WO2013143855A2 - Cosmetic and dermatological preparations containing one or more substances which modulate the gen for the "krüppel-like factor 9" (klf9) - Google Patents

Abstract

The invention relates to the use of polycyclic alcohols for the stabilization of the circadian physiology and their use for modulating the Klf9 gene expression.

Description

 Beiersdorf Aktiengesellschaft

Cosmetic and dermatological preparations containing one or more substances which modulate the gene for the "crippled-like factor 9" (Klf9)

The invention encompasses cosmetic and dermatological preparations containing one or more substances which modulate the gene for the "crippled-like factor 9" (Klf9), in particular those preparations for use on the skin or hair of a human for the repair and regeneration of the human skin.

Practically all human functions change systematically during the day and night, similar to a sine wave with a maximum value and a minimum value: activity and metabolic phases oscillate (with or without daylight) in a (not quite exact) 24-hour rhythm. For this reason one speaks of the inner rhythm (clock) also as the circadian clock.

As sleep is embedded in this vibration, so is the time of recovery, an understanding of the mechanisms of biological programs is all the more important as our modern technological (electivated!) Lifestyle is increasingly capturing the natural time structures of day and night blurred.

We possess innumerable different "internal clocks" whose uppermost control center (the so-called suprachiasmatic nucleus) lies directly above the junction of the two optic nerves, two nerve cell groups lying on the right and left, the size of a rice grain.

The most important timer for the inner clock is the daylight. How much or how little light the internal clock needs to develop its effect is genetically determined and inherited in the form of various chronotypes:

Genetic early risers need much less light than the so-called night owls to wake up, they are fit and active early in the morning, but are also early on Evening weaker and tired. The older you get, the more you become an early riser.

Due to different periods of light, the organism reacts particularly sensitively to differences in light at dawn and dusk. In addition to the daylight but there are also their own timer (rhythm generator) such. regular mealtimes or regular getting up.

The inner clocks cause a variety of chemical and biological processes, which, taken together, fundamentally affect health, performance, experience, behavior and mood.

Chronobiologists have found different time qualities. For example, analgesics have a stronger effect in the evening than in the morning. In the evening, pain is also felt much stronger. At night, the body temperature drops, the circulation is highly unstable, the sense of balance disturbed. The digestive power is optimal between 13 and 14 o'clock, while the brain power is minimal. Alcohol is broken down properly in the evening. Growth and regulation of the hormonal balance takes place in the nocturnal deep sleep phases, as well as the strengthening of cognitive (previously learned) skills.

Sleep is also subject to this circadian rhythm: It is a highly active process, divided into quite different stages of sleep.

Circadian rhytmic is an important regulatory function that also needs skin cells for regeneration and revitalization for a fresher appearance.

The epidermis can be subdivided into cell fractions with a high cell division capacity or cell division rate (stem cells and so-called transiently amplifying keratinocytes) and non-proliferative, stratified cell fractions which form the majority of the epidermis.

To Figure 1: Regulation and function of Klf9.

(a) Klf9 gene expression in epidermal stem cells (Stern Cell), transiently amplifying keratinocytes (TA Cell) and stratified epidermis (epidermis) in n = 3 donors. Expression levels are shown relative to the stem cell fraction. (b) Cell count of primary keratinocytes with genomically integrated overexpression construct for the control protein Green Fluorescent Protein (GFP OE) or KLF9 (KLF9 OE), n = 10 measurements.

(c) Cell number determination of primary keratinocytes with genomically integrated short hairpin (sh) RNA constructs for the suppression of Klf9 gene expression, non-silencing (ns) control: nonspecific shRNA. Klf9 # 1 and # 3: specific shRNA against Klf9. Measured values are given relative to ns control (n = 3).

(d) Keratinocytes were irradiated with the specified dose of UVB and harvested 3 hours and 24 hours after irradiation. Error bar: standard deviation. ( ^** ) significance level p <0.05.

Keratinocytes are derived from epidermal stem cells that are located in the area of the stratum basale or in the area of the outer root sheath of the hair follicles. They traverse several stages of development as they are pushed up by coming cells, until they form a layer of flattened, dead corneocytes in the stratum corneum.

The time between differentiation in the stratum basale and Abschidferung as corneocyte in the stratum disjunctum is about one month, but can be used in certain diseases, e.g. Psoriasis, be shortened.

During this differentiation, the keratinocyte constantly changes its shape and geometric orientation. In the stratum basale, the keratinocytes arise from epidermal stem cells and have a roughly cylindrical shape.

In the stratum spinosum, the remodeling of the cells begins with an increase in volume and a change in the cell axis in a more horizontal direction. Keratohyaline grains are formed and remodeling progresses rapidly. It comes to flattening of the cells, the loss of the nucleus, the shrinkage due to fluid loss and finally to keratinization. In the following stratum corneum (horny layer) one can no longer detect keratinocytes. Keratinocytes became corneocytes.

The stratum corneum forms a barrier that keeps foreign bodies and germs out and protects the body from dehydration. Keratinocytes are actively involved in the immune response, in inflammatory processes and in wound healing. They can produce a variety of cytokines, growth factors and even complement factors. In many chronic inflammatory skin diseases in particular TNF-alpha and IL-1, but also many other interleukins and chemokines are released.

Keratinocytes contribute to UV protection by absorbing melanosomes (melanin-containing vesicles) from melanocytes. The melanin is stored around the nucleus and protects it from UV-related damage.

