heiko A61Q 5/02: A61Q 13/00; A61Q 17/00; Oertling, Holzminden (DE); Claudia A61Q 19/00; A61Q 1/02: A61Q 5/00 Gömann, Warbsen (DE); Antje Köhler, See application file for complete search history. Holzminden (DE); Michael Krohn, Lorsch (DE); Holger Zinke, (56) References Cited Heppenheim (DE) U.S. PATENT DOCUMENTS (73) Assignee: SYMRISE AG, Holzminden (DE) 2.927,127 A 3, 1960 Somerville et al. 5,540,853 A * 7/1996 Trinh et al...... 510,101 (*) Notice: Subject to any disclaimer, the term of this 5,858,958 A 1/1999 Holzner patent is extended or adjusted under 35 6,027,668 A 2/2000 Holzner U.S.C. 154(b) by 345 days. 2007/0021319 A1 1/2007 Kohleet al...... 512/2 (21) Appl. No.: 13A263,016 FOREIGN PATENT DOCUMENTS y x- - - 9 CN 1175900 A 3, 1998 (22) PCT Filed: Apr. 9, 2009 CN 1188.098 A 7, 1998 EP O75591O 1, 1997 (86). PCT No.: PCT/EP2009/054336 JP S5929618 A 2, 1984 JP H115O1081 A 1, 1999 S371 (c)(1), JP 2004107208 A 4, 2004 (2), (4) Date: Dec. 30, 2011 WO WO 97.22332 6, 1997 WO WO-9722332 A1 6, 1997 WO WO-2007042472 A1 4/2007 (87) PCT Pub. No.: WO2009/087242 WO WO 2008.117254 10, 2008 PCT Pub. Date: Jul. 16, 2009 OTHER PUBLICATIONS (65) Prior Publication Data Symrise GmbH & Co. KG, “Trans-tert-butyl cyclohexanol as skin US 2012/O121737 A1 May 17, 2012 irritation-reducing agent. Research Disclosure, Mason Publications, s vol. 542, No. 17, Jun. 1, 2009, p. 595, XP007139063. (51) Int. Cl. Notification of the First Office Action, Chinese Application No. 200980 159616.0, issued Nov. 15, 2012 (English Translation). g: i C International Search Report and Written Opinion of the International ( .01) Searching Authority for PCT/EP2009/054336 sent Aug. 1, 2010. A23C II/It (2006.01) Second Office Action, Chinese Application No. 200980 159616.0, A2.3L I/30 (2006.01) issued by the State Intellectual Property Office (SIPO) on Apr. 17. A2.3L 2/02 (2006.01) 2013, together with the reporting letter from the Chinese patent A2.3L 2/39 (2006.01) associates. A6 IK 8/02 (2006.01) Office Action from the Japanese Patent Office issued in parallel A6 IK3I/045 (2006.01) Japanese Application No. 2012-503873 together with the English A6 IK 45/06 (2006.01) translation, received on Nov. 25, 2013. Office Action from the Japanese Patent Office issued in parallel A61O 39; (2006.01) Japanese Application No. 2012-503873 together with the English C3 (O 3.08: translation, on Dec. 22, 2014. A61O 17/04 (2006.01) * cited by examiner A61 O 19/00 (2006.01) Continued A61 O 19/02 (2006.01) (Continued) A61 O 19/04 (2006.01) (52) U.S. Cl Primary Examiner — Terry A. McKelvey CPC ...... A61K 8/34 (2013.01); A23C 9/1307 Assistant Examiner Catheryne Chen (2013.01), A23C 1 1/103 (2013.01), A23L I/30 (74) Attorney, Agent, or Firm — Novak Druce Connolly (2013.01); A23L 2/02 (2013.01); A23L 2/39 Bove + Quigg LLP (2013.01); A61 K8/0216 (2013.01); A61 K 8/0229 (2013.01); A61K3I/045 (2013.01); (57) ABSTRACT A61K 45/06 (2013.01); A61 K 2800/75 The present invention primarily relates to the use of trans (2013.01); A61 K 2800/874 (2013.01); A61 K tert-butyl cyclohexanol as skin irritation-reducing agent as 2800/92 (2013.01); A61O 5/02 (2013.01); well as compositions (formulations) having a skin irritation A61O 1 1/00 (2013.01); A61O 15/00 (2013.01); reducing action comprising trans-tert-butyl cyclohexanol as A61O 17/04 (2013.01); A61 O 19/004 skin irritation-reducing agent. (2013.01); A61O 19/005 (2013.01); A61O 19/02 (2013.01); A61 O 19/04 (2013.01) 19 Claims, No Drawings US 9,060,943 B2 1. 2 COMPOSITIONS COMPRISING prevalence for self-declared sensitive skin had been reported TRANS-TERT BUTYL. CYCLOHEXANOLAS to be about 50% in the EU, USA and Japan and 36% in China. SKN RRITATION-REDUCINGAGENT People having sensitive skin for example observe facial discomfort with burning, stinging and similar skin sensation. CROSS-REFERENCE TO RELATED Sensitive skin can be caused by rapid changes in temperature, APPLICATIONS wind or by some cosmetics. It clearly is a neurological phe nomenon not correlating with allergic hypersensitivity or This application is a National Phase filing under 35 U.S.C. atopic dermatitis. People having sensitive skin often show an S371 of PCT/EP2009/054336, filed Apr. 9, 2009, the entire enhanced density of TRPV1 receptors on skin nerves and a 10 higher sensitivity towards capsaicin is also frequently contents of which is incorporated herein by reference. observed (which decreases with age due to decrease of skin The present invention primarily relates to the use of trans ennervation). 4-tert-butyl cyclohexanol as skin irritation-reducing (sooth Delicate skin describes a skin having a reduced irritation ing) agent as well as compositions (formulations) and prod threshold for irritants, such as hyper-reactive and intolerant, ucts having a skin irritation-reducing (soothing) action 15 and also atopic skin. In the case of humans with delicate, comprising trans-4-tert-butyl cyclohexanol as skin irritation sensitive or easily injured skin, a phenomenon called "sting reducing agent. ing” (“to sting' becoming injured, burn, be painful) can be It also relates to a medicament (pharmaceutical composi observed. Typical adverse phenomena associated with the tion) for treatment of skin irritations and/or pain conditions terms 'stinging or “sensitive skin' are reddening of the skin, and the use of such a formulation or of such a medicament for tingling, prickling, skin tightness and burning of the skin. prophylaxis (prevention) of skin irritation and/or treatment of They can be caused by stimulating environmental conditions, skin irritations for medical and/or other than medical, in Such as e.g. massage, action of Surfactants, influence of particular cosmetic, purposes. weather, such as heat, cold, dryness and also damp heat, In some Subjects, especially humans with sensitive skin, thermal radiation and UV radiation, e.g. from the Sun, or certain Substances may cause skin irritation, said skin irrita 25 psychological stress. tion being perceived as a stinging effect or burning sensation A “sensitive' scalp is likewise characterized by reddening if the Substance applied on the skin, especially on the face. of the skin, tingling, prickling, burning. Triggers are, for Examples of such substances used in the field of cosmetics are example, soap, shampoos or other hair care compositions, skin lighteners, skintanning agents, antibacterial agents, anti Surfactants, hard water having high lime concentrations and/ dandruff agents, antiacne agents, compounds against ageing 30 or mechanical stress. Erythemas and hyperseborrhoea (ex of the skin, emulsifiers, detergents, deodorizing agents, anti cessive production of sebum) of the scalp and dandruff are perspirants, skin warming agents, hair removing agents, abra often associated with the phenomena described. sives, anti-cellulite agents or certain classes of chemical com In about 10-20% of the population of industrial countries, pounds, e.g. phenol derivatives or C-hydroxy acids. with an increasing trend, atopy is to be observed, a hypersen Thus, the present invention moreover relates to a process 35 sitivity, of familial origin, of the skin and mucous membranes for the preparation of a formulation or of a medicament (phar to environmental Substances with an increased readiness to maceutical composition) having a skin irritation-reducing develop hyperSensitivity reactions of the immediate type (al action, a cosmetic ortherapeutic method for prophylaxis (pre lergies) to Substances from the natural environment. Atopy is vention) of skin irritations, a cosmetic or therapeutic method presumed to be of genetic origin. Atopy can manifest itself as for treatment of skin irritations, a method for prophylaxis of 40 atopic dermatitis. In this case, the skin barrier is damaged and the skin-irritating action and a method for reducing, eliminat the skin is often inflamed. ing or Suppressing the skin-irritating action of a Substance or The erythematous action of the ultraviolet part of sunlight Substance mixture able to cause skin irritation. or artificial radiation on the skin is generally known. While In the cosmetics and pharmaceuticals industry, there is a rays having a wavelength of less than 290 nm (the so-called constant need for agents having a skin irritation-reducing 45 UVC range) are absorbed by the ozone layer in the earth's action. atmosphere, rays in the range between 290 nm and 320 nm, The skin, in particular the epidermis, as a barrier organ of the so-called UVB range, cause erythema, simple Sunburn or the human organism is subjected to external influences to a even more or less severe burns. particular extent. Many intrinsic (e.g. genetic predisposition) Erythematous skin symptoms also occur as concomitant and extrinsic (e.g. damage to the skin barrier, action of UV 50 symptoms with certain skin diseases or irregularities. For light, irritating or allergy-inducing Substances) factors can example, the typical skin rash of the symptoms of acne is lead to skin irritation. In connection with this invention, skin regularly reddened to a greater or lesser degree and impairs irritation is to be understood as meaning any change to the the well-being of those affected even in mild cases. skin which induces sensorial malaise in humans and/or is Erythemas also occur to an increased extent in the nappy characterized by the symptoms a dry, reddened and/or 55 region of infants, and all the more so of babies (nappy der inflamed skin. The term sensorial malaise here also includes matitis). Incontinence, a condition which occurs to an states such as pain. Skin irritation can include, in particular, increased extent especially in old age, is also often associated phenomenologically different skin states: delicate skin, sen with erythemas and reddening of the skin as a consequence of sitive skin, including sensitive Scalp, easily injured skin, continual exposure to moisture and irritants (incontinence atopic skin, irritated skin or inflamed skin, which manifests 60 dermatitis). itself in an in each case higher severity in a reddening of the A large number of active compounds having a skin irrita skin, so-called erythema. tion-reducing action are indeed already employed in the tech The problem of “delicate skin' affects a growing number nical fields referred to, but alternatives nevertheless continue of adults and children. It is now assumed that up to 50% of the to be sought. In the connection with this invention skin irri population have a delicate skin. 65 tation-reducing action is to be understood as meaning the Sensitive skin is one of the most common disturbing skin moderation, reduction, elimination or prevention of skin irri conditions and can have high influence on life quality. The tations, in particular that of the skin symptoms described US 9,060,943 B2 3 4 above. The skin irritation-reducing action here is based in ment (pharmaceutical composition), especially for treating particular on Soothing of the skin, inhibition of inflammation pain conditions, mediated by the vanilloid receptor TRPV1. and/or alleviation of reddening. In this text, the term “skin' In the context of the present invention, the term “trans-4- also includes the term "mucous membrane'. In the search for tert-butyl cyclohexanol here includes (+)-trans-4-tert-butyl alternative agents, however, it should be remembered that the cyclohexanol, (-)-trans-4-tert-butyl cyclohexanol, repre Substances used must be toxicologically acceptable, tolerated sented by the following formulae, and mixtures thereof. well by the skin and stable (in particular in the conventional cosmetic and/or pharmaceutical formulations), should have the lowest possible intrinsic odour and the lowest possible OH H intrinsic colour and must be inexpensive to prepare. In accor 10 Y dance with the persistent trend towards natural active com pounds, novel active compounds of natural, in particular plant origin are sought in particular. Persons skilled in the art have already addressed the prob 15 lem of skin irritation and have described, e.g. the skin irrita tion-reducing properties of bisabolol and of ginger (Zingiber officinale) extract. WO 2007/042472 discloses mixtures of ginger extract or the compounds contained in ginger extract In particular, the term “trans-4-tert-butyl cyclohexanol with bisabolol having a significantly improved, synergistic, includes the racemic mixture of (+)-trans- and (-)-trans skin irritation-reducing action compared with the compo 4-tert-butyl cyclohexanol. nents used individually. The present invention also relates to a (preferably topical) Capsaicin is a natural agonist of the Transient Receptor cosmetic composition having a skin irritation-reducing action Potential V1 (TRPV1, vanilloid receptor, VR1). TRPV1 is consisting of or comprising: expressed on central and peripheral neurons. Different types 25 of stimuli activate the receptor such as low pH (<5.9), noxious a) 0.1-4.5 wt.%, preferably 0.25-4.0 wt.%, more preferably heat (>42°C.), the cannabinoid/endovanilloid anandamide, 0.375-3.0 wt.%, even more preferably 0.5-2.5 wt.%, most leukotriene B4 and exogenous capsaicin. As a result e.g. after preferably 0.6-2 wt.% of trans-4-tert-butyl cyclohexanol or capsaicin application, TRPV1 is stimulated to either transmit a cosmetically orpharmaceutically acceptable salt thereof, in burning pain or a burning pruritus. Moreover, the TRPV1 30 particular the Na", K", NH, Mg" or Casalt, based on the receptor may be sensitized by bradykinin and prostaglandins, total weight of the composition, and as well as by Nerve Growth Factor, with lowering of the b) one or more cosmetically acceptable carriers, preferably a activation threshold and facilitated induction of pain. Due to cosmetically acceptable carrier other than water or ethanol. the sensory function of TRPV1 (burning pain, burning pruri The weight percentages of trans-4-tert-butyl cyclohexanol tus), it may be speculated that the TRPV1 is involved in 35 are understood to refer to the total of the (+) and (-) isomers, sensitive skin. respectively, if so present. Thus, for example, if no (-) isomer TRPV1 is also expressed in many non-neuronal cells, is present, the weight percentage refers to the (+) isomer, and among them keratinocytes, differentiated Sebocytes, hair fol if both isomers are present, refers to the total amount of both licle cells, Sweat gland ducts, the secretory portion of eccrine isomers. Sweat glands, mast cells and 3T3-L1-preadipocytes and fibro 40 The compositions according to the present invention, in blasts. TRPV1 activation in keratinocytes by capsaicin or heat particular topical cosmetic compositions, are particularly causes the release of inflammatory mediators such as PGE2 Suitable for reducing skin irritation, in particular for soothing (prostaglandin E2) and IL-8 (interleukin-8), and induction of the skin and/or reducing or alleviating one or more skin matrix metalloproteinases such as MMP-1, respectively. sensations from the group consisting of Stinging, burning, In this context 'antagonistic activity” refers to a pharma 45 tingling, tickling and skin tightness, more particularly sting ceutical and/or cosmetic active inhibition of the TRPV1 ing and burning. related bioactivity. An antagonistically effective amount The compound used in the context of the present invention, means an amount Sufficient to modulate, and preferably trans-4-tert-butyl cyclohexanol, is as Such known in the prior reduce by at least about 30 percent, more preferably at least 50 art. percent, most preferably by at least 80 percent, the TRPV1 50 U.S. Pat. No. 2.927,127 discloses that hydrogenation of receptor activity, preferably measured as described in p-tert-butyl phenol with a Ni catalyst yields p-tert-butyl Example 1.1. cyclohexanol having proportions of approximately 30% cis An object of the present invention was therefore to provide isomer and approximately 70% trans-isomer. U.S. Pat. No. a component which has a, preferably improved, skin irrita 2.927,127 further describes the hydrogenation of p-tert-butyl tion-reducing action, in particular for reducing or alleviating 55 phenol using Rh/C as catalyst in ethanol to yield p-tert-butyl one or more skin sensations from the group consisting of cyclohexanol containing 87.5% of the cis-isomer, which was Stinging, burning, tingling, tickling and skin tightness. Subsequently converted to the corresponding acetates by This object is achieved by using trans-4-tert-butyl cyclo reaction with acetic anhydride. hexanol as skin irritation-reducing agent, in particular for U.S. Pat. No. 5,160,498 describes the hydrogenation of a) reducing or alleviating one or more human skin sensations 60 p-tert-butyl phenol or p-tert-butyl cyclohexanone using a from the group consisting of stinging, burning, tingling, tick BF-modified Rh catalyst in solvents like cyclohexane or ling and skin tightness, tetrahydrofuran to yield p-tert-butyl cyclohexanol containing b) as a TRPV1 antagonist, or more than 80% of the cis-isomer c) for preparing a cosmetical or pharmaceutical composition EP 0755910 relates to a process for preparing 4-tert-butyl for the treatment or prevention of skin irritation. 65 cyclohexanol predominantly containing the cis-isomer by Trans-4-tert-butyl cyclohexanol used in accordance with hydrogenation of p-tert-butyl phenol. The hydrogenations the present invention can also be applied as part of a medica according to EP 0 755 910 can be carried out in various US 9,060,943 B2 5 6 Solvents, e.g. alkanes, cyclic alkanes, acyclic ethers or alco U.S. Pat. No. 5,858,958 relates to the use of 4-tert-butyl hols like ethanol, iso-propanol or 4-methyl-2-pentanol are cyclohexanol as antioxidant, in particular as stabilizing agent mentioned. against oxidation in cleaning or cosmetic products. Improved JP 61-263944. A discloses the preparation of 1-allyloxy-4- antioxidative results were observed when 4-tert-butyl cyclo tert-butylcyclohexane by adding allyl bromide to a mixture of 5 hexanol was combined with tocopherols (alpha- or gamma-), tetra-n-butylammonium bisulphate, 4-tert-butylcyclohex citric acid, ascorbic acid or tartaric acid or their esters. Pre anol (cis:trans ratio=28:72), n-hexane and a 50 wt-% aqueous ferred amounts in cosmetic skin or hair cleaning composi Solution of NaOH. tions indicated are 0.05 to 0.5 wt.% and in perfume compo Highly pure trans-4-tert-butyl cyclohexanol can be sitions 0.5 to 50 wt.%, in both cases based on the total weight obtained as described in Organic Syntheses Collective Vol 10 of the composition. The examples disclose cosmetic products ume 5, 175-178, Wiley, New York, 1973, by reduction of like soap, shampoo, and all-purpose cleaner with a content of p-tert-butyl cyclohexanone with LiAlH and AlCls. Recrys 4-tert-butyl cyclohexanol of from 0.1 to 0.2 wt.%. Further tallization from petroleum ether yields essentially pure trans disclosed therein is a perfume oil comprising 10 wt.% of 4-tert-butyl cyclohexanol (purity >99 wt.%). p-tert-butyl cyclohexanol which was incorporated into a Soap According to J. Am. Chem. Soc. 1955, 77, 5562-5578 the 15 base resulting in amounts of 0.15 to 0.2 wt.% of 4-tert-butyl pure trans-isomer of 4-tert-butyl cyclohexanol is also obtain cyclohexanol in the final soap. However, U.S. Pat. No. 5,858, able from commercially available mixtures of 4-tert-butyl 958 is overall silent regarding the cis- and/or trans-isomer cyclohexanol-isomers via repeated crystallization of the acid content of the 4-tert-butylcyclohexanol used therein. phthalate followed by Saponification of the corresponding Preferably, a (topical) formulation according to the present pure trans ester with sodium hydroxide in water and Subse invention comprising trans-4-tert-butyl cyclohexanol or a quent extraction with pentane. The pure trans-isomer of cosmetically or pharmaceutically acceptable salt thereof is 4-tert-butyl cyclohexanol was also obtained by chromatogra Suitable for topical application on human skin, preferably phy over activated alumina Starting from a mixture of 4-tert used for application in the region of the head. butyl cyclohexanols having a content of the trans-isomer of Cosmetic formulations for application in the region of the about 61%. 25 head are, in particular, those which may come into contact JP 08-012620-A describes the conversion of 4-tert-butyl with the oral cavity even when applied properly to the skin, cyclohexanol (cis:trans ratio=25:75) into esters, preferably for example—cosmetic cleansing or care compositions for the pivalate or benzoate, e.g. via transesterification with the face region, face creams or lotions or ointments, Sun methyl pivalate or methylbenzoate in toluene in the presence screen compositions, lipsticks or other lip cosmetics or lip of a titanate catalyst (e.g. tetrabutyl titanate). Subsequently 30 care compositions. the 4-tert-butylcyclohexanol esters were obtained by crystal An “skin effective amount” in the context of the present lization. invention refers to an amount effective to reduce or alleviate U.S. Pat. No. 2,582,743 states that p-tert-butyl cyclohex skin irritation and/or to avoid skin irritation of human skin, in anol has a musty camphorlike Smell. No information is given particular regarding one or more skin sensations from the regarding the proportion of the cis- and/or trans-isomer. 35 group consisting of stinging, burning, tingling, tickling and U.S. Pat. No. 5,858,958 mentions that p-tert-butyl cyclo tightness. hexanol is a known perfumery ingredient which is not very In one embodiment of the present invention, the (topical) currently used in perfumery due to its not too elegant cam formulation conventionally comprises one or more Sub phoraceous note. stances able to cause skin irritation of human skin, in particu Steffen Arctander describes 4-tert-butyl cyclohexanol in 40 lar one or more skin sensations from the group consisting of “Perfume and Flavor Chemicals, private publication, Mont Stinging, burning, tingling, tickling and skin tightness. clair, N.J., 1969, entry 433, as having an extremely dry, The invention also provides a medicament (pharmaceutical woody-camphoraceous odour with leather-like undertones compositions), preferably for treatment of skin irritations which can used in artificial patchouli oils and to lend power, and/or for treating pain conditions, comprising trans-4-tert diffusiveness and radiance to Soap fragrances. No informa 45 butyl cyclohexanol in an amount having an irritation- and/or tion is given regarding the cis- and/or trans-isomer ratio. pain-reducing action. Such a medicament can be employed in When used as commercially available (fragrance) material the field of human medicine against a large number of pains 4-tert-butyl cyclohexanol essentially consists of the trans and diseases, such as, for example, urticaria, contact derma isomer and the cis-isomer, the weight-ratios being in the titis, atopy and generally all inflammation processes, range from about 68:32 to about 73:27. 50 included tooth and gum inflammations, such as parodontosis. GB 1,580,184 discloses a fragrance mixture in form of a The pure cis-isomer and the pure trans-isomer of racemic patchouli base comprising about 4.9 wt.% of p-tert-butyl 4-tert-butyl cyclohexanol were tested separately for TRPV1 cyclohexanol. No information is given regarding the cis- and/ antagonism at parallel application with capsaicin as agonist. or trans-isomer content of the p-tert-butylcyclohexanol used It was found that the pure trans-isomer was significantly more therein. 55 active than a 50/50 mixture of cis- and trans-isomer, whereas U.S. Pat. No. 6,566,562 uses p-tert-butyl cyclohexanol at a the pure cis-isomer was inactive. level of 3.25 wt.% in a perfume oil having natural patchouli In the process of making the present invention the pure cis character. No information is given regarding the cis- and/or and trans-isomers of 4-tert-butyl cyclohexanol were tested trans-isomer content of the p-tert-butylcyclohexanol used separately in a pre-incubation mode with application of the therein. 60 respective isomer 10 min before addition of the agonist cap WO 2008/117254 describes a perfuming composition of saicin. Also this experiment showed strong activity of trans the patchouli type comprising p-tert-butyl cyclohexanol in an 4-tert-butyl cyclohexanol, also here the cis-isomer was not amount of 12.94 wt.%. Said perfuming composition contains active. dipropylene glycol at a level of 7.09 wt.%, based on the total Based on these results and the in vivo data summarized weight of said perfuming composition. No information is 65 below in Example 1.2, the inventors conclude that trans-4- given regarding the cis- and/or trans-isomer content of the tert-butyl cyclohexanol is a very effective, highly specific p-tert-butylcyclohexanol used therein. TRPV1 antagonist in vitro as well as in vivo. Moreover, only US 9,060,943 B2 7 8 the trans-isomer of 4-tert-butyl cyclohexanol was shown to be a total amount of at least 40 wt.% and most preferred in the bioactive, TRPV1 antagonizing isomer. a total amount of 60 to 85 wt.%, and which are prefer In addition, the cis-isomer has a marked, unpleasant earthy ably selected from the group consisting of 1,2-propylene odour which was clearly stronger than that of the trans-isomer glycol, 2-methylpropane-1,3-diol. 1.2-butylene glycol, and which was clearly perceivable at a dosage of 1 wt.% in a 1,3-butanediol, 1.2-pentanediol, 1,3-pentanediol, 1.5- non-perfumed cosmetic composition. This odour makes the pentanediol. 2.4-pentanediol, 2-methyl-pentane-2,4- cis-isomer far less Suitable for (topical) cosmetic formula diol. 1.2-hexanediol. 1.6-hexanediol. 1.2-octanediol, tions at higher dosages, in particular at use level above 0.3 wt. dipropylene glycol, preferably 1.2-butylene glycol, 1.2- %, based on the total weight of the cosmetic composition. It pentanediol and/or dipropylene glycol, wherein, option was also found that the trans-isomer exhibits only a weak 10 ally and preferably, the weight ratio as described above odour which is not or only slightly perceivable at a dosage of of trans-4-tert-butyl cyclohexanol to cis-4-tert-butyl 1 wt.% in a non-perfumed cosmetic composition. cyclohexanol, if present, is 75:25 or greater, preferably Thus, in preferred compositions according to the present greater than 80:20, more preferably greater than 90:10, invention the weight ratio of trans-4-tert-butyl cyclohexanol most preferably greater than 95:5. (that is: the total of all respective trans-isomers) to cis-4-tert 15 These compositions are easy to handle and stable over a butyl cyclohexanol (that is: the total of all respective cis prolonged period of time (even at lower temperatures of about isomers), if present, is 75:25 or greater, preferably greater +10°C.), typically more than 3 months, preferably more than than 80:20, more preferably greater than 90:10, most prefer 6 months (at +5°C.), without trans-4-tert-butyl cyclohexanol ably greater than 95:5. crystallizing out of these compositions. It was further observed by the inventors that trans-4-tert Such compositions comprising one or more (alkane) diols butyl cyclohexanol is a solid at 20° C. having a pronounced having 3 to 10 carbon atoms prepared according to the inven Sublimation behaviour. In addition, it has a tendency to (re-) tion are readily further processable, in particular for (topical) crystallize out of (topical) cosmetic compositions and prod cosmetic purposes. ucts, in particular at levels of 0.5 wt.% and above. This makes The present inventionals relates to the use of Such a con trans-4-tert-butyl cyclohexanol rather difficult to handle and 25 centrated composition for the preparation of a cosmetic for to store, in particular in (topical) cosmetic compositions and mulation or product or for the preparation of a medicament. products, in particular those comprising water in an amount In another preferred embodiment of the present invention of 10 wt.% or more, based on the total weight of the formu the one or more cosmetically acceptable carriers b) are lation or product, or comprising a water and an oil phase (e.g. selected from the group consisting of O/W or W/O-emulsions). 30 (i) one or more diols, preferably alkane diol(s), having 3 to 10 Without wishing to be bound by theory, it is assumed by the carbon atoms, preferably selected from the group consisting inventors that the combinations of the cosmetically accept of 1,2-propylene glycol, 2-methylpropane-1,3-diol. 1,2-buty able carriers and fragrance materials mentioned below (in lene glycol. 1,3-butanediol. 1.2-pentanediol. 1,3-pen particular those with higher Clog Pvalues) reduce the vapour tanediol. 1,5-pentanediol. 2.4-pentanediol, 2-methyl-pen pressure of trans-4-tert-butyl cyclohexanol and thereby 35 tane-2,4-diol. 1.2-hexanediol, 1.6-hexanediol. 1.2- improve the sublimation behaviour of trans-4-tert-butyl octanediol, dipropylene glycol, preferably 1.2-butylene cyclohexanol. These cosmetically acceptable carriers and fra glycol, 1.2-pentanediol and/or dipropylene glycol, grance materials thereby “trap' and hold the trans-4-tert and/or butyl cyclohexanol within the (topical) cosmetic composi (ii) a cosmetically acceptable carrier having a Clog Pvalue of tions and products. 40 at least 4, preferably of at least 5, more preferably of at least Further, it was also found by the inventors that the (pre 6, and preferably selected from groups (i-1) and/or (ii-2) ferred) cosmetically acceptable carriers and fragrance mate and/or (ii-3) or mixtures thereof, said groups consisting of rials mentioned (in particular those with higher C log P val (ii-1) esters having 6 to 36 carbon atoms, preferably ues) improve or even avoid the tendency of trans-4-tert-butyl monoesters, diesters or triesters, preferably selected from the cyclohexanol to (re-)crystallize out of (topical) cosmetic 45 group consisting of diethyl phthalate, diethylhexyl 2.6-naph compositions. thalate, isopropyl myristate, isopropyl palmitate, isopropyl Preferred formulations and products according to the Stearate, isopropyl oleate, n-butyl Stearate, n-hexyl laurate, invention comprising (preferred) cosmetically acceptable n-decyl oleate, isooctyl Stearate, isononyl Stearate, isononyl carriers and fragrance materials mentioned (in particular isononanoate, 3.5.5-trimethylhexyl 3.5.5-trimethylhex those with higher C log P values) were found to have 50 anoate, 2-ethylhexyl isononanoate, 2-ethylhexyl 3.5.5-trim improved Stability (regarding the Sublimation and/or (re-) ethylhexanoate, 2-ethylhexyl 2-ethylhexanoate, 2-ethylhexyl crystallization properties of trans-4-tert-butyl cyclohexanol), palmitate, 2-ethylhexyl laurate, 2-hexyldecyl Stearate, cet in particular in (topical) cosmetic composition and products, earyl ethylhexanoate, Stearylheptanoate, Stearyl caprylate, in particular those comprising water (preferably in an amount 2-octyldodecyl palmitate, oleyl oleate, oleyl erucate, erucyl of 10 to 95 wt.%, more preferably 25 to 90 wt.%, even more 55 oleate, erucyl erucate, 2-ethylhexyl isostearate, isotridecyl preferably 40 to 90 wt.%, in each case based on the total isononanoate, 2-ethylhexyl cocoate, C-s-alkylbenzoates, weight of the composition or product), and in (topical) cos cetyl palmitate, triethyl citrate, triacetin (triacetyl citrate), metic composition and products comprising water and an oil benzyl benzoate, benzyl acetate, vegetable oils (preferably phase (e.g. O/W or W/O-emulsions). olive oil, Sunflower oil, Soya oil, groundnut oil, rapeseed oil, The present invention thus also relates to a concentrated 60 almond oil, palm oil, coconut oil, palm kernel oil) and trig composition comprising or consisting of lycerides, in particular glyceryl Stearate, glyceryl tri 5 to 55 wt.%, preferably 15-40 wt.%, of trans-4-tert-butyl isononanoate, glyceryl laurate or triglycerides with identical cyclohexanol, based on the total weight of the composi or different C6 to C10 fatty acid radicals (so-called medium tion, -one or more diols, preferably alkane diol(s), hav chain triglycerides, in particular caprylic?capric triglyceride, ing 3 to 10 carbon atoms, preferably in a total amount of 65 like glyceryl tricaprylate, glyceryl tricaprate), and/or 7.5 wt.% or more, more preferably at least 12.5 wt.%. (ii-2) branched and unbranched alkyl or alkenyl alkohols, even more preferably 25 to 95 wt.%, most preferably in preferably selected from the group consisting of decanol, US 9,060,943 B2 9 10 decenol, octanol, octenol, dodecanol, dodecenol, octadienol, a total amount of 20 wt.% or more (preferably up to 35 wt. decadienol, dodecadienol, oleyl alcohol, ricinoleyl alcohol, %) of the one or more (preferred) cosmetically accept erucyl alcohol, Stearyl alcohol, isostearyl alcohol, cetyl alco able carriers b) were present in case the amount of trans hol, lauryl alcohol, myristyl alcohol, arachidyl alcohol, lino 4-tert-butyl cyclohexanol was higher than 1.0 wt.% to leyl alcohol, linolenyl alcohol, hexyldecanol, octyldodecanol 5 about 2.0 wt.%, (in particular 2-octyl-1-dodecanol) and cetearyl alcohol and in each case based on the total weight of the composition or behenyl alcohol, and/or product. In some preferred embodiments compositions and prod (ii-3) branched and unbranched hydrocarbons and waxes, ucts according to the present invention comprise water in an cyclic or linear silicone oils and dialkyl ethers having 6 to 24 10 amount of up to 98 wt.%, preferably 10 to 95 wt.%, more carbon atoms, preferably selected from the group consisting preferably 25 to 90 wt.%, in each case based on the total of jojoba oil, isoeicosane, dicaprylyl ether, mineral oil, pet weight of the composition or product. rolatum, squalane, squalene, cyclomethicone, decamethylcy In another preferred embodiment a composition or product clopentasiloxane, undecamethylcyclotrisiloxane, polydim according to the present invention additionally comprises one ethylsiloxane and poly(methyl-phenyl siloxane, 15 or more fragrance materials, preferably having a Clog Pvalue wherein, optionally and preferably, the weight ratio as of at least 3, preferably of at least 4, more preferably of at least described above of trans-4-tert-butyl cyclohexanol to cis-4- 5. Suitable fragrance materials are mentioned in S. Arctander, tert-butyl cyclohexanol, if present, is 75:25 or greater, pref Perfume and Flavor Chemicals, Vol. I and II, Montclair, N.J., 1969, self-published or H. Surburg and J. Panten, Common erably greater than 80:20, more preferably greater than 90:10, Fragrance and Flavor Materials, 5th. Ed., Wiley-VCH. Wein most preferably greater than 95:5. heim 2006, particularly those explicitly mentioned in US The C log P value (also known as log Pow) is the decimal 2008/OO70825. logarithm of the distribution coefficient of a substance or Compositions and products according to the present inven material between 1-octanol to water. C log P values are well tion advantageously comprise a total amount of 0.1 to 5 wt.%. known in the chemical arts as a calculated value that repre 25 preferably 0.2 to 4 wt.%, more preferably 0.25 to 3 wt.%, sents the relative affinity that a substance or material has for even more preferably 0.3–2.5 wt.%, of the one or more partitioning between octanol and water. Clog Pvalues can be (preferred) fragrance materials, in each case based on the total obtained or calculated as described and referenced in WO weight of the composition or product. 2008/114 189. In a further preferred embodiment a composition or prod 30 uct according to the present invention additionally comprises Such preferred compositions or products comprising one one or more of fragrance materials having a boiling point of or more cosmetically acceptable carriers b) according to the 250° C. or greater (at 1013 mbar). The total amount of fra invention are easy to handle and stable over a long period of grance materials having a boiling point of 250° C. or greater time, typically more than 3 months, preferably more than 6 (at 1013 mbar) preferably is at least 10 wt.%, more preferably months, without trans-4-tert-butyl cyclohexanol crystallizing 35 at least 20 wt.%, based on the total amount of fragrance out of these compositions, which is particularly of importance materials presentina composition or product according to the in (cosmetic) compositions or (cosmetic) products compris present invention. ing water in an amount of 10 wt.% or more, based on the total More preferably the fragrance materials, preferably having weight of the formulation or product, or comprising a water a boiling point of 250° C. or greater at 1013 mbar, are selected and an oil phase, in particular emulsions, e.g. of the O/W - or 40 from (here in some cases the normal industrial product names W/O-type. and registered trademarks of various firms are given): alpha-amyl cinnamic aldehyde, alpha-hexyl cinnamic These compositions are readily further processable, in par aldehyde, 2-phenoxyethylisobutyrate (Phenirat), methyl ticular for (topical) cosmetic purposes. dihydrojasmonate preferably with a content of cis-isomers Compositions and products according to the present inven 45 of >60 by weight (Hedione, Hedione HC), 4.6,6,7,8,8-hex tion advantageously comprise a total amount of 5 to 70 wt.%. amethyl-1,3,4,6,7,8-hexahydrocyclopentagbenzopyran preferably 7.5 to 60 wt.%, more preferably 10 to 50 wt.%, (Galaxolide), benzylsalicylate, 2-methyl-3-(4-tert-butyl even more preferably 10-40 wt.% of the one or more (pre phenyl)propanal (Lilial), 4.7-methano-3a,4,5,6,7,7a-hexahy ferred) cosmetically acceptable carriers b), in each case based dro-5-indenyl acetate and/or 4.7-methano-3a,4,5,6,7,7a on the total weight of the composition or product. 50 hexahydro-6-indenyl acetate (Herbaflorat), styrallyl acetate It was also found that compositions and products (in par (1-phenylethyl acetate), octahydro-2,3,8,8-tetramethyl-2-ac ticular emulsions having a water content of more than 40 wt. etonaphthone and/or 2-acetyl-1,2,3,4,6,7,8-octahydro-2.3,8. %, based on the total weight of the emulsion) according to the 8-tetramethylnaphthaline (Iso E Super), hexylsalicylate, present invention had improved storage stability (more than 3 4-tert-butylcyclohexyl acetate (Oryclon), 2-tert-butylcyclo 55 hexyl acetate (Agrumex HC), alpha-ionone (4-(2.2,6-trim months, generally more than 5 months) without trans-4-tert ethyl-2-cyclohexen-1-yl)-3-buten-2-one), 4-(4-hydroxy-4- butyl cyclohexanol (re-)crystallizing from these composi methylpentyl)-3-cyclohexene carboxaldehyde (Lyral), (E)- tions and products when and/or (Z)-3-methylcyclopentadec-5-enone (MuScenone), a total amount of 10 wt.% or more of the one or more 15-pentadec-11-enolide and/or 15-pentadec-12-enolide (preferred) cosmetically acceptable carriers b) were 60 (Globalide), 15-cyclopentadecanolide (Macrollide), 1-(5,6,7, present in case the amount of trans-4-tert-butyl cyclo 8-tetrahydro-3.5,5,6,8,8-hexamethyl-2-naphthalenyl)etha hexanol was about 0.25 wt.% to 0.5 wt.%, and none (Tonalide), ethylene brassylate, 2-ethyl-4-(2,2,3-trim a total amount of 15 wt.% or more (preferably up to 30 wt. ethyl-3-cyclopenten-1-yl)-2-buten-1-ol (Sandranol), alpha %) of the one or more (preferred) cosmetically accept Santalol, 2,2-dimethyl-3-(3-methylphenyl)-propanol able carriers b) were present in case the amount of trans 65 (Majantol), allyl heptanoate, 4-methylacetophenone, (4aR, 4-tert-butyl cyclohexanol was higher than 0.5 wt.% to 5R,7aS.9R)-octahydro-2,2,5,8,8.9a-hexamethyl-4H-4a,9- about 1.0 wt.%, methanoaZuleno(5,6-d)-1,3-dioxol) (Ambrocenide), Tim US 9,060,943 B2 11 12 berol (1-(2.2,6-trimethylcyclohexyl)hexan-3-ol), rides, preferably glucose, galactose, fructose, mannose, lae benzylacetone, methyl cinnamate, 3a,6,6,9a-tetramethyl Vulose and lactose, poly Sugars, such as B-glucans, in particu dodecahydronaphtho2,1-bfuran (Ambroxid). lar 1,3-1,4-3-glucan from oats, alpha-hydroxy-fatty acids, The total amount of fragrance materials selected from the triterpenic acids, such as betulic acid or ursolic acid, and algae above group, preferably having a boiling point of 250° C. or extracts; and/or greater at 1013 mbar, preferably is at least 10 wt.%, more (vi) physiological cooling agents, preferably selected from preferably at least 20 wt.%, based on the total amount of the group consisting of menthone glycerolacetal (also known fragrance materials present in a composition or product as FrescolatrMGA), menthyl lactate (also known as according to the present invention. FrescolatrML, menthyl lactate is preferably 1-menthyl lac According to a further preferred embodiment a composi 10 tate, in particular 1-menthyll-lactate), substituted menthyl-3- tion or product according to the present invention is in carboxylic acid amides (e.g. menthyl-3-carboxylic acid contrast to WO 2008/117254 free of 2,6,10,10-Tetram N-ethylamide, also known as WS-3, N'-(L-menthanecarbo ethyl-1-oxaspiro4.5 decan-6-ol (CAS number 65620-50-0). nyl)glycine ethyl ester, also known as WS-5), 2-isopropyl-N- Compositions according to the present invention advanta 2,3-trimethylbutanamide (also known as WS-23), substituted geously additionally comprise one or more actives providing 15 cyclohexanecarboxylic acid amides, 3-menthoxypropane-1, a benefit for the skin, in particular other skin irritation-reduc 2-diol, 2-hydroxyethyl menthyl carbonate, 2-hydroxypropyl ing or skin-Soothing agents, preferably selected from the menthyl carbonate, N-acetylglycine menthyl ester, isopule group consisting of anti-inflammatory agents, physiological gol, menthyl hydroxycarboxylic acid esters (e.g. menthyl cooling agents, compounds that alleviate itching and/or com 3-hydroxybutyrate), monomenthyl Succinate, monomenthyl pounds that alleviate reddening which are suitable for cos glutarate, 2-mercaptocyclodecanone, menthyl 2-pyrrolidin metic and/or dermatological applications. 5-onecarboxylate, 2,3-dihydroxy-p-menthane, 3,3,5-trim Also preferred composition according to the present inven ethylcyclohexanone glycerol ketal, 3-menthyl 3,6-di- and tion comprise the one or more actives selected from the -trioxaalkanoates, 3-menthyl methoxyacetate and icilin. groups consisting of: Preferably said compositions comprise one or more actives (i) steroidal anti-inflammatory Substances of the corticoster 25 selected from the groups consisting of: oid type, in particular hydrocortisone, hydrocortisone deriva (iii) extracts or fractions from camomile, Aloe Vera, oats, tives such as hydrocortisone 17-butyrate, dexamethasone, calendula, arnica, honeysuckle, rosemary, witch hazel, ginger dexamethasone phosphate, methylprednisolone or cortisone; or Echinacea; and/or and/or (iv) alpha-bisabolol, gingerols, shogaols, gingerdiols, dehy (ii) non-steroidal anti-inflammatory Substances, in particular 30 drogingerdiones, paradols, natural avenanthramides, non oxicams such as piroxicam or tenoxicam, Salicylates Such as natural avenanthramides, preferably dihydroavenanthramide aspirin, disalcid, Solprin or fendosal, acetic acid derivatives D. boswellic acid, phytosterols, glycyrrhizin, and licochal Such as diclofenac, fenclofenac, indomethacin, Sulindac, tol cone A.; and/or metin or clindanac, fenamates such as mefenamic, meclofe (v) urea, hyaluronic acid, allantoin, panthenol, lanolin, alpha namic, flufenamic or niflumic, propionic acid derivatives 35 hydroxy acids (preferably citric acid, lactic acid), Vitamin E Such as ibuprofen, naproxen or benoxaprofen, pyrazoles Such and derivatives (preferably tocopherol, tocopheryl acetate). as phenylbutaZone, oxyphenylbutaZone, febraZone or aza When bisabolol is used in the context of the present inven propaZone; and/or tion it can be of natural or synthetic origin, and is preferably (iii) natural or naturally occurring anti-inflammatory Sub “alpha-bisabolol. Preferably, the bisabolol used is syntheti stances or Substances that alleviate reddening and/or itching, 40 cally prepared or natural (-)-alpha-bisabolol and/or synthetic in particular extracts or fractions from camomile, Aloe Vera, mixed-isomer alpha-bisabolol. If natural (-)-alpha-bisabolol Commiphora species, Rubia species, willow, willow-herb, is used, this can also be employed as a constituent of an oats, calendula, arnica, St John’s wort, honeysuckle, rose essential oil or of a plant extract or of a fraction thereof, for mary, Passiflora incarnata, witch hazel, ginger or Echinacea, example as a constituent of (fractions of) oil or extracts of and/or 45 camomile or of Vanillosmopsis (in particular Vanillosmopsis (iv) pure Substances, preferably alpha-bisabolol, apigenin, erythropappa or Vanillosmopsis arborea). Synthetic alpha apigenin-7-glucoside, gingerols, shogaols, gingerdiols, bisabolol is obtainable, for example, under the name “Dra dehydrogingerdiones, paradols, natural avenanthramides, gosantol’ from Symrise. non-natural avenanthramides, preferably dihydroavenanthra In case ginger extract is used in the context of the present mide D, boswellic acid, phytosterols, glycyrrhizin, glabridin 50 invention, preferably extracts of the fresh or dried ginger root and licochalcone A, and/or are used which are prepared by extraction with methanol, (v) skin care agents, preferably skin moisture retention regu ethanol, iso-propanol, acetone, ethyl acetate, carbon dioxide lators or skin repair agents, preferably selected from the (CO), hexane, methylene chloride, chloroform or other sol group consisting of sodium lactate, urea and derivatives, glyc vents or solvent mixtures of comparable polarity. The extracts erol, propylene glycol, 1.2-pentanediol. 1.2-hexanediol and 55 are characterized by the presence of active skin irritation 1.2-octanediol, collagen, elastin or hyaluronic acid, diacyl reducing amounts of constituents such as e.g. gingerols, adipates, petrolatum, urocanic acid, lecithin, allantoin, pan shogaols, gingerdiols, dehydrogingerdiones and/or paradols. thenol, phytantriol, lycopene, (pseudo-)ceramides prefer The amount of other antiirritants (one or more compounds, ably Ceramide 2, hydroxypropyl bispalmitamide MEA, cety other than trans-4-tert-butyl cyclohexanol) in the formulation loxypropyl glyceryl methoxypropyl myristamide, N-(1- 60 of the present invention is preferably 0.0001 to 20 wt.%. hexadecanoyl)-4-hydroxy-L-proline (1-hexadecyl) ester, particularly preferably 0.0001-10 wt.%, in particular 0.001-5 hydroxyethyl palmityl oxyhydroxypropyl palmitamide, gly wt.%, based on the total weight of the formulation. cosphingolipids, cholesterol, phytosterols, chitosan, chon The formulation according to the invention or the liquid or droitin Sulfate, lanolin, lanolin esters, amino acids, vitamin E Solid formulation comprising the formulation can further and derivatives (preferably tocopherol, tocopheryl acetate), 65 more also be further processed by encapsulation. According alpha-hydroxy acids (preferably citric acid, lactic acid, malic to the invention, the formulation according to the invention acid) and derivatives thereof, mono-, di- and oligosaccha and/or the liquid or Solid formulation comprising this is US 9,060,943 B2 13 14 encapsulated with a solid shell material, which is preferably cream, lotion or milk of the W/O, O/W or multiple emulsion, chosen from starches, degraded or chemically or physically PIT emulsion, emulsion foam, micro-, nanoemulsion, Pick modified Starches (in particular dextrins and maltodextrins), ering emulsion type), ointment, paste, gel (preferably hydro-, gelatines, wax materials, liposomes, gum arabic, agar-agar, hydrodispersion-, oleogel), balm, serum, powder, wipe, Eau ghatti gum, gellan gum, modified and non-modified cellulo de Toilette, Eau de Cologne, perfume, Stick, roll-on, (pump) ses, pullulan, curdlan, carrageenans, algic acid, alginates, spray, aerosol, leave-on skin care composition (preferably pectin, inulin, Xanthan gum and mixtures of two or more of face-care composition), leave-on insect repellent composi the Substances mentioned. tion, Sunscreen composition, skin-lightening composition, The cosmetic, dermatological or therapeutic products self-tanning composition, afterSun preparation, after-shave according to the invention can be produced by conventional 10 composition, hair care composition, preferably conditioner, processes known perse, such that trans-4-tert-butyl cyclohex hair lotion, hair tonic, styling cream, pomade, Styling aid anol is incorporated into (topical) cosmetic, dermatological (preferably gel or wax), decorative cosmetic composition or therapeutic products which can have a conventional com (preferably face powder, eye shadow, kajal pencil, lipstick), position and which in addition to the aforementioned effects deodorant and/or antiperspirant composition. can also be used for the treatment, care and cleansing of the 15 The present invention also relates to a cosmetic or thera skin or hair. peutic method for prophylaxis of and/or treatment of human Preferred fields of use for compositions according to the skin irritation, comprising the step of invention are (preferably topical) cosmetic, dermatological or provision of trans-4-tert-butyl cyclohexanol or a cosmeti therapeutic products which serve for cosmetic or dermato cally orpharmaceutically acceptable Salt thereof, in par logical light protection, for treatment, care and cleansing of ticular the Na", K", NH, Mg" or Ca" salt, or of a the skin and/or hair or as a make-up product in decorative composition or a medicament (pharmaceutical compo cosmetics. Such products can accordingly be present e.g. as a sition) according to the present invention, cleansing composition, Such as e.g. soap, Syndet, liquid wash application of trans-4-tert-butyl cyclohexanol, of the com ing, shower and bath preparation, skin care composition, Such position or of the medicament to non-irritated (prophy as e.g. emulsion (as a solution, dispersion, Suspension; cream, 25 laxis) or irritated (treatment) skin in an effective amount, lotion or milk of the W/O, O/W or multiple emulsion, PIT said application preferably remaining for at least 5 min emulsion, emulsion foam, micro- or nanoemulsion, Pickering utes, more preferably for at least 10 minutes, on said skin emulsion type, depending on the preparation process and (“leave-on product”). constituents), ointment, paste, gel (including hydro-, hydro Compositions and products, in particular (topical) cos dispersion-, oleogel), alcoholic or aqueous/alcoholic solu 30 metic products, according to the present invention can advan tion, oil, toner, balsam, serum, powder (e.g. face powder, tageously comprise (apart from trans-4-tert-butyl cyclohex body powder), soaking liquid for wipes, Eau de Toilette, Eau anol used according to the invention) suitable auxiliary de Cologne, perfume, wax, including the presentation form as Substances and additives, such as, for example: a mask, mousse, Stick, pencil, roll-on, (pump) spray, aerosol preservatives, in particular those described in US 2006/ (foaming, non-foaming or after-foaming), skin care compo 35 0089413, antimicrobial agents, such as e.g. antibacterial sition (as described above) as a foot care composition (includ agents or agents to treat yeast and mold, in particular those ing keratolytics, deodorant), as an insect repellent composi described in WO 2005/123101, antiacne and sebum reducing tion, as a Sunscreen composition, as a self-tanning agents, in particular those described in WO 2008/04.6791, composition and/or afterSun preparation, skin care composi compounds against ageing of the skin, in particular those tion as a shaving composition or after-shave, as a hair-remov 40 described in WO 2005/123101, antidandruff agents, in par ing composition, as a hair care composition, Such as e.g. ticular those described in WO 2008/046795, antirritants (an shampoo (including shampoo for normal hair, for greasy hair, tiinflammatory agents, irritation-preventing agents, irrita for dry, stressed (damaged) hair, 2-in-1 shampoo, anti-dan tion-inhibiting agents), in particular those described in WO druff shampoo, baby shampoo, shampoo for a dry scalp. 2007/042472 and US 2006/0089413, antioxidants, in particu shampoo concentrate), conditioner, hair treatment cure, hair 45 lar those described in WO 2005/123101, carrier materials, in tonic, hair lotion, hair rinse, styling cream, pomade, perma particular those described in WO 2005/123101, chelating nent wave and fixing compositions, hair Smoothing compo agents, in particular those described in WO 2005/123101, sition (straightening composition, relaxer), hair setting com deodorizing agents and antiperspirants, in particular those position, styling aid (e.g. gel or wax); blonding composition, described in WO 2005/123101, moisture regulators (mois hair colouring composition, Such as e.g. temporary, directly 50 ture-donating agents, moisturizing Substance, moisture-re absorbed, semi-permanent hair colouring composition, per taining substances), in particular those described in WO manent hair colouring composition), skin care composition 2005/123101, osmolytes, in particular those described in WO as a decorative body care composition, such as e.g. nail care 2005/123101, compatible solutes, in particular those composition (nail varnish and nail varnish remover), decora described in WO 01/76572 and WO 02/15868, proteins and tive cosmetic (e.g. powder, eye shadow, kajal pencil, lipstick, 55 protein hydrolysates, in particular those described in WO mascara), make-up, make-up remover, skin care composition 2005/123101 and WO 2008/46676, skin-lightening agents, in as a deodorant and/or antiperspirant. particular those described in WO 2007/110415, skin-tanning Preferred products according to the present inventions are agents, in particular those described in WO 2006/045760, selected from the group of cosmetic products for treatment, cooling agents, in particular those described in WO 2005/ protecting, care and cleansing of the skin and/or hair or as a 60 123101, skin-cooling agents, in particular those described in make-up product, preferably as a leave-on product (meaning WO 2005/123101, skin warming agents, in particular those that trans-4-tert-butyl cyclohexanol stays on the skin for a described in WO 2005/123101, UV-absorbing agents, in par longer period of time, e.g. compared to rinse-off products, so ticular those described in WO 2005/123101, UV filters, in that the skin-irritation reducing action thereof is more pro particular those described in WO 2005/123101, benzylidene nounced), more preferably in the form or selected from the 65 beta-dicarbonyl compounds in accordance with WO 2005/ product group consisting of alcoholic or aqueous/alcoholic 107692 and alpha-benzoyl-cinnamic acid nitriles in accor Solution, dispersion, Suspension, emulsion (preferably dance with WO 2006/015954, insect repellents, in particular US 9,060,943 B2 15 16 those described in WO 2005/123101, plant parts, plant ceramides), softening, moisturizing and/or humectant Sub extracts, in particular those described in WO 2005/123101, stances, fats, oils, Saturated fatty acids, mono- or polyunsatu vitamins, in particular those described in WO 2005/123101, rated fatty acids, C.