Organisms are naturally exposed to a rotation of the Earth during the day-night cycle, which has led to an evolutionary adaptation of the physiology and behavior of almost all living things to this rhythm.

At the molecular level, evolutionarily highly conserved endogenous regulatory mechanisms have been formed, which enable the regulation of physiological processes in a circadian (-24 h) rhythm. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus serves as the central clock of the circadian clock. For synchronization of physiological processes in peripheral organs, the SCN controls i.a. the cyclical release of certain hormones (e.g., cortisol, melatonin), temperature homeostasis and neuronal signals.

In addition to central control, almost all organs at the cellular level have an autonomous mechanism for generating circadian rhythms. At the molecular level, the circadian rhythm is formed by self-regulating feedback loops that allow cyclic expression of genes and corresponding proteins of the molecular clockwork. Peripheral oscillators are essential for the circadian control of tissue-specific cellular and physiological processes.

Here, the daytime-dependent regulation of physiology and metabolism is largely controlled by the circadian control of tissue-specific gene regulators (so-called transcription factors) or central enzymes. The control of circadian regulated genes has strong variations between different tissues, indicating specific functions of the circadian clock in individual organs. Recent studies are increasingly providing evidence for circadian control of cell division processes by clock-controlled cell cycle regulators. Demensprechend leads a systematic disorder of the circadian system to increased occurrence of diseases associated with the loss of proliferation control (eg, cancer).

Although the skin, as the ultimate barrier between the organism and the environment, is particularly exposed to daytime variations of the environment (e.g., temperature, UV radiation), surprisingly few studies have been performed to characterize the circadian system in the skin.

Studies on mouse models revealed rhythmic gene expression of clock genes in skin biopsies and recently the circadian regulation of DNA repair in murine epidermis has been described. In the human system, however, a molecular clock in epidermal skin cells has so far not been characterized. Interestingly, however, the time-dependent proliferation of epidermal keratinocytes has been known for some time, but the molecular regulatory mechanisms of this observation are not yet known.

There is also increased evidence of a circadian regulation of essential skin functions such as barrier formation, blood circulation and skin hydration, skin pH and skin temperature. However, the age dependence of this daytime specific variation of skin functions as well as underlying molecular mechanisms has not been elucidated yet.

The daily use of cosmetic products, which develop their regenerating effect with topical application, can therefore make a significant contribution to increasing the well-being of consumers.

It is therefore desirable to develop cosmetic products that adapt to the specific daily requirements of the skin, it is also desirable to provide concrete individual substances that achieve cosmetic effects by exploiting the biorhythm of the skin. It is also desirable that these substances can be used in cosmetic preparations.

Which genes in the skin are regulated depending on the time of day was not yet known. The work underlying the present invention led to the identification of circadianly regulated genes in the skin, their functional characterization, and in particular the active substance-side modulation of individual circadian-regulated genes for influencing cell growth in skin cells. Accordingly, the gene Krüppel-like factor 9 {Klf9) could be identified as circadian regulated and its growth-inhibiting function of Klf9 in epidermal keratinocytes detected.

On the drug side, it has been discovered that Klf9 can be modulated via the glucocorticoid signaling pathway by the application of polycyclic alcohols, especially oridonine / withaferin.

The present invention therefore relates to the use of polycyclic alcohols, in particular Oridonin / Withaferin, for stabilizing the circadian physiology of skin functions.

Dusk is the fluid transition between day and night before the beginning of the day or after the end of the day, which is created by light scattering in the atmosphere. One differentiates between the dusk - the evening transition from the brightness of the day to the darkness of the night after sunset - and the dawn - the contrasting case of the morning transition from the darkness to the brightness before sunrise. Physically, twilight means the period in which scattered light from the sun, which is below the horizon, is visible.

It has been found that certain tetracyclic alcohols such as oridonin or withaferin administered during the period of bourgeois twilight lead to particularly relaxed skin conditions. According to the invention therefore also the use of oridonine and / or withaferin for daytime specific modulation of Klf9 gene expression, characterized in that an effective amount of Oridonine and / or Withaferin is applied in a cosmetic preparation during the evening civil twilight on the skin.

The following conditions can be understood as skin functions: deficient, sensitive or hypoactive states of the skin or of skin appendages degenerative phenomena of the skin (eg skin slackening, age spots, telangiectasias and disappearance of the epidermal and dermal cell layers, the components of the connective tissue, the reed cones and capillaries of the skin) and / or the skin appendages,

 decreased fatty acid replenishment (e.g., after washing).

Visible vascular dilations (telangiectasia, cuperosis); Slackness and formation of wrinkles;

 local hyper-, hypo- and false pigmentation (e.g., age spots) and

 increased susceptibility to mechanical stress (e.g., cracking).

 environmental factors (smoking, smog, reactive oxygen species, free radicals) and in particular light - induced negative changes in the skin and the

Skin appendages.

 light-induced skin damage

 pigmentation,

 Itching,

 Horny layer barrier disorders,

 Hair loss and for improved hair growth

 inflammatory skin conditions as well as atopic eczema, seborrheic eczema, polymorphic photodermatosis, psoriasis, vitiligo

 relaxed skin conditions

 sensitive or irritated skin

 Pre- and post-treatment for topical application of laser and Abschleifbehandlungen z. As the reduction of skin wrinkles and scars serve to counteract the resulting skin irritation and promote the regeneration processes in the injured skin.

To identify circadian regulated genes in human skin, 20 healthy donors were sampled every 4 hours for a period of 28 hours. The skin biopsies were mechanically separated into the epidermis (epidermis) and dermis (subcutis). Subsequently, genome-wide gene expression profiles of the corresponding skin samples were prepared. In addition to known genes of the circadian clockwork (Bmall and Perl) as a positive control, a day-specific regulation of Klf9 was also observed (Fig. 1 a-c).

Klf9 is described as a growth regulator in the epithelial tissue of the uterus (Pabona et al., 2009, Simmen et al., 2008; Simmen et al., 2007), but no growth-modulating effect of Klf9 has been reported to date for the skin.

It could be shown that Klf9 gene expression in non-proliferative active cells is increased by a factor of -30 (Figure 2a). To test whether Klf9 has a direct influence on cell growth, the Klf9 gene dose was artificially modulated in keratinocytes. Increasing the K / 9 level (overexpression) resulted in reduced cell growth (Figure 2b). In contrast, an artificial reduction of Klf9 levels increased increased cell growth (Fig. 2c). Thus, the cell growth of keratinocytes can be directly influenced by the modulation of Klf9.

Sun exposure of the skin is a manifestly daytime-dependent phenomenon, and UV radiation can lead to decreased keratinocyte growth. As // 9-levels in the skin have their maximum at noon (correlating with maximum sun exposure), the question arose between UV exposure and Klf9 gene expression.

It could be shown that Klf9 is dose-dependently induced by UVB radiation (Fig. 2d). This effect is short-lived, so that the Klf9 levels 24h after irradiation are at the base level again (Figure 2c).

UV-induced growth reduction can be counteracted by modulation of Klf9.

It could also be shown that Klf9 modulating substances should be used for specific purposes in terms of daytime, especially in the evening hours.

For example, the graph in Figure 2 indicates the altered skin lipid status at different times of the day. It can be seen that in the evening, the fatty acid content in the skin is higher.

For the drug-side modulation of Klf9, the cortisol signaling pathway was identified.

 Comparable effects of KLF9 modulation show certain tetracyclic alcohols, such as withaferin A and oridonine.

Withaferin: CAS No: 5119-48-2

Origin: native to the plant: Whitania somnifera, different Ashwagandha, or Indian ginseng. The plant is known from traditional Ayurvedic medicine.

Structural formula:

Oridonine: CAS No: 28957-04-2

Origin: native to the plant abdosia rubescens, known from traditional Chinese phytomedicine.

Structural formula:

The natural products mentioned above are currently being evaluated as pharmaceutical active ingredients.

Nevertheless, it was surprising that the use of Withaferin A and Oridonin to stabilize the circadian physiology of the skin remedies the disadvantages of the prior art.

The term "stabilizing the circadian physiology of the skin" is understood to mean that the substances used according to the invention put the skin into a nocturnal state of recovery, as a result of which it is also possible to restore or at least to equalize the external appearance of the recovered skin.

According to the invention, the Withaferin A and Oridonin are used in cosmetic or dermatological compositions, a content of 0.00001 - 50.0 wt .-%, in particular 0.001 to 20.0 wt .-%, based on the total weight of the composition are preferred. Advantageously, the compositions contain 0.002 to 10.0 wt .-%, more preferably 0.002 to 5.0 wt .-% of the preservatives used in the invention, most preferably 0.005 to 3.0 wt .-%, each based on the total weight of Composition..

Emulsions are advantageous dosage forms in the sense of the present invention, e.g. in the form of a cream, a lotion, a cosmetic milk are advantageous and contain e.g. Fats, oils, waxes and / or other fatty substances, as well as water and one or more emulsifiers, as they are commonly used for such a type of formulation.

Medicinal topical compositions according to the present invention usually contain one or more drugs in effective concentration. For the sake of simplicity, reference is made to the clear distinction between cosmetic and medical use and corresponding products to the statutory provisions of the Federal Republic of Germany (for example, Cosmetics Regulation, Food and Medicines Act).

It is also advantageous to add the active ingredient used according to the invention as an additive to preparations which already contain other active ingredients for other purposes.

If the cosmetic or dermatological preparation in the sense of the present invention is a solution or emulsion or dispersion, it is possible to use as solvent:

 Water or aqueous solutions

 Oils, such as triglycerides of capric or caprylic acid, but preferably castor oil;

Fats, waxes and other natural and synthetic fats, preferably esters of fatty acids with lower C-number alcohols, e.g. with isopropanol, propylene glycol or glycerol, or esters of fatty alcohols with alkanoic acids of low C number or with fatty acids;

Alcohols, diols or polyols of low C number, and their ethers, preferably ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl or monobutyl ether, propylene glycol monomethyl, monoethyl or monobutyl ether, diethylene glycol monomethyl or monoethyl ether and analogous products , In particular, mixtures of the abovementioned solvents are used. For alcoholic solvents, water can be another ingredient.