-hydroxy acids, polyhydroxy-fatty acids or emulsifiers, in particular those described in WO 2005/ derivatives thereof, waxes or other conventional constituents 123101, gelling agents, in particular those described in WO of a cosmetic or dermatological formulation, such as alco 2005/123101, oils in particular those described in WO 2005/ hols, polyols, polymers, foam stabilizers, electrolytes, 123101, waxes in particular those described in WO 2005/ organic solvents, silicone derivatives of chelating agents (e.g. 123101, fats in particular those described in WO 2005/ ethylenediaminetetraacetic acid and derivatives), antidan 123101, phospholipids, in particular those described in WO druff active compounds (e.g. climbazole, ketoconazole, 2005/123101, saturated fatty acids and mono- or polyunsatu 10 piroctonoleamine, Zinc pyrithione), hair care agents, per rated fatty acids and C-hydroxy acids and polyhydroxy-fatty fumes, Substances for preventing foaming, dyestuffs, pig acids and esters of Saturated and/or unsaturated branched ments which have a colouring action, thickening agents (ad and/or unbranched alkane carboxylic acids, in particular Vantageously silicon dioxide, aluminium silicates. Such as those described in WO 2005/123101, surface-active sub e.g. bentonites, polysaccharides or derivatives thereof, e.g. stances (surfactants) in particular those described in WO 15 hyaluronic acid, guar bean flour, Xanthan gum, hydroxypro 2005/123101, skin repair agents comprising cholesterol and/ pylmethylcellulose or allulose derivatives, particularly or fatty acids and/or ceramides and/or pseudoceramides, in advantageously polyacrylates, such as e.g. Carbopols or poly particular those described in WO 2006/053912, dyestuffs and urethanes), Surface-active Substances and emulsifiers. colorants and pigments, in particular those described in WO Auxiliary Substances and additives (excluding water) can 2005/123101, aroma chemicals and flavors and fragrances, in generally be included in products according to the present particular those described in S. Arctander, Perfume and Fla invention in quantities of 1 to 95 wt.%, preferably 5 to 70 wt. vor Chemicals, private publishing house, Montclair, N.J., %, more preferably 5 to 50 wt.%, in each case based on the 1969 and Surburg, Panten, Common Fragrance and Flavor total weight of the product. The amounts of cosmetic or Materials, 5th Edition, Wiley-VCH. Weinheim 2006, prefer dermatological auxiliary agents and additives and perfume to ably those explicitly mentioned in US 2008/0070825, alco 25 be used in each case can easily be determined by the person hols and polyols, in particular those described in WO 2005/ skilled in the art by simple trials, depending on the nature of 123101, organic solvents, in particular those described in WO the particular product. 2005/123101, silicones and silicone oils and silicone deriva The products according to the present invention preferably tives in particular those described in WO 2008/046676, viru contain water in a quantity of up to 98 wt.%, preferably 10 to cides, abrasives, anti-cellulite agents, astringents, antiseptic 30 95 wt.%, more preferably 25 to 90 wt.%, even more prefer agents, antistatics, binders, buffers, cell stimulants, cleansing ably 40 to 90 wt.%, in each case based on the total weight of agents, care agents, depilatory agents, softeners, enzymes, the product. essential oils, in particular those described in US 2008/ The formulations according to the invention can also com 0070825, fibres, film-forming agents, fixatives, foam-form prise antioxidants, it being possible for all the antioxidants ing agents, foam stabilizers, Substances for preventing foam 35 which are Suitable or usual for cosmetic and/or dermatologi ing, foam boosters, gel-forming agents, hair growth cal uses to be used. The antioxidants are advantageously activators, hair growth inhibitors, hair care agents, hair-set chosen from the group consisting of amino acids (e.g. gly ting agents, hair-straightening agents, hair-Smoothening, cine, histidine, tyrosine, tryptophan) and derivatives thereof, bleaching agents, strengthening agents, stain-removing imidazoles (e.g. urocanic acid) and derivatives thereof, pep agents, optically brightening agents, impregnating agents, 40 tides, such as D.L-carnosine, D-carnosine, L-carnosine and dirt-repellent agents, friction-reducing agents, lubricants, derivatives thereof (e.g. anserine), carotenoids, carotenes opacifying agents, plasticizing agents, covering agents, pol (e.g. C-carotene, B-carotene, lycopene) and derivatives ish, gloss agents, polymers in particular those described in thereof, chlorogenic acid and derivatives thereof, liponic acid WO 2008/046676, powders, peptides, mono-, di- and oli and derivatives thereof (e.g. dihydroliponic acid), aurothio gosaccharides, re-oiling agents, abrading agents, skin-Sooth 45 glucose, propylthiouracil and other thiols (e.g. thioredoxin, ing agents, skin-cleansing agents, skin care agents, skin-heal glutathione, cysteine, cystine, cystamine and glycosyl, ing agents, skin-protecting agents, skin-Softening agents, N-acetyl, methyl, ethyl, propyl, amyl, butyl and lauryl, palmi skin-Smoothing agents, nourishing agents, skin-Warming toyl, oleyl, Y-linoleyl, cholesteryl and glyceryl esters thereof) agents, stabilizers, detergents, fabric conditioning agents, and salts thereof, dilauryl thiodipropionate, distearyl thio Suspending agents, thickeners, yeast extracts, algae or 50 dipropionate, thiodipropionic acid and derivatives thereof microalgae extracts, animal extracts, liquefiers, color-pro (esters, ethers, peptides, lipids, nucleotides, nucleosides and tecting agents, and electrolytes. salts), (metal) chelators, e.g. C-hydroxy-fatty acids, palmitic The (in particular topical) cosmetic or pharmaceutical acid, phytic acid, lactoferrin, C-hydroxy acids (e.g. citric products according to the invention can comprise cosmetic acid, lactic acid, malic acid), humic acid, bile acid, bile auxiliary Substances and additives such as are conventionally 55 extracts, bilirubin, biliverdin, EDTA, EGTA and derivatives used in Such formulations, e.g. Sunscreen agents, preserva thereof, unsaturated fatty acids and derivatives thereof (e.g. tives, bactericides, fungicides, virucides, cooling active com Y-linolenic acid, linoleic acid, oleic acid), folic acid and pounds, insect repellents (e.g. DEET, IR3225), plant extracts, derivatives thereof, ubiquinone and ubiquinol and derivatives plant parts, antiinflammatory active compounds, Substances thereof, vitamin C and derivatives (e.g. ascorbyl palmitate, which accelerate wound healing (e.g. chitin or chitosan and 60 Mg ascorbyl phosphate, ascorbyl acetate, ascorbyl glyco derivatives thereof), film-forming Substances (e.g. polyvi sides, such as e.g. 6-O-acyl-2-O-O-D-glucopyranosyl-L- nylpyrrolidones or chitosan or derivatives thereof), antioxi ascorbic acid, 6-O-acyl-2-O-B-D-glucopyranosyl-L-ascor dants, vitamins, 2-hydroxycarboxylic acids (e.g. citric acid, bic acid, 2-O-O-D-glucopyranosyl-L-ascorbic acid or 2-O-B- malic acid, L-, D- or d1-lactic acid), skin-colouring agents D-glucopyranosyl-L-ascorbic acid), tocopherols and (e.g. walnut extracts or dihydroxyacetone), active com 65 derivatives thereof (e.g. vitamin E acetate), vitamin A and pounds for promoting hair growth or inhibiting hair growth, derivatives thereof (vitamin A palmitate) as well as conifer skin care compositions (e.g. cholesterol, ceramides, pseuod ylbenzoate of benzoin resin, rutic acid and derivatives US 9,060,943 B2 17 18 thereof, C-glucosylrutin, quercetin and derivatives thereof, salts (Neo Heliopan RHydro), 3-(4-trimethylammonium)- rosemary acid, carnosol, carnosol acid, resveratrol, caffeic benzylidene-bornan-2-one methyl-sulfate, tereph acid and derivatives thereof. Sinapic acid and derivatives thalylidene-dibornanesulfonic acid and salts (Mexoryl(RSX), thereof, ferulic acid and derivatives thereof, furfurylideneglu 4-t-butyl-4'-methoxy-dibenzoylmethane (avobenzone)/(Neo citol, curcuminoids, butylhydroxytoluene, butylhydroxyani Heliopan R357), B-Imidazole-4(5)-acrylic acid (urocanic sole, nordihydroguaiac resin acid, nordihydroguaiaretic acid, acid), 2-hydroxy-4-methoxybenzophenone (Neo trihydroxybutyrophenone, uric acid and derivatives thereof, Heliopan RBB), 2-hydroxy-4-methoxybenzophenone-5-sul mannose and derivatives thereof. Superoxide dismutase, Zinc fonic acid, dihydroxy-4-methoxybenzophenone, 2,4-dihy and derivatives thereof (e.g. ZnO, ZnSO), selenium and droxybenzophenone, tetrahydroxybenzophenone, 2,2'-dihy derivatives thereof (e.g. selenium methionine), Stilbenes and 10 droxy-4,4'-dimethoxybenzophenone, 2-hydroxy-4-n- derivatives thereof (e.g. stilbene oxide, trans-stilbene oxide) octoxybenzophenone, 2-hydroxy-4-methoxy-4'- and derivatives (salts, esters, ethers, Sugars, nucleotides, methylbenzophenone, 3-(4'-sulfo)benzylidene-bornan-2- nucleosides, peptides and lipids) of these active compounds one and salts, 3-(4-methylbenzylidene)-d.l-camphor (Neo mentioned orantioxidatively active extracts or fractions from Heliopan RMBC), 3-benzylidene-dil-camphor, 4-isopropy plants, such as e.g. green tea, rooibos, honeybush, grape, 15 ldibenzoylmethane, 2,4,6-trianilino-(p-carbo-2'-ethylhexyl rosemary, Sage, Melissa, thyme, lavender, olive, oats, cocoa, 1'-oxy)-1,3,5-triazine, phenylene-bis-benzimidazyl-tetrasul ginkgo, ginseng, liquorice, honeysuckle, Sophora, Pueraria, fonic acid disodium salt (Neo Heliopan RAP), 2,2'-(1,4- Pinus, Citrus, Phyllanthus emblica or St. John’s wort. phenylene)-bis-(1H-benzimidazole-4,6-disulfonic acid), The amount of antioxidants (one or more compounds) in monosodium salt, N-(2 and 4)-2-(Oxoborn-3-ylidene)me the formulations according to the invention is preferably 0.01 thylbenzyl-acrylamide polymer, phenol, -(2H-benzotria to 20 wt.%, particularly preferably 0.05 to 10 wt.%, in Zol-2-yl)-4-methyl-6-(2-methyl-3(1,3,3,3-tetramethyl-1- particular 0.2-5 wt.%, based on the total weight of the for (trimethylsilyl)-oxy)-disiloxyanyl)-propyl), (Mexoryl(RXL), mulation. 4,4'-(6-4-(1,1-dimethyl)-aminocarbonyl)-phenylamino-1, The formulations and products according to the present 3,5-triazine-2,4-diyl)diimino-bis-(benzoic acid 2-ethyl invention can also comprise physiological warming (heating) 25 hexyl ester) (Uvasorb(RHEB), 2,2'-methylene-bis-(6-(2H agents, which in Some cases are TRPV1 agonists and thus are benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl)-phenol), Substances which may cause skin irritations. Such physi (Tinosorb(RM), 2.4-bis-(4-(2-ethylhexyloxy)-2-hydrox ological warming agents preferably are selected from the yphenyl-1,3,5-triazine, benzylidene malonate-polysiloxane group consisting of Vanillyl alcohol n-butyl ether, Vanillyl (Parsol RSLX), glyceryl ethylhexanoate dimethoxycin alcohol n-propyl ether, Vanillyl alcohol isopropyl ether, Vanil 30 namate, disodium 2,2'-dihydroxy-4,4'-dimethoxy-5,5'-dis lyl alcohol isobutyl ether, vanillyl alcohol n-amino ether, ulfo-benzophenone, dipropylene glycol salicylate, sodium vanillyl alcohol isoamyl ether, vanillyl alcohol n-hexyl ether, hydroxymethoxybenzophenone-sulfonate, 4.4.4-(1,3,5-tri vanillyl alcohol methyl ether, vanillyl alcohol ethyl ether, azine-2,4,6-triyltrimino)-tris-benzoic acid tris(2-ethylhexyl gingerol, shogaol, Zingerone, capsaicin, dihydrocapsaicin, ester) (Uvinul RT150), 2.4-bis-(4-(2-ethyl-hexyloxy)-2- nordihydrocapsaicin, homocapsaicin, homodihydrocapsai 35 hydroxy)-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazine, cin, iso-propyl alcohol, iso-amylalcohol, benzyl alcohol, (Tinosorb(RS), 2,4-bis-((4-(3-sulfonato)-2-hydroxy-propy eugenol, cinnamon oil, cinnamic aldehyde, and mixtures loxy)-2-hydroxy)-phenyl]-6-(4-methoxyphenyl)-1,3,5-tri thereof. The formulations according to the invention advan azine sodium salt, 2.4-bis-(3-(2-propyloxy)-2-hydroxy tageously comprise at least one UVA filter and/or at least one propyloxy)-2-hydroxy)-phenyl]-6-(4-methoxy-phenyl)-1,3, UVB filter and/or at least one inorganic pigment. In this 40 5-triazine, 2,4-bis-(4-(2-ethyl-hexyloxy)-2-hydroxy context, the formulations can be in various forms such as are phenyl-6-4-(2-methoxyethyl-carbonyl)-phenylamino-1,3, conventionally employed e.g. for Sunscreen formulations for 5-triazine, 2.4-bis-(4-(3-(2-propyloxy)-2-hydroxy protecting the skin and hair against ultraviolet radiation. They propyloxy)-2-hydroxy)-phenyl]-6-4-(2-ethylcarboxyl)- can thus form e.g. a solution, an emulsion of the water-in-oil phenylamino-1,3,5-triazine, 2,4-bis-(4-(2-ethyl (W/O) type or of the oil-in-water (O/W) type or a multiple 45 hexyloxy)-2-hydroxy)-phenyl]-6-(1-methyl-pyrrol-2-yl)-1, emulsion, for example of the water-in-oil-in-water (W/O/W) 3,5-triazine, 2,4-bis-(4-tris-(trimethylsiloxy type, a gel, a hydrodispersion, a Solid stick or also an aerosol. silylpropyloxy)-2-hydroxy)-phenyl]-6-(4-methoxyphenyl)- In this context, the total amount of UV-filter substances is 1,3,5-triazine, 2.4-bis-(4-(2"-methylpropenyloxy)-2- from 0.01 wt.% to 40 wt.%, preferably 0.1 to 10 wt.%, in hydroxy)-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazine, 2.4- particular 1.0 to 5.0 wt.%, based on the total weight of the 50 bis-(4-(1", 1", 1',3',5'.5',5'-heptamethylsiloxy-2"-methyl formulations. propyloxy)-2-hydroxy)-phenyl]-6-(4-methoxyphenyl)-1,3, Advantageous UV filters are e.g.: p-aminobenzoic acid, 5-triazine, 2-(4-diethylamino-2-hydroxybenzoyl)-benzoic p-aminobenzoic acid ethyl ester (25 mol) ethoxylated, p-dim acid hexyl ester (Uvinul R A Plus) and indanylidene com ethylaminobenzoic acid 2-ethylhexyl ester, p-aminobenzoic pounds according to DE 100 55940 (=WO 02/38537). acid ethyl ester (2 mol) N-propoxylated, p-aminobenzoic 55 In this context, UV absorbers which are particularly suit acid glycerol ester, Salicylic acid homomethyl ester (homos able for combination are p-aminobenzoic acid, 3-(4-trim alate) (Neo Heliopan RHMS), salicylic acid 2-ethylhexyl ethylammonium)-benzylidene-bornan-2-one methyl-sulfate, ester (Neo Heliopan ROS), triethanolamine salicylate, 4-iso salicylic acid homomethyl ester (Neo Heliopan RHMS), propylbenzyl salicylate, anthranilic acid menthyl ester (Neo 2-hydroxy-4-methoxy-benzophenone (Neo Heliopan RBB), Heliopan RMA), diisopropylcinnamic acid ethyl ester, 60 2-phenylbenzimidazolesulfonic acid (Neo p-methoxycinnamic acid 2-ethylhexyl ester (Neo Heliopan RHydro), terephthalylidene-dibornanesulfonic Heliopan RAV), diisopropylcinnamic acid methyl ester, acid and salts (Mexoryl(RSX), 4-tert-butyl-4'-methoxydiben p-methoxycinnamic acid isoamyl ester (Neo Heliopan RE Zoylmethane (Neo Heliopan R357), 3-(4-sulfo)benzylidene 1000), p-methoxycinnamic acid diethanolamine salt, p-meth bornan-2-one and salts, 2-ethylhexyl 2-cyano-3,3-dipheny oxycinnamic acid isopropyl ester, 2-ethylhexyl 2-cyano-3,3- 65 lacrylate (Neo Heliopan R303), N-(2 and 4)-2-(oxoborn-3- diphenylacrylate (Neo Heliopan R303), ethyl 2-cyano-3,3'- ylidene)methylbenzyl-acrylamide polymer, diphenylacrylate, 2-phenylbenzimidazolesulfonic acid and p-methoxycinnamic acid 2-ethylhexyl ester (Neo US 9,060,943 B2 19 20 Heliopan RAV), p-aminobenzoic acid ethyl ester (25 mol) retinol, retinol palmitate, propyl gallate, precocenes, 6-hy ethoxylated, p-methoxycinnamic acid isoamyl ester (Neo droxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran, 3,4-di Heliopan RE 1000), 2,4,6-trianilino-(p-carbo-2'-ethylhexyl hydro-6-hydroxy-7-methoxy-2,2-dimethyl-1 (2H)-benzopy 1'-oxy)-1,3,5-triazine (Uvinul RT150), phenol, 2-(2H-benzo ran, creatine or other synthetic or natural active compounds triazol-2-yl)-4-methyl-6-(2-methyl-3(1,3,3,3-tetramethyl-1- against ageing of the skin and wrinkles, it being possible for (trimethylsilyl)-oxy)-disiloxyanyl)-propyl), (Mexoryl(RXL), the latter also to be used in the form of an extract from plants, 4.44 (6-4-(1,1-dimethyl)-aminocarbonyl)-phenylamino-1, Such as e.g. green tea, Rubus fruticosus, Sanguisorba offici 3,5-triazine-2,4-diyl)-diimino-bis-(benzoic acid 2-ethyl nalis, Centella asiatica, Ribes nigrum, Passiflora incarnate, hexyl ester), (UvasorbHEB), 3-(4-methylbenzylidene)-d.1- Filipendula ulmaria, Phyllanthus emblica, Potentilla species, camphor (Neo Heliopan RMBC), 3-benzylidenecamphor, 10 okra, algae, evening primrose, pomegranate, lady's mantle, salicylic acid 2-ethylhexyl ester (Neo Heliopan ROS), 4-dim rosemary, Sage, Echinacea, birch, apple or Soya. ethylaminobenzoic acid 2-ethylhexyl ester (Padimate O), Substances which are particularly preferred for use as fur hydroxy-4-methoxy-benzophenone-5-sulfonic acid and Na ther active compounds against ageing of the skin are B-glu salt, 2,2'-methylene-bis-(6-(2H-benzotriazol-2-yl)-4-(1,1,3, cans, and 1.3-1.4-linked B-glucan from oats, Rubus fruticosus 3-tetramethylbutyl)-phenol), (Tinosorb(RM), phenylene-bis 15 extract or wheat protein is particularly preferred. benzimidazyl-tetrasulfonic acid disodium salt (Neo The formulations according to the invention can also com Heliopan RAP), 2,4-bis-(4-(2-ethyl-hexyloxy)-2-hy prise active compounds which stimulate shading or tanning of droxy)-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazine, the skin and hair in a chemical or natural manner. A faster (Tinosorb(RS), benzylidene malonate-polysiloxane action based on synergistic effects is thereby achieved. Sub (Parsol RSLX), menthyl anthranilate (Neo Heliopan RMA), stances which are particularly preferred in this context are 2-(4-diethylamino-2-hydroxybenzoyl)-benzoic acid hexyl Substrates or Substrate analogues of tyrosinase, Such as L-ty ester (Uvinul R A Plus) and indanylidene compounds accord rosine, L-DOPA or L-dihydroxyphenylalanine, stimulators ing to DE 100 55940 (=WO 02/38537). of tyrosinase activity or expression, such as theophylline, Advantageous inorganic Sunscreenpigments arefinely dis caffeine, propiomelanocortin peptides, such as ACTH, alpha perse metal oxides and metal salts, for example titanium 25 MSH, peptide analogues thereof and other substances which dioxides, Zinc oxide (ZnO), iron oxides (e.g. FeO), alu bind to the melanocortin receptor, peptides, such as Val-Gly minium oxide (Al2O); cerium oxides (e.g. CeO), manga Val-Ala-Pro-Gly, Lys-Ile-Gly-Arg-Lys or Leu-Ile-Gly-Lys, nese oxides (e.g. MnO), Zirconium oxide (ZrO), silicon purines, pyrimidines, folic acid, copper salts, such as copper oxide (SiO), mixed oxides of the corresponding metals and gluconate, chloride or pyrrolidonate, flavonoids, flavanone mixtures of Such oxides, barium Sulfate and Zinc Stearate. 30 glycosides, such as maringin and hesperidin, melanin deriva They are particularly preferably pigments based on TiO, or tives, such as Melasyn-100 and MelanZe, diacylglycerols, Zinc oxide. In preferred embodiments, the particles have an aliphatic or cyclic diols, psoralene, prostaglandins and ana average diameter of less than 100 nm, preferably between 5 logues thereof, activators of adenylate cyclase and com and 50 nm and particularly preferably between 15 and 30 nm. pounds which activate the transfer of melanosomes into kera They can have a spherical shape, but those particles which 35 tinocytes, such as serine proteases or agonists of the PAR-2 have an ellipsoid shape or a shape which deviates otherwise receptor, extracts from plants and plant parts of the Chrysan from the spherical can also be employed. The pigments can themum species or Sanguisorba species, walnut extracts, uru also be in a form treated on the surface, i.e. hydrophilized or cum extracts, rhubarb extracts, erytrulose and dihydroxyac hydrophobized. Typical examples are coated titanium diox etOne. ides, such as e.g. titanium dioxide T805 (Degussa) or Euso 40 The formulations according to the invention can also be lex(R) Eusolex(RT2000 (Merck), or coated zinc oxide, such as employed in combination with skin-lightening active com e.g. Zinc Oxide NDM. In this context, possible hydrophobic pounds. According to the invention, all the skin-lightening coating agents are, above all, silicones, and in this case spe active compounds which are suitable or usual for cosmetic cifically trialkoxyoctysilanes or simethicone. So-called and/or dermatological uses can be used here. Advantageous micro- or nanopigments are preferably employed in Sun 45 skin-lightening active compounds in this respect are kojic screen compositions. Zinc micro- or nanopigments are pref acid (5-hydroxy-2-hydroxymethyl-4-pyranone), kojic acid erably employed. derivatives. Such as e.g. kojic acid dipalmitate, arbutin, ascor The total amount of inorganic pigments, in particular bic acid, ascorbic acid derivatives, hydroquinone, hydro hydrophobic inorganic micropigments, in the finished cos quinone derivatives, resorcinol, Sulfur-containing molecules, metic or dermatological formulations is advantageously in 50 Such as e.g. cysteine, alpha-hydroxy acids (e.g. citric acid, the range of from 0.1 to 30 wt.%, preferably 0.1 to 10.0, in lactic acid, malic acid) and derivatives thereof, N-acetyl particular 0.5 to 6.0 wt.%, based on the total weight of the tyrosine and derivatives, undecenoylphenylalanine, gluconic formulations. acid, 4-alkylresorcinols, 4-(1-phenylethyl)-1,3-benzenediol. Cosmetic formulations according to the invention which chromone derivatives, such as aloesin, flavonoids, thymol comprise a formulation according to the invention having a 55 derivatives, 1-aminoethylphosphinic acid, thiourea deriva skin irritation-reducing action can also comprise active com tives, elagic acid, nicotinamide, Zinc salts, such as e.g. Zinc pounds and active compound combinations against ageing of chloride orgluconate, thujaplicin and derivatives, triterpenes, the skin and wrinkles. According to the invention, all the Such as maslic acid, Sterols, such as ergosterol, benzofura active compounds against ageing of the skin and wrinkles nones, such as Senkyunolide, vinyl- and ethylguaiacol, inhibi which are Suitable or usual for cosmetic and/or dermatologi 60 tors of nitrogen oxide synthesis, such as e.g. L-nitroarginine cal uses can be used here. Advantageous active compounds and derivatives thereof, 2,7-dinitroindazole or thiocitrullin, againstageing of the skin and wrinkles in this respectare Soya metal chelators (e.g. C-hydroxy-fatty acids, palmitic acid, protein or protein hydrolysates, soya isoflavones, hydrolyzed phytic acid, lactoferrin, humic acid, bile acid, bile extracts, rice protein, hydrolysed hazelnut protein, oligopeptides from bilirubin, biliverdin, EDTA, EGTA and derivatives thereof), hydrolysed Hibiscus esculentus extract, wheat protein, B-glu 65 retinoids, soya milk, serine protease inhibitors or liponic acid cans, e.g. from oats, and derivatives thereof glycoproteins, or other synthetic or natural active compounds for lightening ursolic acid and its salts, betulin, betulic acid and its salts, of the skin and hair, the latter also being used in the form of an US 9,060,943 B2 21 22 extract from plants. Such as e.g. bearberry extract, rice extract, glutamine, glycine, alanine, glutamate, aspartate or proline, liquorice root extract or constituents concentrated therefrom, phosphatidylcholine, phosphatidylinositol and inorganic Such as glabridin or licochalcone A, Artocarpus extract, phosphates, as well as polymers of the compounds men extract from Rumex and Ramulus species, extracts from pine tioned, such as proteins, peptides, poly-amino acids and poly species (Pinus) and extracts from Vitis species or stilbene ols. All osmolytes at the same time have a skin-moisturizing derivatives concentrated therefrom, and extract from Saxi action. fraga, mulberry, Scutelleria or/and grape. Formulations according to the invention can advanta Advantageous skin and hair tanning active ingredients in geously also comprise vitamins and Vitamin precursors, it this respectare Substrates or Substrate analogues of tyrosinase being possible for all the vitamins and vitamin precursors such as L-tyrosine, N-acetyl tyrosine, L-DOPA or L-dihy 10 which are Suitable or usual for cosmetic and/or dermatologi droxyphenylalanine, Xanthine alkaloids such as caffeine, cal uses to be used. Vitamins and vitamin precursors which theobromine and theophylline and derivatives thereof, proo may be mentioned by way of example are: VitaminA (retinol) piomelanocortin peptides such as ACTH, alpha-MSH, pep and its derivatives (e.g. vitamin A acetate, vitamin A acid, tide analogues thereof and other substances which bind to the Vitamin A aldehyde, vitamin A palmitate, vitamin A propi melanocortin receptor, peptides such as Val-Gly-Val-Ala 15 onate), Vitamin B1 (thiamine) and its salts (e.g. vitamin B1 Pro-Gly, Lys-Ile-Gly-Arg-Lys or Leu-Ile-Gly-Lys, purines, hydrochloride, vitamin B1 mononitrate, thiamine diphos pyrimidines, folic acid, copper salts such as copper gluconate, phate, thiamine pyrophosphate), Vitamin B12 (cobalamin), chloride or pyrrolidonate, 1,3,4-oxadiazole-2-thiols such as vitamin B2 (vitamin G, riboflavin) and its derivatives (e.g. 5-pyrazin-2-yl-1,3,4-oxadiazole-2-thiol, curcumin, Zinc dig vitamin B2 tetraacetate), vitamin B3 and its derivatives (e.g. lycinate (Zn(Gly)), manganese(II) bicarbonate complexes nicotinamide ascorbate, nicotinamide glycolate, nicotina (“pseudocatalases') as described for example in EP O 584 mide hydroxycitrate, nicotinamide lactate, nicotinamide 178, tetrasubstituted cyclohexene derivatives as described for malate, nicotinamide mandelate, nicotinamide Salicylate, example in WO 2005/032501, isoprenoids as described in nicotinamide thioctate), Vitamin B4 (adenine) and its deriva WO 2005/102252 and in WO 2006/010661, melanin deriva tives (e.g. adenine riboside, disodium flavin adenine dinucle tives such as Melasyn-100 and MelanZe, diacyl glycerols, 25 otide, nicotinamide adenine dinucleotide), provitamin B5. aliphatic or cyclic diols, psoralens, prostaglandins and ana Vitamin B5 (pantothenic acid) and its derivatives (e.g. acetyl logues thereof, activators of adenylate cyclase and com pantothenyl ethyl ether, allantoin calcium pantothenate, pounds which activate the transfer of melanosomes to kera allantoin DL-pantothenyl alcohol, bis(pantothenamidoethyl) tinocytes such as serine proteases or agonists of the PAR-2 disulfide, calcium pantothenate, hydroxyethyl pantothena receptor, extracts of plants and plant parts of the chrysanthe 30 mide MEA, sodium pantothenate, N-D-pantothenoyl-2-(2- mum species, sanguisorba species, walnut extracts, urucum aminoethoxy)ethanol, N-D-pantothenoyl-2-aminoethanol, extracts, rhubarb extracts, trehalose, erythrulose and dihy N-hydroxyethoxyethyl pantothenamide, N-hydroxyethyl droxyacetone. Flavonoids which bring about skin and hair pantothenamide, pantothenamide MEA, pantothenol, pan tinting or tanning (e.g. quercetin, rhamnetin, kaempferol, tothenic acid lactone, pantothenic acid polypeptide, pantoth fisetin, genistein, daidzein, chrysin and apigenin, epicatechin, 35 enyl ethyl ether), vitamin B6 (pyridoxol, pyroxidal, pyridox dioSmin and dioSmetin, morin, quercitrin, naringenin, hespe amine) and its derivatives (e.g. pyridoxine dicaprylate, ridin, phloridzin and phloretin) can also be used. vitamin B6 dilaurate, vitamin B6 dioctanoate, vitamin B6 The amount of the aforementioned examples of additional dipalmitate, pyridoxine glycyrrhetinate, vitamin B6 hydro active ingredients for the modulation of skin and hairpigmen chloride, vitamin B6 phosphate, vitamin B6 serine, vitamin tation (one or more compounds) in the products according to 40 B6 tripalmitate), vitamin C (ascorbic acid) and its derivatives the invention is then preferably 0.00001 to 30 wt.