The oil phase of the emulsions, oleogels or hydrodispersions or lipodispersions in the context of the present invention is advantageously selected from the group of esters of saturated and / or unsaturated, branched and / or unbranched alkanecarboxylic acids having a chain length of 3 to 30 carbon atoms and saturated and / or or unsaturated, branched and / or unbranched alcohols having a chain length of 3 to 30 carbon atoms, from the group of esters of aromatic carboxylic acids and saturated and / or unsaturated, branched and / or unbranched alcohols having a chain length of 3 to 30 carbon atoms. Such ester oils can then advantageously be selected from the group isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl stearate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-ethylhexyl laurate, 2-hexyldecyl stearate, 2 Octyldodecyl palmitate, oleyl oleate, oleyl erucate, erucyl oleate, erucyl erucate and synthetic, semi-synthetic and natural mixtures of such esters, eg Jojoba oil.

Furthermore, the oil phase can be advantageously selected from the group of branched and unbranched hydrocarbons and waxes, the silicone oils, the dialkyl ethers, the group of saturated or unsaturated, branched or unbranched alcohols, and the fatty acid triglycerides, namely the triglycerol esters of saturated and / or unsaturated, branched and / or unbranched alkanecarboxylic acids of a chain length of 8 to 24, in particular 12 to 18 carbon atoms. For example, the fatty acid triglycerides can be advantageously selected from the group of synthetic, semi-synthetic and natural oils, e.g. Olive oil, sunflower oil, soybean oil, peanut oil, rapeseed oil, almond oil, palm oil, coconut oil, palm kernel oil, and the like.

If appropriate, the aqueous phase of the preparations according to the invention advantageously contains alcohols, diols or polyols of low C number, and their ethers, preferably ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl or monobutyl ether, propylene glycol monomethyl, monoethyl or monobutyl ether , Diethylene glycol monomethyl or monoethyl ether and analogous products, furthermore low-C alcohols, for example ethanol, isopropanol, 1,2-propanediol, glycerol and, in particular, one or more thickeners, which may advantageously be selected from the group silicon dioxide, Aluminum silicates, polysaccharides or their derivatives, for example hyaluronic acid, xanthan gum, hydroxypropylmethylcellulose, particularly advantageously from the group of polyacrylates, preferably a polyacrylate from the group of so-called Carbopols, for example Carbopols types 980, 981, 1382, 2984, 5984, each individually or in combination.

Gels used in the present invention usually contain low C number alcohols, e.g. Ethanol, isopropanol, 1, 2-propanediol, glycerol and water or an above-mentioned oil in the presence of a thickener which is preferably silica or an aluminum silicate in oily-alcoholic gels, preferably a polyacrylate in aqueous-alcoholic or alcoholic gels.

Fixed pins contain e.g. natural or synthetic waxes, fatty alcohols or fatty acid esters.

Conventional base materials which are suitable for use as cosmetic sticks in the context of the present invention are liquid oils (for example paraffin oils, castor oil, isopropyl myristate), semi-solid constituents (eg petrolatum, lanolin), solid constituents (eg beeswax, ceresin and microcrystalline Waxes or ozokerite) and high-melting waxes (eg carnauba wax, candelilla wax)

Suitable propellants for sprayable from aerosol containers cosmetic and / or dermatological preparations in the context of the present invention, the usual known volatile, liquefied propellants, such as hydrocarbons (propane, butane, isobutane) are suitable, which can be used alone or in mixture with each other. Also, compressed air is advantageous to use.

The following examples are intended to illustrate the present invention.

Formulation example 1 2 3 4

INCI name weight% weight% weight% weight%

Stearic acid 2.5 2.0 2.0 2.5

Glyceryl Stearate 1.0 1.0 1.0 1.0

C12-15 alkyl benzoate 3.0 5.00 3.0 2.0

Caprylic Acid / Capric Acid Triglycerides 2.5 2.50 2.0 2.5

Isopropyl Palmitate 2.0 - 2.0

Cetyl stearyl alcohol 3.0 2.0 3.0

Cetyl Alcohol - 2.00 - -

Stearyl Alcohol - 2.00 1.0 -

Cyclomethicone 1.0 1.0 0.5 -

Dicaprylyl Carbonate 2.0 2.00 2.00 2.0

Dimethicone 1.0 - 0.5 1.0

Glycerol 5, 7.0 5.0 9.0

Methylparaben 0.2 -

Phenoxyethanol 0.4 0.50 0.5 0.4

Propylparaben 0.1 - - 0.1

1,2-hexanediol - 0.1 0.1

Ethylhexylglycerol - 0.2 -

Methylisothiazolinone 0.05 - -

Butylene Glycol 2.0 -

Carbomer 0.15 0.10 0.15 0.1

Carrageenan 0.10 0.10 -

Xanthan gum 0.10 -

Acrylates / C10-30 alkyl acrylates

Crosspolymer 0.10 0.1

Trisodium EDTA 0.20 0.20 0.2 0.2

Tapioca starch 1.5 1.0 -

Nylon 12 - 0.2 - 0.5

Polymethylsisquioxane - 1.0 1.0 -

Aluminum starch octenyl succinate - 1.0 -

Distarch phosphate 1.0 1.0

Butyl Methoxydibenzoylmethane 1.00 2.00 1.00 1.00

Phenylbenzimidazole sulfonic acid 1.00 2.00

 Octocrylene 2.00 1.00

 Ethylhexyl Salicylate 1.00 - - 1.00

Sodium hydroxide q.s. q.s. q.s. q.s.

Hydroxyisohexyl 3-cyclohexene carboxaldehydes 0.1 0.05

Withaferin A 0.5 1.0 0.1 2.0

Perfume 0.3 0.2 0.2 0.2

Sodium hydroxide q.s. q.s. q.s. q.s.

Water ad 100 ad 100 ad 100 ad 100 Recipe example 5 6 7 8

INCI name weight% weight% weight% weight%

Glyceryl Stearate Citrate 2.0 1.5 2.0 2.0

Behenyl Alcohol 1.5 1.0 1.0 1.0

C12-15 alkyl benzoate 2.0 2.5 2.0 2.5

Caprylic Acid / Capric Acid Triglycerides 2.0 2.0 2.5 2.5

Cetyl Alcohol 2.0 2.0 - 2.0

Cetyl stearyl alcohol - - 2.0 -

Cyclomethicone 1.0 1.0 2.0 2.0

Dicaprylyl carbonate - 2.0 2.5 2.5

Paraffinum Liquidum - _. 0,5 _.

Octyldodecanol - 2.0 _.

 Dimethicone 0.5 1.00 1.00

 Glycerine 3.00 5.00 7.00 9.00

Methylparaben 0.20 0.15

 Phenoxyethanol 0.40 0.60 0.5 0.50

Propylparaben 0.10 -

Methylisothiazolinone - - 0.05

 Piroctone Olamine - 0.15

Glyceryl caprylates - 0.2

Carbomer 0.20 - 0.15 0.15

Sodium polyacrylate 0.4 -

Xanthan gum 0.10 - 0.10 -

Acrylates / C10-30 alkyl acrylates

Crosspolymer 0.1 0.1

Tapioca starch 0,50 - 0,50 -

Nylon 12 1.0 - - 1.0

Polymethylsisquioxane 1.0 1.0

 Aluminum starch octenylsuccinate 1.0 1.00

Glycyrrhiza Inflata oot Extract 0.03 0.05 0.05 0.03

Titanium dioxide - 1.0 - -

Octocrylene - 1.0 - 2.0

Until Ethylhexyloxyphenol

Methoxyphenyl triazines 1.0 1.0

 2-ethylhexyl methoxycinnamate - 1.0 2.0 2.0

Homosalate (3,3,5-trimethylcyclohexylsalicylate) 1.0 1.0

Sodium hydroxide q.s. q.s. q.s. q.s.

1- (1,2,3,4,5,6,7,8-octahydro-2,3,8,8, -tetramethyl-2-naphthyl) ethane-1-one 0.1 q.s. q.s.

Oridonin 0.1 0.2 1.0 2.0

Perfume 0.1 0.2 0.3 0.2

Water ad 100 ad 100 ad 100 ad 100 Formulation Examples 9 10 11 12

INCI name weight% weight% weight% weight%

Polyglyceryl-3 methylglucose

Distearate 2.00 2.50 2.50 2.50

Sorbitan Stearate 1.50 3.00 1.50 3.00

C12-15 alkyl benzoate 2.50 2.50 2.50 2.50

Caprylic acid / capric acid triglycerides 2.50 2.50 2.50 2.50

Stearyl Alcohol 1.00 1.50 1.00 1.50

Cyclomethicone 3.00 1.00 2.00 1.00

Isopropyl myristate _. 2.50 2.0 2.50

Isopropyl Palmitate 2.0 _. 1,0 _.

Dimethicone 1.00 1.00

Glycerine 5.00 7.50 3.00 7.50

Butyrospermum Parkii Butter 2,0 -

Methylparaben 0.20 0.20 0.1

Phenoxyethanol 0.40 0.40 0.40 0.40

Propylparaben 0.10 - - -

Benzethonium chloride - - 0.1 -

Caprylyl glycol 0.2 -

Ethylhexylglycerol 0.2 0.2

Carbomer 0.15 0.10 0.15 0.10

Ammonium acryloyldimethyltaurate / VP

Copolymer 0.2 0.2

Carrageenan 0.1 0.15

 Trisodium EDTA - 1.00 - 1.00

Tapioca starch - 1.00 1.0 -

Distarch phosphate - 1.00 - 1.0

Acrylonitrile-methacrylonitrile-methyl-methacrylate copolymer + isopentane

+ Magnesium hydroxides 1.0 1.0

Diethylamino Hydroxybenzoyl Hexyl

Benzoate 1.0

 Ethylhexyl methoxycinnamate - 1.00 - 2.00

Butyl Methoxydibenzoylmethane - 2.00 - 2.00

Octocrylene - 1.00 2.0 1.00

Titanium Dioxide - - 1.0 -

Sodium hydroxide q.s. q.s. q.s. q.s.

Ubiquinone 0.1 - - -

Sodium Metabisulfite - 0.15 - -

BHT (tert-butylhydroxytoluene) - - 0.05 -

Linalyacetate 0,005 - - -

Hexyl salicylate - 0.05 - -

Benzyl salicylate - - 0.01 -

Withaferin 0.1 2.0 1.0 0.5

Perfume q.s. q.s. q.s. q.s.

Water ad 100 ad 100 ad 100 ad 100 Formulation Examples 13 14 15 16

INCI name weight% weight% weight% weight%

PEG-40 Stearate 0.80 1, 00 1, 00 1, 00

Glyceryl Stearate 2.50 3.00 3.00 3.00

C12-15 alkyl benzoate 2.00 2.50 2.00 2.00

Caprylic Acid / Capric Acid Triglycerides 2.00 2.50 2.50 2.00

Cetylstearyl alcohol 3.00 3.00 3.00 3.00

Cyclomethicone 2.00 2.00 2.00 2.00

Dicaprylyl Carbonates _. 2.00 2.50 2.50

Octyldodecanol 1, 0 _. _. 1, 50

Butyrospermum Parkii Butter 2.0 _. _. _.