%, prefer (e.g. 3-O-ethylascorbic acid, allantoin ascorbate, aminopro ably 0.0001 to 20 wt.%, particularly preferably 0.001 to 5 wt. pyl ascorbyl phosphate, araboascorbic acid, monosodium %, based on the total weight of the preparation. salt, ascorbic acid palmitate, ascorbic acid polypeptide, Formulations according to the invention can advanta ascorbosilane C, ascorbyl dipalmitate, ascorbyl glucoside, geously also comprise moisture retention regulators. The fol 45 ascorbyl inositol nicotinate, ascorbyl linoleate, ascorbyl lowing Substances e.g. are used as moisture retention regula methylsilanol pectinate, ascorbyl nicotinamide, ascorbyl tors (“moisturizers): sodium lactate, urea and derivatives, phosphate magnesium, ascorbyl Stearate, ascorbyl tetraiso alcohols, glycerol, diols, such as propylene glycol, 1.2-pen palmitate, ascorby1 tocopheryl maleate, calcium ascorbate, tanediol. 1.2-hexanediol and 1.2-octanediol, collagen, elastin chitosanascorbate, D-arabino-ascorbic acid, disodium ascor or hyaluronic acid, diacyl adipates, petrolatum, urocanic acid, 50 byl Sulfate, glucosamine ascorbate, inositol hexanicotinate lecithin, panthenol, phytantriol, lycopene, (pseudo-)ceram hexa-ascorbate, isoascorbic acid, L-ascorbic acid, 2-(dihy ides, glycosphingolipids, cholesterol, phytosterols, chitosan, drogen phosphate), trisodium salt, L-ascorbic acid, 2-(3- chondroitin Sulfate, lanolin, lanolin esters, amino acids, cholest-5-en-3-yl hydrogen phosphate, monosodium salt, alpha-hydroxy acids (e.g. citric acid, lactic acid, malic acid) L-ascorbic acid, 2-O-D-glucopyranosyl-, L-ascorbic acid, and derivatives thereof, mono-, di- and oligosaccharides, 55 3-O-ethyl ether, magnesium ascorbate, magnesium ascorby Such as, for example, glucose, galactose, fructose, mannose, lborate, methoxy PEG-7 ascorbic acid, methylsilanol ascor laevulose and lactose, poly Sugars, such as 3-glucans, in par bate, potassium ascorby1 tocopheryl phosphate, potassium ticular 1,3-1,4-3-glucan from oats, alpha-hydroxy-fatty ascorbylborate, sodium ascorbate, sodium ascorbyl phos acids, triterpenic acids. Such as betulic acid or ursolic acid, phate, Sodium ascorbyl/cholesteryl phosphate, Sodium and algae extracts. 60 isoascorbate, Sodium L-ascorbyl 2-phosphate, tetrahexylde Formulations according to the invention can also be cyl ascorbate), provitamin D. Vitamin D (calciol) and its employed together with osmolytes. Osmolytes which may be derivatives (e.g. vitamin D2, vitamin D3), vitamin E (D-al mentioned by way of example are: Substances from the group pha-tocopherol) and its derivatives (e.g. di-alpha-tocopherol, consisting of Sugar alcohols (myo-inositol, mannitol, Sorbi polyoxypropylene/polyoxyethylene?tocopherol ether, tol), quaternary amines, such as taurine, choline, betaine, 65 polypropylene glycol/tocopherol ether, tocopherol cysteam betaine-glycine and ectoin, diglycerol phosphate, phospho ine, tocopherol phosphate, sodium vitamin Ephosphate, Vita rylcholine, glycerophosphorylcholines, amino acids, such as min E acetate, vitamin E linoleate, Vitamin E nicotinate, US 9,060,943 B2 23 24 Vitamin E Succinate), Vitamin F (essential fatty acids, lino hyperhidrosis, a pathologically increased secretion of perspi lenic acid and linoleic acid) and its derivatives (e.g. vitamin F ration, and the action of which is based on an irreversible ethyl ester, vitamin F glyceryl ester), vitamin H (vitamin B7, blocking of the release of the transmitter substance acetyl biotin), vitamin K1 (phylloquinone, phytonadione) and Vita choline, which is relevant for secretion of perspiration. min K3 (menadione, menaquinone). Odour absorbers are, for example, the laminar silicates Formulations according to the invention can likewise com described in DE 40 09347, and of these in particular mont prise one or more further plant extracts, which are conven morillonite, kaolinite, nontronite, Saponite, hectorite, bento tionally prepared by extraction of the whole plant, but in nite and Smectite, and furthermore, for example, Zinc salts of individual cases also exclusively from blossom and/or leaves, ricinoleic acid. These likewise include deodorants, bacteri wood, bark or roots of the plant. In respect of the plant extracts 10 cidal or bacteriostatic deodorizing Substances, such as e.g. which can be used, reference is made in particular to the hexachlorophene, 2,4,4'-trichloro-2' hydroxydiphenyl ether extracts which are listed in the table starting on page 44 of the (Irgasan), 1,6-di-(4-chlorophenylbiguanido)-hexane (chlo 3rd edition of the Leitfaden Zur Inhaltsstoffdeklaration kos rhexidine) and 3,4,4'-trichlorocarbanilide, as well as the metischer Mittel Manual of Declaration of the Constituents active agents described in DE 3740 186, DE 3938 140, DE of Cosmetic Compositions, published by Industrieverband 15 42 04321, DE 42 29 707, DE 42 29737, DE 42 37 081, DE Körperpflegemittel and Waschmittel e.V. (IKW), Frankfurt. 43 09372 and DE 4324219, and cationic substances, such as Extracts which are advantageous in particular are those from e.g. quaternary ammonium salts, and odour absorbers, such aloe, algae, apple, apricot, arnica, avocado, pear, stinging as e.g. (R.Grillocin (combination of Zinc ricinoleate and vari nettle, blackberry, calendula, ivy, hibiscus, oak bark, Straw ous additives) or triethyl citrate, optionally in combination berry, spruce, honeysuckle, barley, ginkgo, ginseng, pome with ion exchange resins. granate, grapefruit, cucumber, oats, witch hazel, restharrow, In various cases it may also be advantageous to employ henna, raspberry, elder, honeybush, hops, coltsfoot, kiwi, bur formulations according to the invention in combination with dock, coconut, lavender, lime, linden, mallow, almond, substances which are chiefly employed for inhibition of the mango, box holly, Melissa, olive, orange, peppermint, Puer growth of undesirable microorganisms. In this respect, along aria, wild thyme, rooibos, rose, rosemary, horse chestnut, 25 side conventional preservatives, further active compounds sage, sandalwood, yarrow, horsetail, Sophora, liquorice, dead which are worth mentioning, alongside the large group of nettle, tea (green, white, black), thyme, grape, juniper, wil conventional antibiotics, are, in particular, the products rel low, rose-bay willow-herb, hawthorn, wheat, lady's smock, evant for cosmetics, such as triclosan, climbazole, Zinc cinnamon, lemon and lemongrass. In this context, the extracts pyrithione, ichthyol, Octopirox (1-hydroxy-4-methyl-6-(2,4, from aloe Vera, algae, arnica, stinging nettle, calendula, witch 30 4-trimethylpentyl)-2(1H)-pyridone, 2-aminoethanol), chito hazel, linden, ginseng, cucumber, rosemary and sage are par san, farnesol, octoxyglycerol, glycerol monolaurate, aryla ticularly preferred. Mixtures oftwo or more plant extracts can lkyl alcohols, such as e.g. phenylethyl alcohol, 3-phenyl-1- also be employed. Extraction agents which can be used for the propanol, Veticolor muguetalcohol, polyglycerolesters, such preparation of the plant extracts mentioned are, inter alia, as e.g. polyglyceryl 3-caprylates, and aliphatic diols, such as water, alcohols and mixtures thereof. In this context, among 35 e.g. 1,2-decanediol, or combinations of the Substances men the alcohols lower alcohols, such as ethanol and isopropanol, tioned, which are employed, inter alia, against underarm and also polyhydric alcohols, such as ethylene glycol, propy odour, foot odour or dandruff formation. lene glycol and butylene glycol, are preferred, and in particu Formulations according to the invention can in numerous lar both as the Sole extraction agent and in mixtures with cases also advantageously comprise preservatives. Preserva water. The plant extracts can be employed both in the pure and 40 tives which are preferably chosen here are those such as in the diluted form. benzoic acid and its esters and salts, 4-hydroxybenzoic acid The formulations according to the invention moreover can and its esters (INCI: Parabens, preferably methylparaben, also preferably comprise perspiration-inhibiting active com ethylparaben, butylparaben, propylparaben and/or isobu pounds (antiperspirants) and odour absorbers. Perspiration tylparaben) and salts, propionic acid and its esters and salts, inhibiting active compounds which are employed are, above 45 salicylic acid and its esters and salts, 2.4-hexadienoic acid all, aluminium salts, such as aluminium chloride, aluminium (sorbic acid) and its esters and salts, formaldehyde and hydrochloride, nitrate, Sulfate, acetate etc. In addition, how paraformaldehyde, 2-hydroxybiphenyl ether and its salts, ever, the use of compounds of Zinc, magnesium and Zirco 2-zinc-sulfidopyridine N-oxide, inorganic Sulfites and nium may also be advantageous. For use in cosmetic and bisulfites, sodium iodate, chlorobutanolum, 4-ethylmercury dermatological antiperspirants, the aluminium salts and—to 50 (II)-5-amino-1,3-bis(2-hydroxybenzoic acid), its salts and a somewhat lesser extent—aluminium/zirconium salt combi esters, dehydracetic acid, formic acid, 1,6-bis(4-amidino-2- nations have essentially proved Suitable. The aluminium bromophenoxy)-n-hexane and its salts, the Sodium salt of hydroxychlorides which are partly neutralized and therefore ethylmercury-(II)-thiosalicylic acid, phenylmercury and its tolerated better by the skin, but not quite so active, are addi salts, 10-undecylenic acid and its salts, 5-amino-1,3-bis(2- tionally worth mentioning. Alongside aluminium salts, fur 55 ethylhexyl)-5-methyl-hexahydropyrimidine, 5-bromo-5-ni ther Substances are also possible. Such as, for example, a) tro-1,3-dioxane, 2-bromo-2-nitro-1,3-propanediol. 2,4- protein-precipitating Substances, such as, interalia, formal dichlorobenzyl alcohol, N-(4-chlorophenyl)-N'-(3,4- dehyde, glutaraldehyde, natural and synthetic tannins and dichlorophenyl)-urea, 4-chloro-m-cresol. 2,4,4'-trichloro-2'- trichloroacetic acid, which bring about blockage of the sweat hydroxy-diphenyl ether, 4-chloro-3,5-dimethylphenol, 1,1'- glands on the Surface, b) local anaesthetics (inter alia dilute 60 methylene-bis(3-(1-hydroxymethyl-2,4-dioximidazolidin Solutions of e.g. lidocaine, prilocalne or mixtures of Such 5-yl)urea), poly-(hexamethylenediguanide) hydrochloride, Substances), which eliminate sympathetic Supply of the Sweat 2-phenoxyethanol, hexamethylenetetramine, 1-(3-chloroal glands by blockade of the peripheral nerve pathways, c) Zeo lyl)-3,5,7-triaza-1-azonia-adamantane chloride, 1-(4-chlo lites of the X. A or Y type, which, alongside the reduction in rophenoxy)-1-(1H-imidazol-1-yl)-3,3-dimethyl-2-butanone, secretion of perspiration, also function as adsorbents for bad 65 1,3-bis-(hydroxy-methyl)-5,5-dimethyl-2,4-imidazo odours, and d) botulinus toxin (toxin of the bacterium Chlo lidinedione, benzyl alcohol, Octopirox, 1,2-dibromo-2,4-di stridium botulinum), which is also employed in cases of cyanobutane, 2,2'-methylene-bis(6-bromo-4-chlorophenol), US 9,060,943 B2 25 26 bromochlorophene, mixture of 5-chloro-2-methyl-3(2H)- oily phase, and the oily phase is advantageously chosen from isothiazolinone and 2-methyl-3(2H)-isothiazolinone with the group which consists of 2-ethylhexyl isostearate, octyl magnesium chloride and magnesium nitrate, 2-benzyl-4- dodecanol, isotridecyl isononanoate, isoeicosane, 2-ethyl chlorophenol, 2-chloroacetamide, chlorhexidine, chlorhexi hexyl cocoate, C2-s-alkyl benzoate, caprylic/capric acid dine acetate, chlorhexidine gluconate, chlorhexidine hydro triglyceride and dicaprylyl ether. Mixtures of C2-s-alkyl chloride, 1-phenoxy-propan-2-ol. N-alkyl (C-C) benzoate and 2-ethylhexyl isostearate, mixtures of C2-s- trimethyl-ammonium bromide and chloride, 4.4-dimethyl-1, alkylbenzoate and isotridecyl isononanoate and mixtures of 3-oxazolidine, N-hydroxymethyl-N-(1,3-di Cis-alkylbenzoate, 2-ethylhexyl isostearate and isotride (hydroxymethyl)-2,5-dioxoimidazolidin-4-yl)-N'-hydroxy cyl isononanoate are particularly advantageous. The hydro methylurea, 1,6-bis(4-amidino-phenoxy)-n-hexane and its 10 carbons paraffin oil, squalane and squalene can also advanta salts, glutaraldehyde, 5-ethyl-1-aza-3,7-dioxabicyclo(3.3.0) geously be used. The oily phase can furthermore have a octane, 3-(4-chlorophenoxy)-1,2-propanediol, hyamines, content of cyclic or linear silicone oils or consist entirely of alkyl-(Cs-Cs)-dimethyl-benzyl-ammonium chloride, alkyl Such oils, it being advantageous to use an additional content (C-C)-dimethyl-benzylammonium bromide, alkyl-(Cs of other oily phase components in addition to the silicone oil Cs)-dimethyl-benzyl-ammonium saccharinate, benzyl 15 or silicone oils. Cyclomethicone (e.g. decamethylcyclopen hemiformal, 3-iodo-2-propynyl butylcarbamate, sodium tasiloxane) can advantageously be employed as a silicone oil. hydroxymethyl-aminoacetate or sodium hydroxymethyl However, other silicone oils, for example undecamethyl aminoacetate. cyclotrisiloxane, polydimethylsiloxane and poly(methyl Cosmetic or dermatological formulations which comprise phenylsiloxane), can also advantageously be used. Mixtures formulations according to the invention can also be in the of cyclomethicone and isotridecyl isononanoate and of form of emulsions. cyclomethicone and 2-ethylhexyl isostearate are furthermore The oily phase can advantageously be chosen from the particularly advantageous. following Substance group: Formulations in the form of an emulsion which comprise a mineral oils, mineral waxes formulation according to the invention advantageously com fatty oils, fats, waxes and other natural and synthetic fat 25 prise one or more emulsifiers. O/W emulsifiers can advanta substances, preferably esters of fatty acids with alcohols geously be chosen, for example, from the group consisting of of low C number, e.g. with isopropanol, propylene gly polyethoxylated or polypropoxylated or polyethoxylated and color glycerol, or esters of fatty alcohols with alkanoic polypropoxylated products. acids of low C number or with fatty acids; According to the invention, the polyethoxylated or alkylbenzoates; 30 polypropoxylated or polyethoxylated and polypropoxylated silicone oils, such as dimethylpolysiloxanes, diethylpol O/W emulsifiers employed are particularly advantageously ysiloxanes, diphenylpolysiloxanes and mixed forms chosen from the group consisting of substances having HLB thereof. values of 11-18, very particularly advantageously having Compounds which can advantageously be employed are HLB values of 14.5-15.5, if the O/W emulsifiers contain (a) esters of Saturated and/or unsaturated branched and/or 35 saturated radicals R and R. If the O/W emulsifiers contain unbranched alkanecarboxylic acids having a chain length of unsaturated radicals R and/or R', or isoalkyl derivatives are from 3 to 30 C atoms and saturated and/or unsaturated, present, the preferred HLB value of such emulsifiers can also branched and/or unbranched alcohols having a chain length be lower or higher. of from 3 to 30 C atoms, (b) esters of aromatic carboxylic It is of advantage to choose the fatty alcohol ethoxylates acids and Saturated and/or unsaturated, branched and/or 40 from the group consisting of ethoxylated Stearyl alcohols, unbranched alcohols having a chain length of from 3 to 30 C cetyl alcohols and cetyl Stearyl alcohols (cetearyl alcohols). atoms. Preferred ester oils are isopropyl myristate, isopropyl Advantageous W/O emulsifiers which can be employed palmitate, isopropyl Stearate, isopropyl oleate, n-butyl Stear are: fatty alcohols having 8 to 30 carbonatoms, monoglycerol ate, n-hexyllaurate, n-decyloleate, isooctyl Stearate, isononyl esters of Saturated and/or unsaturated, branched and/or stearate, isononyl isononanoate, 3.5.5-trimethylhexyl 3.5.5- 45 unbranched alkanecarboxylic acids having a chain length of trimethylhexanoate, 2-ethylhexylisononanoate, 2-ethylhexyl from 8 to 24, in particular 12 to 18 C atoms, diglycerol esters 3.5.5-trimethylhexanoate, 2-ethylhexyl 2-ethylhexanoate, of saturated and/or unsaturated, branched and/or unbranched 2-ethylhexyl palmitate, 2-ethylhexyl laurate, 2-hexyldecyl alkanecarboxylic acids having a chain length of from 8 to 24, Stearate, 2-octyldodecyl palmitate, oleyl oleate, oleylerucate, in particular 12 to 18 C atoms, monoglycerol ethers of Satu erucyl oleate, erucyl erucate and synthetic, semi-synthetic 50 rated and/or unsaturated, branched and/or unbranched alco and natural mixtures of Such esters, e.g. jojoba oil. hols having a chain length of from 8 to 24, in particular 12 to The oily phase can furthermore advantageously be chosen 18C atoms, diglycerol ethers of saturated and/or unsaturated, from the group consisting of branched and unbranched branched and/or unbranched alcohols having a chain length hydrocarbons and waxes, silicone oils and dialkyl ethers, the of from 8 to 24, in particular 12 to 18 C atoms, propylene group consisting of Saturated or unsaturated, branched or 55 glycol esters of saturated and/or unsaturated, branched and/or unbranched alcohols, and the fatty acid triglycerides, namely unbranched alkanecarboxylic acids having a chain length of the triglycerol esters of Saturated and/or unsaturated, from 8 to 24, in particular 12 to 18 C atoms and sorbitan esters branched and/or unbranched alkanecarboxylic acids having a of saturated and/or unsaturated, branched and/or unbranched chain length of from 8 to 24, in particular 12 to 18 C atoms. alkanecarboxylic acids having a chain length of from 8 to 24, The fatty acid triglycerides can advantageously be chosen 60 in particular 12 to 18 C atoms. from the group consisting of synthetic, semi-synthetic and Formulations according to the invention for cosmetic (topi natural oils, e.g. olive oil, Sunflower oil, Soya oil, groundnut cal) prophylactic (preventive) treatment of the skin can regu oil, rapeseed oil, almond oil, palm oil, coconut oil, palm larly comprise a high content of care substances. According to kernel oil and more of the like. Any desired blends of such oil a preferred embodiment, the compositions comprise one or and wax components can also advantageously be employed. 65 more animal and/or plant fats and oils having care properties, In some cases it is also advantageous to employ waxes, for Such as olive oil, Sunflower oil, refined soya oil, palm oil, example cetyl palmitate, as the sole lipid component of the sesame oil, rapeseed oil, almond oil, borage oil, evening US 9,060,943 B2 27 28 primrose oil, coconut oil, shea butter, jojoba oil, oat oil, sperm prising trans-4-tert-butyl cyclohexanol or a pharmaceutically oil, beef tallow, neats foot oil and lard, and optionally further acceptable salt thereof, in particular the Na", K", NH, Mg" care constituents, such as, for example, fatty alcohols having or Ca" salt, in an effective amount, preferably in an amount 8-30 C atoms. The fatty alcohols here can be saturated or in the range of 0.1 to 20 wt.%, preferably 0.5 to 10 wt.%, unsaturated and linear or branched. Alcohols which can be based on the total weight of the medicament. employed are, for example, decanol, decenol, octanol, The term “pharmaceutical composition” as used herein octenol, dodecanol, dodecenol, octadienol, decadienol, comprises trans-4-tert-butyl cyclohexanol of the present dodecadienol, oleyl alcohol, ricinoleyl alcohol, erucyl alco invention and one or more pharmaceutically acceptable car hol, Stearyl alcohol, isostearyl alcohol, cetyl alcohol, lauryl riers. As described above, trans-4-tert-butyl cyclohexanol can alcohol, myristyl alcohol, arachidyl alcohol, caprylyl alco 10 hol, capryl alcohol, linoleyl alcohol, linolenyl alcohol and be formulated as pharmaceutically acceptable salt. Typical behenyl alcohol, and Guerbet alcohols thereof, it being pos pharmaceutically acceptable salts include those salts pre sible for the list to be extended virtually as desired by further pared by reaction of trans-4-tert-butyl cyclohexanol of the alcohols of related structural chemistry. The fatty alcohols present invention with a pharmaceutically acceptable inor preferably originate from natural fatty acids, being conven 15 ganic base. Base addition salts include those derived from tionally prepared from the corresponding esters of the fatty inorganic bases, such as ammonium or alkali or alkaline earth acids by reduction. Fatty alcohol fractions which are formed metal hydroxides, carbonates, bicarbonates, and the like. by reduction from naturally occurring fats and fatty oils, such Such bases useful in preparing the salts of this invention thus as e.g. beef tallow, groundnut oil, colza oil, cottonseed oil, include Sodium hydroxide, potassium hydroxide, ammonium Soya oil, Sunflower oil, palm kernel oil, linseed oil, maize oil, hydroxide, potassium carbonate, Sodium carbonate, sodium castor oil, rape oil, Sesame oil, cacao butter and coconut fat, bicarbonate, potassium bicarbonate, calcium hydroxide, cal can furthermore be employed. cium carbonate, and the like. The potassium and sodium salt Care substances which can be combined in an outstanding forms are particularly preferred. It should be recognized that manner with formulations according to the invention more the particular counterion forming a part of any salt of this over also include 25 invention is usually not of a critical nature, so long as the salt waxes, such as e.g. candelilla wax or carnauba wax as a whole is pharmacologically acceptable and as long as the ceramides, where ceramides are understood as meaning counterion does not contribute undesired qualities to the salt N-acylsphingosins (fatty acid amides of sphingosin) or as a whole. synthetic analogues of Such lipids (so-called pseudo The pharmaceutical compositions are, preferably, admin ceramides), which significantly improve the water reten 30 istered topically or systemically. Suitable routes of adminis tion capacity of the stratum corneum. tration conventionally used for drug administration are oral, phospholipids, for example soya lecithin, egg lecithin and intravenous, dermal or parenteral administration as well as cephalins inhalation. Vaseline, paraffin oils and silicone oils; the latter include, The pharmaceutical carrier must be acceptable in the sense interalia, dialkyl- and alkylarylsiloxanes, such as dim 35 of being compatible with the other ingredients of the formu ethylpolysiloxane and methylphenylpolysiloxane, as lation and being not deleterious to the recipient thereof. The well as alkoxylated and quaternized derivatives thereof. pharmaceutical carrier employed shall be, preferably, a solid, The invention also provides the use of a formulation a gel or a liquid. Preferred pharmaceutical Solid carriers are according to the invention or of a medicament (pharmaceuti lactose, terra alba, Sucrose, talc, gelatin, agar, pectin, acacia, cal composition) according to the invention for prophylaxis 40 magnesium Stearate, Stearic acid and the like. Preferred liquid (prevention) of skin irritations and/or for treatment of skin carriers are phosphate buffered saline Solution, syrup, oil Such irritations for medical and/or other than medical purposes. It as peanut oil and olive oil, water, emulsions, various types of also relates to a medicament for the treatment of pain condi wetting agents, sterile solutions and the like. Similarly, the tions. The invention likewise provides the use of a formula carrier may include time delay material well known to the art, tion according to the invention or of a medicament (pharma 45 Such as glyceryl mono-stearate or glyceryl di-stearate alone ceutical composition) according to the invention for the or with a wax. Further suitable carriers are well known in the preparation of a medicament for treatment of skin irritations art, see, e.g., Remington’s Pharmaceutical Sciences, Mack and/or pain. Publishing Company, Easton, Pa. The invention furthermore provides the use of a formula The diluent is, preferably, selected so as not to affect the tion according to the invention or of a medicament according 50 biological activity of the combination. Preferred diluents are to the invention for the preparation of a cosmetic or pharma distilled water, physiological saline, Ringers solutions, dex ceutical formulation. trose solution, and Hank's solution. In some embodiments, in particular for medical purposes, The pharmaceutical composition or formulation, prefer it is advantageous to administer a composition according to ably, may comprise more than one of the aforementioned the present invention orally e.g. in the form of (compressed) 55 carriers or diluents as well as other components such as adju tablets, dragees, comprimates, powders, capsules, juices, vants or non-toxic, non-therapeutic, non-immunogenic stabi Solutions and granules or in form of orally consumable prod lizers and the like. ucts used for alimentation which in addition to their function A therapeutically effective dosage or amount refers to an as foodstuff provide beauty from inside. amount of