Octyldodecyl myristate 1, 0 _. 1, 5 1, 0

Dimethicone 1, 00 1, 00 1, 00 1, 00

Glycerine 7.50 5.0 9.0 7.50

Methylparaben 0.20 0, 1

 Phenoxyethanol 0.40 0.50 0.40 0.40

Propylparaben 0.10 - -

Glyceryl Caprylate - 0.25 -

Pentylene glycol 0.5

 Butylene glycol 3.0

 Carbomer 0.15 0.10 0, 10 0.15

Sodium Polyacrylate 0.20 0.20 -

Xanthan Gum 0.10 -

Acrylates / C10-30 alkyl acrylates

Crosspolymer 0, 1

Trisodium EDTA + water (20%

aqueous solution) 1.00 1.00 1, 00

Tapioca strength - 1, 00 1, 00 1, 00

Dioxide of phosphate - 1, 00 1, 00 1, 00

Aluminum starch octenylsuccinate 2.0

 Acrylonitrile-methacrylonitrile-methyl-methacrylate copolymer + Isopentane +

Magnesium hydroxides 1, 0

 Ethylhexyl methoxycinnamate - 1.00 1.00 2.00

Diethylamino Hydroxybenzoyl Hexyl

Benzoate 1, 00 1, 00

Titanium Dioxide - - 1, 0 -

Homosalates (3,3,5-trimethylcyclohexylsalicylate) 2.0

 Phenylbenzimidazole sulfonic acid 1, 0

 Sodium Metabisulfite 0, 1 - - -

Sodium hydroxide q.s. q.s. q.s. q.s.

Ascorbyl palmitate 0, 1 - - -

Oridonin 0.5 0, 1 0.2 1, 0

Perfume q.s. q.s. q.s. q.s.

Water ad 100 ad 100 ad 100 ad 100 Formulation Examples 17 18 19 20

INCI name weight% weight% weight% weight%

Glyceryl Stearate Citrate 2.0 2.0 2.0 2.0

Isopropyl palmitate 3.0 2.0 3.0 1, 0

Cetyl stearyl alcohol 4.0 3.0 3.0 -

Cetyl alcohol 4.0

Caprylic Acid / Capric Acid Triglycerides 3.0 2.5 2.0 3.0

C12-15 alkyl benzoate 3.0 2.5 2.0 2.0

Cyclomethicone 1, 0 1, 0 _.

Dicaprylyl carbonate - 2.5 -

Dimethicone 0.50

 Octyldodecyl myristate 1, 0

 Glycerine 4.00 6.00 5.00 6.00

Methyl paraben 0.20-0.10

 Phenoxyethanol 0.40 0.40 0.40 0.40

Piroctone Olamine - - 0, 10

Ethylhexylglycerol - 0.3 - -

Glyceryl Caprylate 0.3 -

2-methyl-1,3-propanediol 2.0 2.0

Carbomer 0.20 0, 10 0.15

 Sodium polyacrylate 0.40 -

Xanthan gum 0.10 - 0.15

Acrylates / C10-30 alkyl acrylates

Crosspolymer 0, 1 0.2

Acrylonitrile-methacrylonitrile-methyl-methacrylate copolymer + isopentane

+ Magnesium hydroxides 0.50 0.50

 Aluminum Starch Octenylsuccinate - 1.00 - 1.00

Methyl Methacrylate Crosspolymer 1, 0 1, 0

Until Ethylhexyloxyphenol

Methoxyphenyl Triazines 1, 0

 Titanium dioxide - 1, 00 - 1, 00

Octocrylene - 1, 00 1, 0 1, 00

Butyl Methoxydibenzoylmethane - 1, 00 - 1, 00

Ethyl hexyl salicylates - - 1, 0 -

Mexoryl SX hemihydrate 0, 1 0.5 1 2

Triethyl citrate - 0.05 0.05

Sodium hydroxide q.s. q.s. q.s. q.s.

 Withaferin 1, 0 1, 0 2.0 2.0

Water ad 100 ad 100 ad 100 ad 100 Recipe examples 21 22 23 24

INCI name weight% weight% weight% weight%

Sucrose Polystearate + Hydrogynated

Polyisobutenes 1.00 1.00 2.00 2.00

Sodium stearoyl glutamate 0.20 0.20 0.30 0.30

C12-15 alkyl benzoate 1.50 1.50

 Cetyl Alcohol 0.50 0.50

 Cyclomethicone 10.00 10.00 5.00 5.00

Dimethicone 3.00 3.00 2.50 2.50

Glycerine 7.50 7.50 5.00 5.00

Isopropyl Stearate 1.00 1.00 2.00 2.00

Paraffinum Liquidum 3.00 3.00 1.00 1.00

Methylparaben 0.10-0.10

Ethylhexylglycerol - 0.3 0.10

Propylparaben 0.1

 Methylisothiazolinone 0.05

 Phenoxyethanol 0.40 0.50 0.40 0.40

Ethylhexyl Methoxycinnamate 3.00 2.00 3.00 3.0

Butyl Methoxydibenzoylmethane 2.00 2.00 1.00 1.0

Phenylbenzimidazole sulfonic acid - 1.5 - 1.0

Butylene Glycol - - 3.0 -

 Polymethylsissesquioxane - - 1,0 1,0

Nylon 12 - 1.0 1.0 -

Distarch phosphate - 1.0 - 1.0

Methyl Methacrylate Crosspolymer 1.0 - - -

Aluminum Starch Octenylsuccinate 1.0 - - -

Ammonium acryloyldimethyltaurate / VP

Copolymer 0.25 0.25

Xanthan gum 0.10 - - 0.1

Acrylates / C10-30 Alkyl Acrylate Crosspolymer 0.25 0.1 - -

Carbomer - 0.1 0.1 -

Perfume 0,2 0,2 0,2 0,2

Sodium hydroxide q.s. q.s. q.s. q.s.