trans-4-tert-butyl cyclohexanol in a pharmaceuti The invention also provides the use of a formulation 60 cal composition of the present invention which prevents, according to the invention or of a medicament (pharmaceuti ameliorates or treats the symptoms accompanying a disease cal composition) according to the invention for reducing, or condition referred to in this specification. eliminating or Suppressing the skin-irritating action of a Sub Moreover, a therapeutically effective dosage can be also stance or Substance mixture. described by the IC50 value, i.e. the amount of a therapeuti The present invention also relates to a medicament (phar 65 cally active compound which is required to achieve half of the maceutical composition) for a human being, in particular for maximum inhibition for an enzyme or signalling molecule, treatment of human skin irritation or for treating pain, com such as TRPV1 in the present case. US 9,060,943 B2 29 30 The dosage regimen will be determined by the attending tion, such as skin inflammation or irritation. Preferably, the physician and other clinical factors; preferably in accordance said pain condition is selected from the group consisting of with any one of the above described methods. As is well Somatic pain, inflammatory pain, visceral pain, neuropathic known in the medical arts, dosages for any one patient pain, dental pain, general headache, migraine, cluster head depends upon many factors, including the patient's size, body ache, mixed-vascular and non-vascular syndromes, tension Surface area, age, sex, time and route of administration, gen headache, general inflammation, neurogenic inflammation, eral health, and other drugs being administered concurrently. irritation, arthritis, rheumatic diseases, osteoarthritis, inflam Progress can be monitored by periodic assessment. matory bowel disorders, depression, anxiety, inflammatory The pharmaceutical composition referred to herein are eye disorders, inflammatory or unstable bladder disorders, administered at least once in order to treat or ameliorate or 10 psoriasis, skin complaints with inflammatory components, prevent a disease or condition recited in this specification. chronic inflammatory conditions, inflammatory pain and However, the said pharmaceutical compositions may be associated hyperalgesia and allodynia, neuropathic pain and administered more than one time, for example from one to associated hyperalgesia and allodynia, diabetic neuropathy four times daily up to a non-limited number of days. pain, causalgia, sympathetically maintained pain, deafferen The pharmaceutical composition of the present invention 15 tation syndromes, asthma, epithelial tissue damage or dys can be formulated as a capsule, Sachet, cachet, paper or other function, herpes simplex, disturbances of visceral motility at suitable container or vehicle. The resulting formulations are respiratory, genitourinary, gastrointestinal or vascular to be adapted to the mode of administration, i.e. in the forms regions, wounds, burns, allergic skin reactions, pruritus, viti of tablets, capsules, Suppositories, solutions, Suspensions or ligo, general gastrointestinal disorders, gastric ulceration, the like. Dosage recommendations shall be indicated in the duodenal ulcers, diarrhea, gastric lesions induced by necro prescribers or users instructions in order to anticipate dose tising agents, hair growth, vasomotor or allergic rhinitis, adjustments depending on the considered recipient. The bronchial disorders and bladder disorders. aforementioned carriers or diluents may be present in From the above, it follows that trans-4-tert-butyl cyclohex amounts of 1 to 99% weight (w/w) or even more, preferably anol is applied in a method for treating or preventing a pain of 10 to 80% weight (w/w) based on the total weight of the 25 condition in a subject suffering therefrom comprising admin envisaged composition. The required amounts of the Sub istering a therapeutically effective amount of trans-4-tert stances or additives can be determined by those skilled in the butyl cyclohexanol to the said subject. art without furtherado, e.g. by trial and error, dependent on Advantageously, it has been found in the studies underly the envisaged formulation and its application provided that ing the present invention that trans-4-tert-butyl cyclohexanol the formulation provides a therapeutically effective dosage of 30 can be successfully applied for treating pain conditions and trans-4-tert-butyl cyclohexanol as discussed above. symptoms accompanied therewith, in particular, the pain con Moreover, trans-4-tert-butyl cyclohexanol can be adminis ditions mediated by receptor TRPV1. Specifically, antagonis tered in combination with other Substances, such as drugs or tic activity for TRPV1 was demonstrated in cell culture for cosmetic agents, either in a common pharmaceutical compo trans-4-tert-butyl cyclohexanol. sition or as separated pharmaceutical compositions wherein 35 The present invention also relates to the use of trans-4-tert said separated pharmaceutical compositions may be provided butyl cyclohexanol for the manufacture of a pharmaceutical in form of a kit of parts. composition for treating or preventing a pain condition as The present invention also contemplates trans-4-tert-butyl well as to a method for treating or preventing a pain condition cyclohexanol to be used for treating or preventing a pain in a human being Suffering therefrom comprising administer condition or the use of trans-4-tert-butyl cyclohexanol for the 40 ing a therapeutically effective amount of trans-4-tert-butyl manufacture of a pharmaceutical composition for treating or cyclohexanol to said human being, wherein said pain condi preventing a pain condition. tion preferably is selected from the group consisting of The present invention thus also relates to trans-4-tert-butyl Somatic pain, inflammatory pain, visceral pain, neuropathic cyclohexanol for treating or preventing a pain condition. pain, dental pain, general headache, migraine, cluster head The term “pain condition' as used herein refers to an 45 ache, mixed-vascular and non-vascular syndromes, tension unpleasant sensory and emotional experience associated with headache, general inflammation, arthritis, rheumatic dis actual or potential tissue damage or described in terms of such eases, osteoarthritis, inflammatory bowel disorders, depres damage. The said experience is caused by Stimulation of Sion, anxiety, inflammatory eye disorders, inflammatory or specific nerve sensors also called nociceptors. Pain is a unstable bladder disorders, psoriasis, skin complaints with defense reaction of the body which also triggers or encom 50 inflammatory components, chronic inflammatory conditions, passes biological counteractions, i.e. a pain condition is char inflammatory pain and associated hyperalgesia and allo acterized by efferent as well as afferent nervous actions. The dynia, neuropathic pain and associated hyperalgesia and allo vanilloid receptor TRPV1 plays a central role as multiple pain dynia, diabetic neuropathy pain, causalgia, sympathetically stimuli integrator. The receptor is a nonselective cation chan maintained pain, deafferentation syndromes, asthma, epithe nel found in polymodal sensory neurons. It can be activated 55 lial tissue damage or dysfunction, herpes simplex, distur by various physical or chemical pain stimuli such as heat, bances of visceral motility at respiratory, genitourinary, gas noxious compounds or inflammatory molecules (see SZallasi trointestinal or vascular regions, wounds, burns, allergic skin in Nature Rev Drug Discovery 2007, 6:357-372; Patapoutian reactions, pruritus, vitiligo, general gastrointestinal disor in Nature Rev Drug Discovery 2009, 8: 55–68). Inhibition of ders, gastric ulceration, duodenal ulcers, diarrhea, gastric TRPV1 was shown to be efficient in pain treatment (WO 60 lesions induced by necrotising agents, hair growth, vasomo 2006/031852, WO 2007/076104, US 2005/0176726). tor or allergic rhinitis, bronchial disorders and bladder disor Accordingly, a pain condition according to the present inven ders. tion, preferably, refers to a disease or disorder involving sen A further aspect of the present invention relates to formu sory nerve action mediated by TRPV1. lations according to the invention in the form of oral care A pain condition according to the present invention, thus, 65 products (oral hygiene products), wherein the oral care prod may be a sensory experience of "classical” pain in the central uct is preferably in the form of toothpaste, dental cream, nervous system but also a pain associated neurogenic reac dental gel, dental powder, tooth-cleaning liquid, tooth-clean US 9,060,943 B2 31 32 ing foam, mouthwash, dental cream and mouthwash as a Formulations according to the invention (in particular 2-in-1 product, Sweet for Sucking, mouth spray, dental silk or those which are in the form of an oral care product) preferably dental care chewing gum. The activity of the formulations additionally comprise one or more aroma and/or flavouring according to the invention also manifests itself remarkably Substances, such as essential oils and extracts, tinctures and well in the field of oral hygiene. A bad breath-reducing activ balsams, such as, for example, anisole, basil oil, bergamotoil, ity of the formulations according to the invention has more bitter almond oil, camphor oil, citronella oil, lemon oil: Euca over been found in our own studies. lyptus citriodora oil, eucalyptus oil, fennel oil, grapefruit oil, Dental care compositions (as a preferred example of an oral ginger oil, camomile oil, spearmint oil, caraway oil, lime oil, care product according to the invention) in general comprise mandarin oil, nutmeg oil (in particular nutmeg blossom an abrasive system (abrasive or polishing agent). Such as e.g. 10 oilmaces oil, mace oil), myrrh oil, clove oil, clove blossom silicas, calcium carbonates, calcium phosphates, aluminium oil, orange oil, oregano oil, parsley (seed) oil, peppermint oil, oxides and/or hydroxyapatites, Surface-active Substances, rosemary oil, sage oil (clary sage, Dalmatian or Spanish sage Such as e.g. sodium lauryl Sulfate, sodium lauryl sarcosinate oil), star aniseed oil, thyme oil, Vanilla extract, juniper oil (in and/or cocamidopropyl betaine, moisture-retaining agents, 15 particular juniper berry oil), wintergreen oil, cinnamon leaf Such as e.g. glycerol and/or Sorbitol, thickening agents, such oil; cinnamon bark oil, and fractions thereof, or constituents as e.g. carboxymethylcellulose, polyethylene glycols, carra isolated therefrom. geenan and/or Laponite R, Sweeteners, such as e.g. saccharin, It is of particular advantage if the formulations according to flavour correctants for unpleasant taste impressions, flavour the invention comprise at least one aroma Substance, prefer correctants for further, as a rule not unpleasant taste impres ably 2, 3,4,5,6,7,8,9, 10 or more aroma substances, chosen sions, flavour-modulating Substances (e.g. inositol phos from the following group: menthol (preferably 1-menthol phate, nucleotides, such as guanosine monophosphate, and/or racemic menthol), anethole, anisole, anisaldehyde, adenosine monophosphate or other Substances, such as anisyl alcohol, (racemic) neomenthol, eucalyptol (1,8-cin Sodium glutamate or 2-phenoxypropionic acid), cooling eol), menthone (preferably L-menthone), isomenthone (pref agents, such as e.g. menthol derivatives (e.g. L-menthyllac 25 erably D-isomenthone), isopulegol, menthyl acetate (prefer tate, L-menthylalkyl carbonates, menthone ketals, menthan ably L-menthyl acetate), menthyl propionate, carvone ecarboxylic acid amides), 2.2.2-trialkylacetic acid amides (preferably (-)-carvone, optionally as a constituent of a spear (e.g. 2,2-diisopropylpropionic acid methylamide), icilin and mint oil), methyl salicylate (optionally as a constituent of a icilin derivatives, stabilizers and active compounds. Such as wintergreen oil), eugenol acetate, isoeugenol methyl ether, e.g. sodium fluoride, sodium monofluorophosphate, tin dif 30 beta-homocyclocitral, eugenol, isobutyraldehyde, 3-octanol, luoride, quaternary ammonium fluorides, Zinc citrate, Zinc dimethyl sulfide, hexanol, hexanel, trans-2-hexenal, cis-3- sulfate, tin pyrophosphate, tin dichloride, mixtures of various hexenol, 4-terpineol, piperitone, linalool, 8-ocimenyl acetate, pyrophosphates, triclosan, cetylpyridinium chloride, alu isoamyl alcohol, isovaleraldehyde, alpha-pinene, beta minium lactate, potassium citrate, potassium nitrate, potas pinene, limonene (preferably D-limonene, optionally as a sium chloride, strontium chloride, hydrogen peroxide, aro 35 constituent of an essential oil), piperitone, trans-Sabinene mas, sodium bicarbonate and/or odour correctants. hydrate, menthofuran, caryophyllene, germacrene D, cinna Formulations according to the invention in the form of maldehyde, mint lactone, thymol, gamma-octalactone, chewing gums or dental care chewing gums comprise chew gamma-nonalactone, gamma-decalactone, (1.3E.5Z)-undec ing gum bases which comprise elastomers, such as, for atriene, 2-butanone, ethyl formate, 3-octyl acetate, isoamyl example, polyvinyl acetates (PVA), polyethylenes, (low or 40 isovalerate, cis- and trans-carvyl acetate, p-cymol, dama medium molecular weight) polyisobutenes (PIB), polybuta scenone, damascone, cis-rose oxide, trans-rose oxide, fen dienes, isobutene-isoprene copolymers (butyl rubber), poly chol, acetaldehyde diethyl acetal, 1-ethoxyethyl acetate, cis vinyl ethyl ethers (PVE), polyvinylbutyl ethers, copolymers 4-heptenal, cis-jasmone, methyl dihydrojasmonate, of vinyl esters and vinyl ethers, styrene/butadiene copoly 2'-hydroxypropiophenone, menthyl methyl ether, myrtenyl mers (styrene/butadiene rubber, SBR) or vinyl elastomers, 45 acetate, 2-phenylethyl alcohol. 2-phenylethyl isobutyrate, e.g. based on vinyl acetate/vinyl laurate, vinyl acetate/vinyl 2-phenylethyl isovalerate, geraniol, nerol and viridiflorol. Stearate or ethylene/vinyl acetate, and mixtures of the elas Particularly preferred cooling agents for oral care compo tomers mentioned, as described, for example, in EP 0 242 sitions according to the present invention comprise one or 325, U.S. Pat. No. 4,518,615, U.S. Pat. No. 5,093,136, U.S. more cooling agents selected from the group consisting of Pat. No. 5,266,336 U.S. Pat. No. 5,601,858 or U.S. Pat. No. 50 menthone glycerol acetal (trade name: Frescolat(RMGA), 6,986,709. In addition, chewing gum bases comprise further menthyl lactate (preferably 1-menthyl lactate, in particular constituents, such as, for example, (mineral) fillers, plasticiz 1-menthyl l-lactate, trade name: FrescolatrML), substituted ers, emulsifiers, antioxidants, waxes, fats or fatty oils, such as, menthyl-3-carboxylic acid amides (e.g. menthyl-3-carboxy for example, hardened (hydrogenated) plant or animal fats, lic acid N-ethylamide), 2-isopropyl-N-2,3-trimethylbutana and mono-, di- or triglycerides. Suitable (mineral) fillers are, 55 mide, 3-menthoxypropane-1,2-diol, 2-hydroxyethyl menthyl for example, calcium carbonate, titanium dioxide, silicon carbonate, 2-hydroxypropyl menthyl carbonate, isopulegol, dioxide, talc, aluminium oxide, dicalcium phosphate, trical monomenthyl Succinate and monomenthyl glutarate. cium phosphate, magnesium hydroxide and mixtures thereof. Formulations according to the invention which comprise Suitable plasticizers or agents for preventing Sticking (de 1-menthol and at least one, particularly preferably at least two tackifiers) are, for example, lanolin, Stearic acid, sodium 60 cooling Substances are preferred according to the invention. Stearate, ethyl acetate, diacetin (glycerol diacetate), triacetin The invention likewise provides a cosmetic or therapeutic (glycerol triacetate) and triethyl citrate. Suitable waxes are, method for prophylaxis of skin irritation, with the following for example, paraffin waxes, candelilla wax, carnauba wax, steps: microcrystalline waxes and polyethylene waxes. Suitable provision of a formulation according to the invention or of emulsifiers are, for example, phosphatides, such as lecithin, 65 a medicament according to the invention and and mono- and diglycerides of fatty acids, e.g. glycerol application of the formulation or of the medicament to monoStearate. non-irritated skin in an active amount. US 9,060,943 B2 33 34 The invention furthermore provides a cosmetic or thera EXAMPLE 1.1 peutic method for treatment of skin irritation, with the fol lowing steps: In Vitro Assays provision of a formulation according to the invention or of a medicament according to the invention and 5 Three samples of cis- and/or trans-4-tert-butyl cyclohex application of the formulation or of the medicament to anol were assessed: 1) 99% trans-isomer, 2) an isomeric irritated skin in an active amount. mixture enriched in the cis-isomer (59% cis, 41% trans) and The invention furthermore provides a method for prophy 3) 99% cis-isomer. laxis of the skin-irritating action or for reducing, eliminating Assay Conditions: or Suppressing the skin-irritating action of a Substance or 10 Calciumassay based on fluorescent dye Fluo-4-AM Substance mixture, with the following steps: Negative Control: KH-buffer (solvent) a) provision of a Substance or Substance mixture having a Positive Control: lonomycin (generell calcium induction) skin-irritating action, Positive Control Capsaicin (natural agonist of TRPV1) b) provision of trans-4-tert-butyl cyclohexanol or a cosmeti One day prior to performing the assay, HEK293 cells sta 15 bly overexpressing recombinant human TRPV1 were plated cally or pharmaceutically acceptable salt thereof, in particu onto black-walled assay plates, at a density of 45,000 cells per lar the Na", K", NH, Mg" or Casalt, or of a composition well. Using the FLEX Station system the change of the cel or a medicament according to the invention, lular calcium concentration (calcium influx) induced by c) bringing together the Substances of a) and b), so that the TRPV1 activation was monitored using the calcium sensitive skin-irritating action is reduced, eliminated or Suppressed and fluorescent dye fluo-4 (494 nm/516 nm (exitation/emission)). another composition or medicament according to the inven The pharmacological TRPV1 antagonist Ruthenium Red (1 tion is formed. uM) was used as positive control J. Biol. Chem. 2004, 279 The present invention also relates to the use of a formula (34): 35741-8). The dye-loaded stable cells in plates were tion, a product or a medicament according to the present placed into the fluorescence microtiterplate reader to monitor invention 25 fluorescence (excitation 488 nm, emission 520 nm) change for prophylaxis of skin irritation and/or for treatment of after the addition of 50 ul assay buffer (118 mM NaCl; 4.7 skin irritation for medical and/or other than medical mM KCl; 1.2 mM MgSO; 1.2 mM KHPO; 4.2 mM purposes, and/or NaHCOs; 1.3 mM CaCl; 10 mM HEPES (N-(2-hydroxy for reducing, eliminating or Suppressing the skin-irritating ethyl)-piperazine-N'-2-ethanesulfonic acid) (pH: 7.4)) action of a Substance or Substance mixture. 30 Supplemented with an antagonist. Calcium mobilization was One advantage of the method according to the invention quantified as the change of peak fluorescence (AF) over the mentioned last is that the skin-irritating action of substances baseline level (F). The analysis was done with the software of or Substance mixtures can be moderated in this way to the the microtiter plate reader (FLEX Station). Potential TRPV1 extent that they are accessible for uses for which they were antagonists were tested at an effective range of 0.5-50 uM. hitherto not available. On the basis of the method according to 35 The test compounds were either applied in parallel to 30 nM the invention mentioned last, higher concentrations of skin capsaicin or 10 min prior to the agonist. TRPV1 antagonists irritating Substances and Substance mixtures can also be were tested for their antagonistic activity in the presence of 30 employed in uses where there is the possibility of skin con nM capsaicin, which is the ECso effective capsaicin concen tact. In this context, it is particularly preferable if, on the basis tration leading to 80% of the maximum capsaicindependent of the method according to the invention mentioned last, the 40 TRPV1 activation. skin-irritating action of the skin-irritating compound is elimi nated completely (i.e. it no longer exists) or is Suppressed EXAMPLE 1.1A completely (i.e. it no longer has an effect). The method according to the invention mentioned last can be employed, Antagonistic efficacy of the isomers of 4-tert-butyl cyclo for example, against the skin-irritating action of detergents 45 hexanol on transient receptor potential ion channel 1 in cell and allergy-inducing Substances. based fluorescent analysis. Preferred embodiments and further aspects of the present The three samples were tested for TRPV1 antagonism at invention emerge from the attached patent claims and the parallel application with capsaicin as agonist. Sample 1, i.e. following examples, the examples not being intended to limit the pure trans-isomer was significantly more active the invention. Unless indicated otherwise, all data, in particu 50 (ICs 34.1 uM) than sample 2) (ICso 86.9 uM), whereas lar percentages, refer to the weight. sample 3), i.e. the pure cis-isomer, was inactive. Unless indicated otherwise racemic trans-4-tert-butyl cyclohexanol (purity >96 wt.%, amount of racemic cis-iso EXAMPLE 1.1.B mer.<4 wt.%) was used in the following examples, obtainable as described in Organic Syntheses Collective Volume 5, 175 55 TRPV1 antagonist in vitro at incubation prior to capsaicin: 178, Wiley, New York, 1973 or J. Am. Chem. Soc. 1955, 77, cis-4-tert-butyl cyclohexanol and trans-4-tert-butyl cyclo 5562-5578. hexanol were applied to HEK293 cells 10 min before capsai cin treatment. EXAMPLE1 The sequence of application of antagonist and agonist can 60 significantly influence the antagonist efficacy Mol. Pharma In Vitro Assays and In Vivo Testing col. 2006, 69(4): 1166-73). We therefore additionally tested the pure cis- and trans-isomers of 4-tert-butyl cyclohexanol A commercially available mixture consisting of 28% cis respectively in a pre-incubation mode with application of the 4-tert-butyl cyclohexanol and 72% trans-4-tert-butyl cyclo respective isomer 10 min before addition of capsaicin. How hexanol was purified via preparative HPLC to obtain the 65 ever, this experiment did not reveal any difference to the essentially pure cis- and trans-isomers of 4-tert-butyl cyclo parallel incubation mode and it was confirmed that the cis hexanol. isomer was not active. US 9,060,943 B2 35 36 EXAMPLE 1.2 Formulation Examples 1-10: Formulations comprising trans 4-tert-butyl cyclohexanol according to the present invention In Vivo Testing having a skin irritation-reducing action A study was performed with 9 volunteers who were sensi Formulation Example 1: Skin-lightening day cream O/W tive to capsaicin. A freshly prepared solution of 31.6 ppm Formulation Example 2: Skin-soothing lotion with plant capsaicin (which proved to be the most appropriate concen extracts Of W tration: clear stinging perception without erythema or burn feeling) in PBS (phosphate buffered saline) was applied to the Formulation Example 3: Aftersun Balm left and right upper cheekbone area with a cotton tip with Formulation Example 4: Body Spray Smooth rubbing. After 60 seconds all participants sensed a 10 pronounced stinging effect. Then, an O/W-emulsion with 1 Formulation Example 5: Sunscreen lotion (O/W), broad wt.% racemic trans-4-tert-butyl cyclohexanol (purity >99 wt. band protection %) was applied on one cheek and the placebo O/W-emulsion Formulation Example 6: W/O night cream on the other cheek (blinded samples). The stinging effect was Formulation Example 7: Shampoo evaluted 5 minutes later on the following scale: 0 (no effect), 15 1 (stinging slightly reduced), 2 (stinging moderately Formulation Example 8: Self-Tanning Cream reduced), 3 (stinging strongly reduced by still Some stinging Formulation Example 9: Barrier repair cream O/W perceptible), and 4 (stinging completely suppressed). The TRPV1 antagonist (trans-4-tert-butyl cyclohexanol) Formulation Example 10: Antiperspirant/deodorant roll-on was rated an average of 3.10 on said scale (for placebo: 0.25) The following Fragrance “WHITE was used in Formulation and inhibited the stinging sensation with very high signifi Examples 1-10: cance (p<0.000013). Fragrance “WHITE: Perfume Oil with White Blossom EXAMPLE 1.3 Smell Clinical Studies 25 A study was performed with 20 volunteers who were sen Parts by sitive to capsaicin. The following freshly prepared mixtures Component/NAME weight were assessed by application to the nasolabial fold (blinded Benzyl acetate 60.00 30 samples): c1-O/W-emulsion comprising 31.6 ppm capsaicin, Citronellyl acetate 60.00 c2-O/W-emulsion comprising 31.6 ppm capsaicin and 1 wt. Cyclamene aldehyde (2-methyl-3-(4-isopropylphenyl)propanal 2O.OO % racemic trans-4-tert-butyl cyclohexanol (purity >99 wt.%) Dipropylene glycol (DPG) 60.00 and control PBS. On day 1 sample c2 was assessed versus Ethyl linalool 40.00 control. On day 2 sample c1 was assessed versus control. The 35 Florol (2-isobutyl-4-methyltetrahydro-2H-pyran-4-ol) 3O.OO stinging and burning effects were evaluted 3 minutes later on Globanone (E,Z)-8-cyclohexadecen-1-one 18O.OO the same scale as in Example 1.2. Hedione (methyldihydrojasmonate) 140.00 The TRPV1 antagonist (trans-4-tert-butyl cyclohexanol) Hexeny Isalicylate, cis-3 1O.OO was rated an average of 2.95 on said scale (for placebo: 0.35) and inhibited/reduced both stinging and burning sensation Vertocitral (2,4-dimethyl-3-cyclohexene carboxaldehyde) S.OO with high significance (p<0.001). The rating for trans-4-tert 40 Hydratropa aldehyde, 10% in DPG S.OO butyl cyclohexanol regarding inhibition/reduction for the Sodamascone (1-(2,4,4-trimethyl-2-cyclohexen-1-yl)-2-buten-1- S.OO Sum of all sensations stinging, burning, tingling, tickling and one, 10% in DPG skin tightness were confirmed with very high significance Somuscone (cyclohexadecanone) 40.00 (p<0.0001). acinthaflor (2-methyl-4-phenyl-1,3-dioxolane) 1O.OO Similar results were obtained when using a skin whitening 45 Cis-jasmone, 10% in DPG 2O.OO agent (a resorcinol derivative described e.g. in WO 2007/ Linalool SO.OO 077260) instead of capsaicin as agonist, which induced a Linallylacetate 3O.OO stinging sensation on the sensitive skin of the 20 volunteers Methylbenzoate, 10% in DPG 2S.OO who participated in this study. para-methyl cresol, 10% in DPG 1O.OO 50 Nerol 2O.OO Phenylpropyl aldehyde S.OO 2-Phenylethyl alcohol 82.OO EXAMPLE 2 Tetrahydrogeraniol 13.00 55 2,2-dimethyl-3-cyclohexyl-1-propanol 80.00 Concentrated Compositions According to the Present Invention

CC-1 CC-2 CC-3 CC-4 CC-5 CC-6 CC-7 (wt.%) (wt.%) (wt.%) (wt.%) (wt.%) (wt.%) (wt.%) trans-4-tert-butyl cyclohexanol 22.50 33.33 3O.OO 38.50 2S.OO 35.50 28SO 1.2-butylene glycol 77.50 31.50 1.2-pentanediol 66.67 3S.OO 75.00 SO.OO 40.00 1.2-hexanediol 3S.OO 14.50 dipropylene glycol 61. SO US 9,060,943 B2 37 38

RAW MATERIAL NAME % BY WEIGHT FORMULATION EXAMPLE

(MANUFACTURER) INCI 1 2 3 4 5 6 7 8 9 10 trans-4-tert 1.O O.8 1.1 O4 0.55 1.75 O.3 1.O 1.25 0.75 butyl cyclohexanol -(-Alpha-)- Bisabolol O.3 O.1 O.3 O.2 O.1 Bisabolol, natural (Symrise) Ginger CO, Zingiber Extract Officinale (Flavex) (Ginger) Root Extract Abi 350 Dimethicone O.S 2.0 1.O O.S O.S (Degussa Goldschmidt) Allantoin Allantoin O.2 O.1 O.25 (Merck) Aloe Vera Water (Aqua), 3.0 3.0 O45 Gel Aloe Concentrate Barbadensis 10.1 Leaf Juice (Symrise) Alugel 34TH Aluminium 1.O (Baerlocher) Stearate Aqua Cetyloxypropyl O.1 O.1 Ceramide Glyceryl (Kao) Methoxypropyl Myristamide Arbutin B-Arbutin O.2 (Sabinsa) 4-(1- phenylethyl)- 1,3- benzenediol Sodium Sodium 2.0 1.O Ascorbyl Ascorbyl Phosphate Phosphate (EMD Chemicals) Butylene Butylene S.O Glycol Glycol Carbopol Carbomer O.2 ETD 2050 (Noveon) Carbopol Carbomer O.1 Ultrez-10 (Noveon) Ceramide 2 Ceramide 2 O.1 (Sederma) Ceramide Hydroxypropyl O.1 PC104 Bispalmitamide (Pacific MEA Corporation) Ceramide SL Hydroxyethyl O.1 (Sino Lion) Palmityl Oxyhydroxypropyl Palmitamide Cetiol OE Dicaprylyl 4.0 (Cognis) Ether Cetiol SB 45 Butyrospermain 1.O (Cognis) Parkii (Shea Butter) Citric Acid Citric Acid O.3 10%. Sol. Comperlan Cocamide O.S 100 (Cognis) ME Dihydroxyacetone Dihydroxyacetone S.O (Merck) Dow Corning Cyclohexasiloxane 2.0 246 Fluid and (Dow Cyclopentasiloxane Corning) US 9,060,943 B2 39 40 -continued