Oridonine 1.0 1.0 2.0 0.5

Water ad 100 ad 100 ad 100 ad 100

Formulation Examples 25 26 27 28

INCI name weight% weight% weight% weight%

Sodium Cetearyl Sulfate 0.15 0.15 0.15 0.15

Glyceryl Stearate SE 2.00 2.00 1.50 1.50

C12-15 alkyl benzoate 2.50 2.50 2.50 2.50

Octyldodecanol 1.00 1.00

 Caprylic Acid / Capric Acid Triglycerides 2.00 2.00 2.00 2.00

Cetylstearyl alcohol 2.00 2.00 3.00 1.00

Cyclomethicone 1.50 1.50 2.50 2.50

Dimethicone 0.50 0.50 0.50 0.50

Glycerin 5.00 5.00 7.50 7.50

Isopropyl Stearate 3.00 3.00 2.00 2.00

Paraffinum Liquidum 2.00 2.00 1.00 1.00

Methylisothiazolinone - - - 0.05

Phenoxyethanol 0.4 0.5 0.40 0.30

Methyl paraben 0.15 - -

Propylparaben 0.1 -

Piroctone Olamine 0.15

 Benzethonium chloride 0.10

 Ethylhexyl methoxycinnamate 3.00 3.00 5.00 5.00

Butyl Methoxydibenzoylmethane 1.00 1.00 2.00 2.00

Pentylene Glycol - 1.0 1.0 -

Butylene glycol 1.0 1.5 3.0 3.0

2-methyl-1,3-propanediol - - - -

1,2-hexanediol - - - 1.0

Nylon 12 1.0 1.0 1.0 1.0

Carbomer 0.10 0.15

Ammonium acryloyldimethyltaurate / VP

Copolymer 0.20

 Chondrus Crispus 0.10 0.10 - -

Xanthan gum - - 0.10 -

Acrylates / CIO-30 Alkyl Acrylate Crosspolymer - 0.2 0.1 0.1

Coumarin 0.1 - 0.05 0.05

Hydroxyisohexyl 3-cyclohexene carboxaldehydes 0.05 0.05 0.05 0.1.

1- (1,2,3,4,5,6,7,8-octahydro-2,3,8,8, -tetramethyl-2-naphthyl) ethane-1-one 0.05 0.1

 Isoamyl-p-methoxycinnamate 0.1 0.5 1. 2

Sodium hydroxide q.s. q.s. q.s. q.s.

Withaferin 0.5 0.1 1.0 2.0

Water ad 100 ad 100 ad 100 ad 100 Formulation Examples 29 30 31 32

Chemical name Wt.% Wt.% Wt.% Wt.%

Sodium cetearyl sulfate 0, 15 0, 15 0.2 0.2

Glyceryl stearates, self-emulsifying 2 2 1, 5 1, 5

C12-15 alkyl benzoate 2 2 2 2

Octyldodecanol 1 1

 Caprylic acid / capric acid triglycerides 2 2 2 2

Cetylstearyl alcohol 2 2 1 1

Cyclomethicone 1 1 2 2

Dimethicone 0.5 0.5 1 1

Glycerol 5 5 7.5 7.5

Isopropyl palmitate 2.5 2.5 2 2

DMDM Hydantoin 0.05 0.05 0.05 0.05

Phenoxyethanol 0.35 0.25 0.3 0.3

Ethanol 3.0 2.0

Pentylene glycol 1, 0 1, 0 1, 5

Carbomer 0.2 0.2 0.2 0.2

Carrageenan 0, 1 0, 1

 Xanthan Gum - 0.2 0.2

Acrylates / CI O-30 Alkyl Acrylate Crosspolymer - 0, 15

Sodium polyacrylate - 0.2

 Diethylhexyl 2,6-naphthalate - 1.0

 Phenylbenzimidazole sulfonic acid - 1.0 2.0

Titanium dioxide - 1.0

 Diethylamino Hydroxybenzoyl Hexyl Benzoate - 1, 1.0

Octocrylene 4.0 2.0 3.0

3,3,5-trimethylcyclohexyl salicylate 1, 0

 Distarch Phosphate 1, 0 1.0

 Methyl Methacrylate Crosspolymer 1.0 1.0

Polymethylsissesquioxane 1.0 1, 0

Acrylonitrile-methacrylonitrile-methyl-methacrylate copolymer + Isopentane +

 Magnesium Hydroxide 1.0 1.0

 1- (1,2,3,4,5,6,7,8-octahydro-2,3,8,8, -tetramethyl-2-naphthyl) ethane-1-one

 0, 1 0.1 0.05

Hydroxyisohexyl 3-Cyclohexencarboxaldehyde 0.05 0.05 0, 1

 Perfume 0, 15 0, 15 0.3 0.3

Sodium hydroxide q.s. q.s. q.s. q.s.