RAW MATERIAL NAME % BY WEIGHT FORMULATION EXAMPLE (MANUFACTURER) INCI 1 3 4 5 6 7 8 9 10 Dow Corning Cyclomethicone O.S 345 Fluid (Dow Corning) D-Panthenol Panthenol 1.O (BASF) Dracorin CE Glyceryl S.O S.O 1.5 (Symrise) Stearate Citrate Dracorin Glyceryl 2.0 2.O GMS Stearate (Symrise) Dracorin Glyceryl 2.0 GOC Oleate Citrate, (Symrise) Caprylic Capric Triglyceride Drago-Beta Water (Aqua), O.3 Glucan Butylene (Symrise) Glycol, Glycerin, Avena Saiiva (Oat), Kernel Extract Dragocid Phenoxyethanol, 0.7 0.7 O.8 O.8 Liquid Methylparaben, (Symrise) Ethylparaben, Butylparaben, Propylparaben, Isobutylparaben Dragoderm Glycerin, 2.0 (Symrise) Trictim

Gluten, Water (Aqua) Drago-Oat Water (Aqua), 1.O Active Butylene (Symrise) Glycol, Avena Saiva (Oat) Kernel Extract Dragosan Polyglyceryl 1.O W/O Liquid (Symrise) Polyricinoleate, Sorbitan SOStearate Dragosan Sorbitan 6.O WOP SOstearate, (Symrise) Hydrogenated Castor Oil, Ceresin, Beeswax (Cera Alba) Dragoxat EH Ethylhexyl 3.0 3.0 4.0 3.0 (Symrise) hylhexanoate Dragoxat 89 hylhexyl 2.O (Symrise) hylisononanoate EDETAB Tetrasodium O.1 Powder EDTA (BASF) EDETADB Disodium O.1 O.1 (BASF) EDTA Emulsiphos Potassium 2.0 1.5 2.O (Symrise) Cetyl Phosphate, Hydrogenated Palm Glycerides Ethanol.96% Ethanol 2.0 Extrapone G ycerin, Green Tea Water (Aqua), GW Cameia (Symrise) Sinensis Leaf Extract US 9,060,943 B2 41 42 -continued

RAW MATERIAL NAME % BY WEIGHT FORMULATION EXAMPLE (MANUFACTURER) INCI 2 3 4 5 6 7 8 9 10 Extrapone Propylene 1.O Witch Hazel Glycol, Distillate Hamameis colourless Virginiana (Symrise) (Witch Hazel) Water, Water (Aqua), Hamameis Virginiana (Witch Hazel) Extract Extrapone Glycerin, O.3 O.S Rosemary Water (Aqua), GW Rosmarinus (Symrise) officinalis (Rosemary) Leaf Extract Farnesol Farnesol O.S (Symrise) Frescolat Menthone O.3 MGA. Glycerol (Symrise) Acetal Frescolat ML Menthyl O.8 O.2 cryst. Lactate (Symrise) Genapol Sodium 37.0 LRO liquid Laureth (Cognis) Sulfate Givobio GZN Zinc O.S (Seppic) Gluconate Glycerol 85% Glycerin 3.0 2.0 4.0 4.7 2.0 1.5 3.0 Hydrolite-5 Pentylene S.O 3.5 (Symrise) Glycol Hydroviton Water, 1.O (Symrise) Glycerin, Sodium Lactate, TEA Lactate, Serine, Lactic Acid, Urea, Sorbitol, Sodium Chloride, Lauryl Diethylenedi aminoglycine, Lauryl Aminopropyl glycine, Allantoin rgasan DP Triclosan O.3 300 (Ciba Geigy) Sodragol Trisononanoin 2.0 3.0 (Symrise) Sopropyl Isopropyl 4.0 4.0 palmitate Palmitate (Symrise) Karion F Sorbitol 2.0 (Merck) Keltrol RD Xanthan Gum O.1 (CP-Kelco) Keltrol T Xanthan Gum O.2 O.3 (Danby Chemie) Kojic acid Kojic Acid 1.O (Cosmetochem) Lanette 16 Cetyl Alcohol 1.O 1.O (Cognis) Lanette O Cetearyl 3.0 1.O 2.O (Cognis) Alcohol Lara Care A Galactoarabinan O.3 200 (Rahn) US 9,060,943 B2 43 44 -continued

RAW MATERIAL NAME % BY WEIGHT FORMULATION EXAMPLE (MANUFACTURER) INCI 1 4 5 6 7 10 Magnesium Magnesium 0.7 Chloride Chloride (Merck) Merquat 550 Polyguaternium-7 (Ondeo Nalco) NaOH 10% Sodium Sol. Hydroxide Naringin 4,5,7- 2.0 (Exquim) Trihydroxyflavone7 O Neohesperidoside Sodium Sodium benzoate Benzoate Natrosol 250 Hydroxyethyl HHR cellulose

Butyl 1.O Methoxy dibenzoyl

10 Phenyl Dibenzimidazole Tetrasulfonate odium salt) Ethylhexyl S.O 3.0 iopan AV Methoxy ymrise) cinnamate (O Phenylbenz 6.7 eliopan imidazole sydro Sulfonic Acid Symrise) 5% as odium salt) Neo 4 1.5 Heliopan Methylbenzyl MBC idene (Symrise) Camphor Neo Ethylhexyl Heliopan OS Salicylate (Symrise) Neutral Oil Caprylic Capric 6.O 4.0 2.0 6.O Triglyceride Oxynex 2004 BHT O.1 (Merck) Paraffin oil 5 Paraffinum 4.0 Grade E Liquidum (Parafluid) PCL Liquid Cetearyl 3.0 7.0 OO Ethylhexoate (Symrise) PCL Solid Stearyl 2.0 (Symrise) Heptanoate, Stearyl Caprylate PCL-Liquid Cetearyl 12.O 3.0 (Symrise) Ethylhexanoate, Sopropyl Myristate Pemulen TR Acrylates/C10-30 O.3 2 (Noveon) Alkyl Acrylate Crosspolymer 4-(1- 4-(1- O.S Phenylethyl)- Phenylethyl)- 1,3- 1,3- benzenediol benzenediol 1,2- Propylene Propylene Glycol Glycol 99P GC US 9,060,943 B2 45 46 -continued

RAW MATERIAL NAME % BY WEIGHT FORMULATION EXAMPLE

(MANUFACTURER) INCI 2 3 4 5 6 7 8 10 Pseudo N-(1- O.1 O.2 ceramide Hexadecanoyl)- 391 4-hydroxy-L- proline (1- hexadecyl)ester Retinyl Retinyl O.2 Palmitate in Palmitate Oil (DSM Nutrional Products) Sepigel 305 Polyacrylamide, 1.O C13-14 Isoparaffin, Laureth-7 Sodium Sodium 1.O Chloride Chloride Sodium Sodium O.3 O.6 0.4 Hydroxide Hydroxide (10% sol.) Solubilizer PEG-40 2.0 611674 Hydrogenated (Symrise) Castor Oil, Trideceth-9, Water (Aqua) Sun Flower Heianthus S.O Oil (Wagner) Anniitis (Sunflower) Seed Oil Sweet Prunus duticis 5.0 Almond Oil (Wagner) SymMatrix Maltodextrin, O.1 O.3 1.O (Symrise) Rubus Frticostis (Blackberry) Leaf Extract Symdiol 68 1,2- (Symrise) Hexanediol, Caprylylglycol Fragrance Fragrance O.3 O.3 O.3 O.2 0.4 0.4 O.S O.3 O.3 1.O WHITE (Symrise) Tamasterol Phytosterols (Tama Biochemicals) Tego Betain Cocamidopropyl 6.O L7 Betaine (Degussa) Tegosoft PC 31 (Degussa) Tegosoft TN C12-15 Alkyl S.O S.O (Degussa) Benzoate Triethanolamine, Triethanolamine O.S 99% Tocopherol Tocopheryl O.S O.S 3.0 Acetate Acetate (DSM Nutritional Products) Zirkonal L Aluminium 37.0 450 Zirconium (BK Giulini) Pentachloro hydrate (40% aqueous Solution) Water, Water (Aqua) to 100 to 100 to 100 to 100 to 100 to 100 to 100 to 100 to 100 to 100 demineralized US 9,060,943 B2 47 48 Formulation Examples 11-16: Oral hygiene/orally applicable Formulation Example 13: Dental cream against sensitive medicinal products teeth The following Peppermint Flavor PF1 was used in Formu lation Examples 11, 13 and 15: 5 I (%) II (%) III (%) Na carboxymethylcellulose O.70 O.70 O.70 Peppermint Flavor PF1 parts by weight Xanthan gum OSO O.SO O.SO Glycerin 1S.OO 1S.OO 1S.OO sobutyraldehyde O.S Sorbitol 70%, in water 12.00 12.00 12.00 3-Octanol O.S '' K-nitrate S.OO S.OO S.OO Dimethylsulphide O.S Na monofluorophosphate O.8O O.80 O.80 trans-2-Hexenal 1.O PHB methyl ester O.15 O.15 O.15 cis-3-Hexenol 1.O PHB propyl ester O.OS O.OS O.OS 4-Terpineol, natural 1.O Nasaccharinate O.2O O.20 O.20 Sopulegol 1.O 15 Peppermint flavor PF1 1.OO 1.OO 1.OO Piperitone, natural, from eucalyptus 2.0 trans-4-tert-butyl cyclohexanol OSO O.90 1...SO Linalool 3.0 Ca-carbonate 3S.OO 35.00 35.00 8-Ocimenyl acetate, 10% in triacetin S.O Silicon dioxide 1.OO 1.OO 1.OO Soamyl alcohol 1O.O Sodium dodecyl sulfate (SDS) 1...SO 1...SO 1...SO sovaleraldehyde 1O.O 20 Dist. water to 100.00 to 100.00 to 100.00 alpha-Pinene, natural 2SO beta-Pinene, natural 2SO Neomenthol, racemic 40.O Formulation Example 14: Ready-to-use mouthwash with Eucalyptol (1,8-cineol), natural SO.O fluoride L-Menthyl acetate of the formula D 7O.O 25 L-Menthone 22O.O D-Isomenthone SO.O I (%) II (%) III (%) L-Menthol 483.5 Nonenolide 1.O Ethanol 7.00 7.00 7.OO Glycerin 12.00 12.00 12.00 30 Na fluoride O.OS O.OS O.OS Pluronic F-127 (R) (BASF, 140 140 140 Formulation Example 11: Gel dental cream Surface-active Substance) Naphosphate buffer pH 7.0 1.10 1.10 1.10 Sorbic acid O.20 O.20 O.20 Nasaccharinate O.10 O.10 O.10 - I (9. III (9 III (9 - 35 Cinnamonmenthol aroma O.15 O.15 O.15 Na carboxymethylcellulose O4O O.40 O4O trans-4-tert-butyl cyclohexanol O.425 O.65 O.90 Sorbitol 70%, in water 72.OO 72.OO 72.OO Dyestuff O.O1 O.O1 O.O1 Polyethylene glycol (PEG) 1500 3.00 3.00 3.00 Dist. water to 100 to 100 to 100 Nasaccarinate O.O7 O.O7 O.O7 Na fluoride O.24 O.24 O.24 p-Hydroxybenzoic acid (PHB) ethyl O.15 O.15 0.15 40 Formulation Example 15: Sugar-free chewing gum ester Peppermint flavor PF1 1.OO 1.00 1.OO trans-4-tert-butyl cyclohexanol OSO O.90 1...SO Abrasive silica 11.00 11.00 11.00 I (%) II (%) III (%) Thickening silica 6.OO 6.OO 6.OO - - - - - Sodium dodecyl sulfate (SDS) 140 140 140 Chewing gum base 3O.OO 30.00 30.00 Dist. water to 100.00 to 100.00 to 100.00 45 Sorbitol, powder Ad 100.00 Ad 100.00 Ad 100.00 Palatinite 9.SO 9.SO 9.SO Xylitol 2.OO 2.OO 2.OO Mannitol 3.00 3.00 3.00 Formulation Example 12: Dental cream against plaque Aspartame O.10 O.10 O.10 Acesulfame K O.10 O.10 O.10 50 Emulgum, emulsifier O.30 O.30 O.30 I (%) II (%) III (%) Sorbitol 70%, in water 14.00 14.00 14.00 Glycerin 1.OO 1.OO 1.OO Carrageenan O.90 O.90 O.90 Peppermint flavor PF1 1...SO 1...SO 1...SO Glycerin 1S.OO 1S.OO 1S.OO trans-4-tert-butyl cyclohexanol OSO O.90 1...SO Sorbitol 70%, in water 2S.OO 25.00 2S.OO PEG 1 OOO 3.00 3.00 3.00 55 Na fluoride O.24 O.24 O.24 Formulation Example 16: Gelatine capsules for direct con Tetrapotassium diphosphate 4...SO 4SO 4...SO Sumntion Tetrasodium diphosphate 1...SO 1...SO 1...SO p Nasaccarinate O4O O.40 O4O Precipitated silica 2O.OO 2O.OO 2O.OO Titanium dioxide 1.OO 1.00 1.OO 60 I (wt.%) II (wt.%) III (wt.%) PHB methyl ester O.10 O.10 O.10 Spearmint flavor (comprising 60 wt. 1.OO 1.10 1.2O Gelatine shell: % I-carvone and 25 wt.% - menthol) Glycerin 2014 2014 2014 trans-4-tert-butyl cyclohexanol OSO O.90 1...SO Gelatine 240 Bloom 7.91 7.91 7.91 Sodium dodecyl sulfate 1.30 1.30 1.30 Sucralose O.06S O.06S O.06S Dist. water to 100.00 to 100.00 to 100.00 65 Allura Red O.OO6 O.OO6 O.OO6 Brilliant Blue O.OOS O.OOS O.OOS US 9,060,943 B2

-continued -continued

I (wt.%) II (wt.%) III (wt.%) 18 19 2O 21 Core composition: Yoghurt (1.5 wt.% fat) Ad 100 Water Ad 100 Plant oil triglyceride 82.OO 74.OO 60.00 Aroma B 7.85 15.50 28.50 Formulation Examples 22-31: Formulations comprising trans-4-tert-butyl cyclohexanol O.SO O.90 1...SO trans-4-tert-butyl cyclohexanol according to the present Aroma Bhere had the following composition (data in each case in wt.%); 10 invention having a skin irritation-reducing action 0.1% neotame powder, 0.05% aspartame, 29.3%peppermint oilarvensis, 29.3% peppermint Formulation Example 22: "Oil-in-water emulsion with UV piperita oil Willamette, 2.97% sucralose, 2.28% triacetin, 5.4% diethyl tartrate, 12.1% NB-broadband protection peppermint oil yakima, 0.7% ethanol, 3.36% 2-hydroxyethyl menthyl carbonate, 3.0% 2-hydroxypropyl menthyl carbonate, 0.27% vanillin, 5.5% D-limonene, 5.67%L-menthyl Formulation Example 23: "Oil-in-water emulsion with UV acetate, NB-broadband protection Formulation Example 24: Sun spray with UV-NB-broadband The gelatine capsule, which is suitable for direct consump 15 protection with low oil content tion, had a diameter of 5 mm, and the weight ratio of core Formulation Example 25: Skin-lightening balm with UV-A/ material to shell material was 90:10. The capsules opened in UV-B protection the mouth within less than 10 seconds and dissolved com Formulation Example 26: Skin-lightening aerosol foam with UV-B/UV-A protection pletely within less than 50 seconds. Formulation Example 27: Skin-lightening non-aerosol foam Formulation Example 17: Compressed tablets Formulation Example 28: Shampoo with skin-lightening properties Formulation Example 29: Skin-lightening hair conditioner I (wt.%) II (wt.%) III (wt.%) with UV-B/UV-A protection Magnesium stearate (as lubricant) O.90 O.90 O.90 25 Formulation Example 30: Skin-lightening moisturizing Citric acid O.20 O.20 O.20 cream O/W trans-4-tert-butyl cyclohexanol O.SO O.90 1...SO Formulation Example 31: Skin-lightening face cream O/W Dextrose Ad 100 Ad 100 Ad 100 The following Fragrance“ROSE was used in Formulation Examples 22-31: Fragrance “ROSE: Perfume Oil with Rose Smell Formulation Example 18: Instant beverage mix 30 Formulation Example 19: Sugar-Free Instant Beverage Mix Parts by Formulation Example 20: Soja-Fruit Drink Component/NAME weight Formulation Example 21: Low-Fat Yoghurt 35 Acetophenone, 10% in DPG 10.00 n-undecanal S.OO Aldehyde C14 so-called (peach aldehyde) 1S.OO 18 19 2O 21 Allylamylglycolate, 10% in DPG 2O.OO Amyl Salicylate 25.00 trans-4-tert-butyl 3.25 4.40 OSO O.85 Benzyl acetate 60.00 cyclohexanol Citronellol 80.00 Sugar (Sucrose) Ad 100 40 d-limonene SO.OO Citric acid 4.OO 33.33 Decenol trans-9 S.OO Trisodium citrate O.26 Dihydromyrcenol SO.OO Tricalcium phosphate O.22 Dimethylbenzylcarbinyl acetate 30.00 Ascorbic acid (vitamin C) O.24 0.44 Diphenyloxide S.OO Clouding agent and titanium O.20 Eucalyptol O.OO dioxide (E 171) 45 Geraniol 40.00 Xanthan gum (E415) O.O72 Nerol 2O.OO Sodium carboxy methyl O.064 Geranium oil S.OO cellulose (E467) Hexenol cis-3, 10% in DPG S.OO Pectin (E440) O.04 Hexenyl salicylate cis-3 2O.OO Spray-dried lemon and O.40 indole, 10% in DPG O.OO orange flavour, including 50 Alpha-ionone S.OO yellow colorant tartrazine Beta-ionone S.OO Spray-dried raspberry 11...SO Lilial (2-methyl-3-(4-tert-butyl-phenyl)propanal) 60.00 flavor, including red colorant Linalool 40.00 Maltodextrin (powder) Ad 100 Methylphenylacetate O.OO Aspartame 3.30 Phenylethyl alcohol 275.00 Saccharose 6.O S.O Styrallyl acetate 2O.OO Vanilla flavour O.10 O.12S Terpineol 30.00 Mixture of fruit juice 4S.O Tetrahydrolinalool SO.OO concentrates Cinnamyl alcohol 10.00 Soja powder S.O

RAWMATERIALNAME (MANUFACTURER) INCI 22 23 24 25 26 27 28 29 30 31

Trans-4-tert-butyl 1.OS O.9S O3S O.25 1.25 cyclohexanol US 9,060,943 B2 51 -continued

RAW MATERIALNAME (MANUFACTURER) INCI 22 23 24 25 26 27 28 29 30 31 Trans-4-tert-butyl 3.0 1.20 2.75 cyclohexanol as part of CC-2 according to Example 2 Trans-4-tert-butyl 1.15 cyclohexanol as part of CC-3 according to Example 2 Trans-4-tert-butyl 1.OS 1.00 cyclohexanol as part of CC-4 according to Example 2 Skin lightener

4-(1-Phenylethyl)- 3.0 O.OS O2 1.O O.S O.2 ,3-benzenediol 4-Butylresorcinol O.OS 1.O beta-Arbutin Arbutin O.2 Kojic acid Kojic Acid O.S 1.O Liquorice extract 2.0 Mgascorbyl Magnesium Ascorbyl 3.0 phosphate phosphate Niacinamide 1.O Soya extract 1.O 1.O Oil components

Abil 100 (R) Dimethicone 1.O O.3 1.O 2.0 O.3 (Goldschmidt) Cetiol OE (Cognis) Dicaprylyl Ether 3.0 Corapan TQ (R) Diethylhexyl 2,6- 2.O (Symrise) Naphthalate Dragoxat EH Ethylhexyl 1.0 1.0 (Symrise) Ethylhexanoate Isoadipate (Symrise) Diisopropyl Adipate 1.O Isopropyl myristate Isopropyl Myristate 4.0 (Symrise) Isodragol (Symrise) Trisononanoin 6.O Neutral oil (Symrise) Caprylic/Caprict 4.0 2.O 2.0 Triglyceride Paraffin oil Mineral Oil 4.0 PCL Liquid 100 Cetearyl Octanoate 4.0 3.0 3.0 (Symrise) Tegosoft TN (R) C12-C15 Alkyl 4.0 2.0 (Goldschmidt) Benzoate Further ingredients

Arlypon F Laureth-2 2.0 alpha-Bisabolol Bisabolol O.1 O.1 O.1 O.1 (Symrise) 1,3-Butylene glycol 1,3-Butylene Glycol 3.0 Carbopol. 2050 (R) Carbomer O.2 O.1 (B.F. Goodrich) Ceramid Bio 391 Ceramide O.3 (Symrise) Citric Acid Citric Acid O.1 O.3 Copherol 1250 (R) Tocopherol Acetate O.S O.S (Cognis) Criniipan (RAD Climbazole O.S (Symrise) Dehyguart SP Quaternium-52 Dehyton K Cocamidopropyl 12.0 Betaine Dow Corning (R) 193 Dimethicone Polyol 1.O (Dow Corning) D-Panthenol (BASF) Panthenol O.S O.S 0.4 Dragocid Liquid Phenoxyethanol (and) O.8 O.8 O.8 O.S O.8 O.8 (Symrise) Methylparaben (and) Ethylparaben (and) Butylparaben (and) Propylparaben (and) Isobutylparaben US 9,060,943 B2 53 54 -continued

RAWMATERIALNAME (MANUFACTURER) INCI 22 23 24 25 26 27 28 29 30 31 Dragophos S Sodium 2.0 (Symrise) Dihydroxycetyl Phosphate Dracorin CE Glyceryl 1.O Stearate? Citrate Dracorin GMS Glyceryl Stearate 2.0 2.0 2.0 2.0 3.0 (Symrise) Dracorin 100s.e. P Glyceryl Stearate, 3.0 8.0 (Symrise) PEG-100 Stearate Edeta BD (R) (BASF) Disodium EDTA O.1 O.1 O.1 O.1 O.1 Emulgin B2 (R) Ceteareth-20 1.O 0.7 (Cognis) Emulsiphos Potassium 1.5 1.5 (Symrise) Cetylphosphate, Hydrogenated Palm Glycerides Ethanol (96%) Ethyl Alcohol 13.0 Extrapon Aloe Vera 1.O (Symrise) Extrapon Kamilie 1.O (Symrise) Extrapon Hamamelis 1.O (Symrise) FrescolatML Menthyl Lactate Glycerol 99% Glycerin 3.0 4.5 3.0 4.0 Hydrolite-5 Pentylene Glycol 4.5 S.O 3.0 (Symrise) Keltrol T (R) (Kelco) Xanthan Gum O.2 O.2 Lanette E(R) (Cognis) Sodium Cetearyl 0.7 Sulfate Lanette O (R) (Cognis) Cetaeryl Alcohol 1.1 2.5 Lanette 16 (R) Cetyl Alcohol 1.2 0.5 2.O (Cognis) Lanette 18 (Care Stearyl Alcohol 4.5 Chemicals) Lara Care A-200 Galactoarabinan (Rahn) NaOH 10% aq. Sodium Hydroxide 2.8 2.2 2.9 Solution Natrosol 25OHHR Hydroxymethyl O.3 (Aqualon) Cellulose Neo Heliopan (RAP Disodium Phenyl 22.0 (Symrise), 15% as dibenzimidazole Tetra Sodium salt Sulfonate Neo Heliopan (RAP Disodium Phenyl 22.O (Symrise), 10% aq. dibenzimidazole Tetra Solution neutralized Sulphonate with NaOH Neo Heliopan (RAV Ethylhexyl Methoxy 6.O 2.O (Symrise) cinnamate Neo Heliopan (RBB Benzophenone-3 1.O (Symrise) Neo Heliopan (R3 03 Octocrylene 7.0 (Symrise) Neo Heliopan (R 357 Butyl 2.0 1.5 1.5 1.5 O.S O.S (Symrise) Methoxydibenzoyl methane Neo Heliopan (R) Soamyl p 6.0 2.0 E 1000 (Symrise) Methoxycinnamate Neo Heliopan (R) Homosalate S.O HMS (Symrise) Neo Heliopan (R) Phenylbenzimidazole 33.3 13.3 3.3 Hydro Sulfonic Acid (15% aq. solution neutralized with NaOH) (Symrise) Neo Heliopan (RMA Menthyl Anthranilate 3.0 (Symrise) Neo Heliopan (R) 4-Methylbenzylidene 2.0 4.0 3.0 MBC (Symrise) Camphor Neo Heliopan (R) OS Ethylhexyl Salicylate 1.O (Symrise) US 9,060,943 B2 55 56 -continued

RAW MATERIALNAME (MANUFACTURER) NCI 22 23 24 25 26 27 28 29 30 31 Neo PCL WSS. N Trideceth-9, PEG-5 1.O 1.5 1.5 (Symrise) Ethylhexanoate Fragrance “ROSE Perfume (Fragrance) O.3 O.3 O.3 O.3 0.4 O.2 O.S 0.4 O.3 O.3 (Symrise) Pemulen TR2 Acrylates/C10-30 Alkyl O.2 (Novion) Acrylate Crosspolymer Polymer JR 400 Polyguaternium-10 0.4 1.2-Propylene glycol Propylene Glycol S.O Simagel M Quaternium-18 1.O Hectorite Solubilizer (Symrise) PEG 40 Hydrogenated 3.0 Castor Oil, Trideceth 9, Propylene Glycol, alter Symdiol 68 2-Hexanediol, O.S 1.O Caprylylglycol (1:1) Texapon N 70 Sodium Laureth O.S (Cognis) Sulfate Texapon NSO BZ Sodium Laureth 27.0 (Cognis) Sulfate Zink Oxide neutral Zinc Oxide S.O (Symrise) Veegum ultra (R) Magnesium Aluminium 1.O (Vanderbilt) Sulfate Vitamin A Palmitate Retinyl Palmitate O.1 O.1 Witch Hazel Hamamelis Virginiana 1.O Distillate (Symrise) (Witch Hazel) Water, dist. Aqua (Water) ad 100 ad 100 ad 100 ad 100 ad 100 ad 100 ad 100 ad 100 ad 100 ad 100

Formulation Example 32: Deodorant sticks 30 Formulation Example 34: Antiperspirant formulations

A. B Component/NAME I (wt.%) II (wt.%) Component/NAME % by weight % by weight 35 Reach AZP-908 SUF 24.00 22.00 Cyclomethicone (Pentamer) Ad 100 Ad 100 Sodium stearate 8.00 8.OO Polydecene (Silkflo 364 NF) 17.50 2O.OO PPG-3 Myristyl ether 70.00 7O.OO Neo Helipan OS (ethylhexyl salicylate, Symrise) 2.50 1.00 1,2-propylene glygol 10.00 1O.OO L-Menthyl lactate (Frescolate ML, Symrise) O.25 40 1,1-dimethyl-3-phenylpropanol O.20 O.25 Polyethylene 3.00 3.00 2-butyloctanoic acid O.2O Hydrogenated caster oil 2.OO 2.00 Trans-4-tert-butyl cyclohexanol 0.75 O.90 Promyristyl PM-3 7.OO 7.00 Fragrance “WHITE 0.55 PEG-8 Distearate 3.00 3.00 Fragrance “ROSE O.65 45 Silicon dioxide (Cab-O-Sil M-5) 1.OO 1.00 Stearyl alcohol 1S.OO 10.00 Water Ad 100 Ad 100 Octyldodecanol 8.00 Trans-4-tert-butyl cyclohexanol O.8O 1.OS Fragrance “WHITE 0.75 Formulation Example 33: Microemulsion gels 50 Fragrance “ROSE O.80

Component/NAME I (wt.%) II (wt.%) Glycerin isostearate 18O 2.00 Formulation Example 35: Suspension sticks Octoxyglycerin 1.OO O.80 55 Ceteareth-15 S.2O S.OO PEG-150 Distearate 1.OO 1.00 Component/NAME I (wt.%) II (wt.%) III (wt.%) Aluminium chlorohydrate S.OO S.OO Isotridecylisononanoate 3.30 3.SO Stearyl alcohol 2O.OO 2O.OO 2O.OO Cyclomethicone 6.60 6.40 Cyclomethicone Ad 100 Ad 100 Ad 100 PPG-14. Butylether 2.00 2.OO 2.00 Trans-4-tert-butyl cyclohexanol as 1.95 60 Hydrogenated caster oil 1.00 1.OO 1.00 part of CC-2 according to Example 2 Talc 2.00 2.OO 2.00 Trans-4-tert-butyl cyclohexanol as 2.45 Aluminium chlorohydrate, powder 2O.OO 2O.OO 2O.OO part of CC-4 according to Example 2 Triclosan (R) (5-chloro-2-(2,4- O.30 O.30 Fragrance “WHITE 0.55 dichlorophenoxy)phenol) Fragrance “ROSE O.60 Ethylhexylglycerin (Octoxyglycerin) O.SO O.8O O.SO Water Ad 100 Ad 100 65 1,1-Dimethyl-3-phenylpropanol O.30 O4O O.35 Anis alcohol O.15 US 9,060,943 B2 58 -continued The invention claimed is: 1. A cosmetic or pharmaceutical composition for reducing Component/NAME I (wt.%) II (wt.%) III (wt.%) human skin irritation comprising: Trans-4-tert-butyl cyclohexanol 0.55 O.85 1.10 a) 0.1-4.5 wt.% of trans-4-tert-butyl cyclohexanol or a Fragrance “WHITE 0.55 O.25 5 cosmetically or pharmaceutically acceptable salt Fragrance “ROSE O.70 O45 thereof, based on the total weight of the composition; and Formulation Example 36: Deodorant sprays b) one or more cosmetically or pharmaceutically accept 10 able carriers; wherein if the composition comprises cis-4-tert-butyl Component/NAME I (wt.%) II (wt.%) III (wt.%) cyclohexanol, the weight ratio of the trans-4-tert-bu PEG-40-hydrogenated caster oil 3.00 3.00 3.00 tyl cyclohexanol to the cis-4-tert-butyl cyclohexanol Ethylhexylglycerin (Octoxyglycerin) O.80 O.80 O.80 is at least 90:10. Ethanol 40.00 40.OO 40.00 2. The composition according to claim 1, wherein the one Citrate buffer OSO O.SO OSO 15 1.2-Hexanediol. 1,2-octanediol (1:1) O.25 O.35 or more cosmetically acceptable carriers b) are selected from Phenoxyethanol O.25 O.35 the group consisting of Triclosan (R) (5-chloro-2-(2,4- O.25 dichlorophenoxy)phenol) (i) alkane diols having 3 to 10 carbon atoms, 2-Benzylheptan-1-ol (Jasmol) O.OS O.15 (i-1) esters having 6 to 36 carbon atoms, Trans-4-tert-butyl cyclohexanol O45 O.65 O.80 20 (ii-2) branched and unbranched alkyl or alkenyl alcohols, Fragrance “WHITE 0.55 O.25 and Fragrance “ROSE O.70 O45 (ii-3) branched and unbranched hydrocarbons and waxes, Water Ad 100 Ad 100 Ad 100 cyclic or linear silicone oils and dialkyl ethers having 6 to 24 carbon atoms. Formulation Example 37: Recrystallization stability test in 3. The composition according to claim 1, further compris cosmetic emulsions ing at least one fragrance.

II III IV V NCI (wt.%) (wt.%) (wt.%) (wt.%) (wt.%) Emulsiphos Potassium Cetyl 1.3 1.3 2.0 1.8 2.0 Phosphate. Hydrogenated Palm Glycerides Cutina PES Glyceryl Stearate 2.0 2.0 2.0 2.O 2.0 Lanette O Cetearyl Alcohol 3.5 3.5 3.5 3.5 3.5 EDTA BD Disodium EDTA O.1 O.1 O.1 O.1 O.1 Neo Heliopan BB Benzophenone-3 O.S O.S O.S O.S O.S Caprylicicapric Caprylic Capric 3.0 S.O S.O S.O 1S.O triglycerides Triglyceride Coranpan TQ Diethylhexyl 2,6- 1O.O Naphthalate Eutanol G 16 Hexyldecanol Finsolv TN C12-15 Alkyl 1O.O Benzoate Dragoxat 89 Ethylhexyl 4.0 Sononanoate Sodragol Trisononanoin 3.0 PCL-Solid Stearyl Heptanoate, 1.O Stearyl Caprylate Dragosantol 100 Alpha-Bisabolol O.2 O.2 O2 O.2 Vitamin E. Acetate Tocopheryl Acetate O.S O.S O.S O.S Keltrol RD Xanthan Gum O.2 O2 O.2 Benecel Hydroxypropyl methyl 1.O 1.O cellulose Trans-4-tert-butyl O.S 0.75 1.O 1.O 1.2 cyclohexanol Water Water (aqua) Ad 100 Ad 100 Ad 100 Ad 100 Ad 100 Hydrolite-5 Pentylene Glycol 3.0 3.0 3.0 3.0 3.0 (1,2-pentanediol) Glycerin Glycerin 3.0 3.0 3.0 3.0 3.0 SymDiol 68 1.2-Hexandiol, O6 O6 O6 O.6 Caprylyl Glycol (1:1 (w?w)) Caffeine Caffeine 1.O 3.0 Citric acid Citric acid O.15 O.15 O.15 O.15 O.15

The emulsions Ito V were stored at 5°C. for 6 months and no crystallization of trans-4-tert-butyl cyclohexanol was observed neither visually nor using microscopic analysis, US 9,060,943 B2 59 60 4. The composition according to claim 1, further compris 11. The composition according to claim3, further compris ing at least one additional active ingredient that provides a ing at least one fragrance having a C P value of at least 3. benefit to the skin. 12. The composition according to claim3, further compris 5. The composition according to claim 4, wherein the at ing at least one fragrance selected from the group consisting least one additional active ingredient is selected from the of alpha-amyl cinnamic aldehyde, alpha-hexyl cinnamic group consisting of aldehyde, 2-phenoxyethylisobutyrate, methyl dihydrojas extracts or fractions from camomile, Aloe Vera, oats, cal monate, 4.6,6,7,8,8-hexamethyl-1,3,4,6,7,8-hexahydrocy endula, arnica, honeysuckle, rosemary, witch hazel, gin clopentagbenzopyran, benzylsalicylate, 2-methyl-3-(4- ger or Echinacea; tert-butyl-phenyl)propanal, 47-methano-3a,4,5,6,7,7a alpha-bisabolol, gingerols, shogaols, gingerdiols, dehy 10 hexahydro-5-indenyl acetate and/or 4.7-methano-3a,4,5,6,7, drogingerdiones, paradols, natural avenanthramides, 7a-hexahydro-6-indenyl acetate, styrallyl acetate, octahydro non-natural avenanthramides, boswellic acid, phytoster 2.3,8,8-tetramethyl-2-acetonaphthone and/or 2-acetyl-1,2,3, ols, glycyrrhizin, or licochalcone A, and 4,6,7,8-octahydro-2.3,8,8-tetramethylnaphthaline, urea, hyaluronic acid, allantoin, panthenol, lanolin, alpha 15 hexylsalicylate, 4-tert.-butylcyclohexyl acetate, 2-tert-butyl hydroxy acids, or vitamin E or derivatives. cyclohexyl acetate, alpha-ionone, 4-(4-hydroxy-4-methyl 6. The composition according to claim 1, wherein the com pentyl)-3-cyclohexene carboxaldehyde, (E)- and/or (Z)-3- position is selected from the group consisting of a cosmetic methylcyclopentadec-5-enone, 15-pentadec-11-enolide and/ product for treatment, protection, care and cleansing of the or 15-pentadec-12-enolide, 15-cyclopentadecanolide, 1-(5,6, skin and/or hair and a make-up product. 7,8-tetrahydro-3.5,5,6,8,8-hexamethyl-2-naphthalenyl) 7. A concentrated composition comprising ethanone, ethylene brassylate, 2-ethyl-4-(2,2,3-trimethyl-3- 5 to 55 wt.% trans-4-tert-butyl cyclohexanol; and cyclopenten-1-yl)-2-buten-1-ol. alpha-Santalol, 2.2- at least one diol having 3 to 10 carbon atoms; dimethyl-3-(3-methylphenyl)-propanol (Majantol), allyl wherein if the composition comprises cis-4-tert-butyl heptanoate, 4-methylacetophenone, (4aR,5R,7aS,9R)-oc cyclohexanol, the weight ratio of the trans-4-tert-bu 25 tahydro-2,2,5,8,8,9a-hexamethyl-4H-4a,9-methanoaZuleno tyl cyclohexanol to the cis-4-tert-butyl cyclohexanol (5,6-d)-1,3-dioxol), 1-(2.2,6-trimethylcyclohexyl)hexan-3- is at least 90:10. ol, benzylacetone, methyl cinnamate, and 3a,6.6.9a 8. A cosmetic formulation or medicament comprising the tetramethyldodecahydronaphtho2,1-bfuran. composition according to claim 7. 13. The composition according to claim 4, wherein the 9. The cosmetic composition according to claim 1, wherein 30 the one or more cosmetically acceptable carriers are not water additional active ingredient that provides a benefit to the skin or ethanol. is selected from the group consisting of anti-inflammatory 10. The composition according to claim 2, wherein the one agents, physiological cooling agents, compounds that allevi or more cosmetically acceptable carriers b) are selected from ate itching and compounds that alleviate reddening, wherein the group consisting of 35 the active is Suitable for cosmetic and/or dermatological (i) 1.2-propylene glycol, 2-methylpropane-1,3-diol, 1.2- applications. butylene glycol, 1,3-butanediol. 1.2-pentanediol. 1,3- 14. The concentrated composition according to claim 7. pentanediol. 1.5-pentanediol. 2.4-pentanediol, 2-me comprising 7.5 wt.% or more of an alkane diol selected from thyl-pentane-2,4-diol. 1.2-hexanediol, 1.6-hexanediol, the group consisting of 1,2-propylene glycol, 2-methylpro 1.2-octanediol, or dipropylene glycol, 40 pane-1,3-diol. 1.2-butylene glycol. 1,3-butanediol. 1.2-pen (ii-1) diethyl phthalate, diethylhexyl 2,6-naphthalate, iso tanediol. 1,3-pentanediol. 1.5-pentanediol. 2.4-pentanediol. propyl myristate, isopropyl palmitate, isopropyl Stear 2-methyl-pentane-2,4-diol. 1.2-hexanediol, 1.6-hexanediol. ate, isopropyl oleate, n-butyl Stearate, n-hexyl laurate, 1.2-octanediol, and dipropylene glycol. n-decyl oleate, isooctyl Stearate, isononyl Stearate, 15. The composition according to claim 1, wherein if the isononyl isononanoate, 3.5.5-trimethylhexyl 3.5.5-trim 45 composition comprises cis-4-tert-butyl cyclohexanol, the ethylhexanoate, 2-ethylhexyl isononanoate, 2-ethyl weight ratio of the trans-4-tert-butyl cyclohexanol to the cis hexyl 3.5.5-trimethylhexanoate, 2-ethylhexyl 2-ethyl 4-tert-butyl cyclohexanol is at least 95:5. hexanoate, 2-ethylhexyl palmitate, 2-ethylhexyl laurate, 16. A cosmetic or pharmaceutical composition for reduc 2-hexyldecyl Stearate, cetearyl ethylhexanoate, Stearyl ing human skin irritation comprising: heptanoate, Stearyl caprylate, 2-octyldodecyl palmitate, 50 a) 0.1-4.5 wt.% of trans-4-tert-butyl cyclohexanol or a oleyl oleate, oleylerucate, erucyl oleate, erucyl erucate, cosmetically or pharmaceutically acceptable salt 2-ethylhexyl isostearate, isotridecyl isononanoate, 2-ethylhexyl cocoate, C2-s-alkyl benzoates, cetyl thereof, based on the total weight of the composition, palmitate, triethyl citrate, triacetin, benzyl benzoate, wherein if the composition comprises cis-4-tert-butyl benzyl acetate, or vegetable oils and triglycerides; 55 cyclohexanol, the weight ratio of the trans-4-tert-bu (ii-2) decanol, decenol, octanol, octenol, dodecanol, dode tyl cyclohexanol to the cis-4-tert-butyl cyclohexanol cenol, octadienol, decadienol, dodecadienol, oleyl alco is at least 95:5; hol, ricinoleyl alcohol, erucyl alcohol, Stearyl alcohol, b) one or more cosmetically or pharmaceutically accept isostearyl alcohol, cetyl alcohol, lauryl alcohol, myristyl able carriers selected from the group consisting of: alcohol, arachidyl alcohol, linoleyl alcohol, linolenyl 60 (i) an alkane diol having 3 to 10 carbon atoms, alcohol, hexyldecanol, or octyldodecanol and cetearyl (i-1) an ester having 6 to 36 carbon atoms, alcohol and behenyl alcohol; and (ii-2) a branched or unbranched alkyl or alkenyl alcohol, (ii-3) jojoba oil, isoeicosane, dicaprylyl ether, mineral oil, and petrolatum, squalane, squalene, cyclomethicone, deca (ii-3) a branched or unbranched hydrocarbon, a wax, a methylcyclopentasiloxane, undecamethylcyclotrisilox 65 cyclic or linear silicone oil, or an ether having 6 to 24 ane, polydimethylsiloxane or poly(methyl-phenyl silox carbon atoms; and a. c) at least one fragrance having a C P value of at least 3. US 9,060,943 B2 61 62 17. The composition according to claim 16, further com prising: (d) an additional active ingredient Suitable for cosmetic application to the skin selected from the group consist ing of an anti-inflammatory agent, a physiological cool ing agent, a compound that alleviates itching, and a compound that alleviates reddening. 18. The composition according to claim 16 comprising (i) an alkane diol having 3 to 10 carbon atoms selected from the group consisting of 1,2-propylene glycol, 2-methylpropane 10 1,3-diol, 1.2-butylene glycol, 1,3-butanediol. 1.2-pen tanediol. 1,3-pentanediol. 1.5-pentanediol. 2.4-pentanediol. 2-methyl-pentane-2,4-diol. 1.2-hexanediol, 1.6-hexanediol. 1.2-octanediol, and dipropylene glycol. 19. A method for reducing human skin irritation compris 15 ing applying to the skin of a human an effective amount of a cosmetic composition according to claim 1. k k k k k