Oridonine 0, 1 0, 1 0.5 1, 0

Water ad 100 ad 100 ad 100 ad 100 Recipe Examples 33 34 35 36

Chemical name Wt.% Wt.% Wt.% Wt.%

Sodium cetearyl sulfate 0.15 0.15 0.15 0.15

Glyceryl stearate, self-emulsifying 1.0 1.0 1.0 1.0

C12-15 alkyl benzoate 2.0 2.5 2.0 2.0

Isopropyl palmitate 3.5 3.0 2.5 3.5

Dimethicone 1.0 1.0 1.0 1.0

Cetylstearyl alcohol 1.0 1.0 1.0 1.0

Octyldodecyl myristate 1.0

Butyrospermum Parkii Butter 1.0

 Glycerol 7.0 3.0 9.0 5.0

Carbomer 0.1 0.15 0.1 0.1

Acrylates / CIO-30 Alkyl Acrylate Crosspolymer 0.15 0.1 0.1 0.15

Xanthan gum 0.15 0.15 0.15 0.15

Phenylbenzimidazole sulfonic acid 1.0 1.0 1.0

 1.5 1.5 1.5 1.5

Butyl methoxydibenzoylmethane

 Ethyl hexyl salicylates 2.0 2.5 2.5 2.5

Disodium phenyl dibenzimidazole sulfonic acid 1.5 1.5 2.5 1.5

TitanDioxide + Trimethoxycaprylylsilan 1,0 1,0

 Aluminum starch octenyl succinate 1.0 0.5

 0.5 0.5

 Methyl Methacrylate Crosspolymer

 Nylon-12 (Powder Resin) 0.5 1.0

 Tapioca strength 0.5 0.5 1.0

Phenoxyethanol 0.5 0.5 0.5 0.4

Ethylhexylglycerol 0.25 0.25

 1,2-hexanediol 1.0 3.0

Caprylyl Glycol 0.3 0.3 -

2-methyl-1,2-propanediol 2.0 2.0 2.0 -

Sodium hydroxide q.s. q.s. q.s. q.s.

Withaferin 1.0 1.0 0.5 1.0

Water ad 100 ad 100 ad 100 ad 100 Recipe Examples 37 38 39 40

Chemical name Wt.% Wt.% Wt.% Wt.%

Polyglyceryl-10 stearate 0.2 0.20 0.20 0.20

Glyceryl Stearate 3.0 0.50 0.50 0.50

C12-15 alkyl benzoate 4.0 2.0 1, 5 2.5

Isopropyl palmitate 4.0 1, 0 2.0 2.5

Caprylic Acid / Capric Acid Triglycerides 4.0 3.0 2.0 2.5

Hydrogenated Coco Glycerides 3.0 2.0

Butyrospermum Parkii Butter 3.0 2.5

 Cetylstearyl alcohol 5.0 3.5 4.0 3.0

Paraffin Liquidum 1, 0

Glycerol 5.0 3.0 7.0 9.0

Acrylates / C10-30 Alkyl Acrylate Crosspolymer 0.3 0.2 0.15 0.2

Methylisothiazolinone 0.05 0.05

Phenoxyethanol 0.5 0.4 0.4 0.4

Carbomer 0, 1 0, 15 0, 1 0, 1

Methylparaben 0, 1 0, 1 -

Propylparaben 0, 1 -

Nylon 12 (Powder Resin) 1.0 0.5

 1, 0 0.5

 Polymethylsissesquioxane

 Methyl Methacrylate Crosspolymer - 1, 0.5

Tapioca starch 0.5 0.5

Ethanol 3.0 2.0

 Benzophenone-4 1 0.5 2 0.3

Perfume 0.2 0, 15 0.3 0.3

Sodium hydroxide q.s. q.s. q.s. q.s.

Oridonin 1, 0 1, 0 2.0 0.5

Water ad 100 ad 100 ad 100 ad 100 Formulation examples 41 42 43 44

Chemical name Wt.% Wt.% Wt.% Wt.%

Polyglyceryl-10 stearate 0.2 0.2 0.15 0.15

C12-15 alkyl benzoate 2.5 2.5 2.0 3.0

Isopropyl Palmitate 2.5 2.5 2.0 2.0

Caprylic acid / capric acid triglycerides 2.0 2.5 1, 0 2.0

Glyceryl Stearate 1, 0 1, 0 0.5 0.5

Octyldodecanol 0.5 1, 0

Cyclomethicone - 0.5 0.5

Butyl Methoxydibenzoylmethane - 2.0 2.0

 Benzophenone-3 - 2.0 3.0 2.0

Polysilicones-15 - 1, 0 1, 0

 Phenylbenzimidazole sulfonic acid - 1, 0 1.5

Titanium dioxide 1, 0 1, 0

3,3,5-trimethylcyclohexyl salicylate 1.0 1, 0

Glycerine 9.0 5.0 7.0 7.0

Tapioca strength 1, 0 1, 0

 Acrylonitrile-methacrylonitrile-methyl-methacrylate copolymer + Isopentane +

Magnesium hydroxides 1, 0 0.5

 Aluminum starch octenyl succinate 1, 0 1.0

Distarch phosphate 1, 0

Methylisothiazolinone 0.05 0.05

 Phenoxyethanol 0.5 0.5 0.4 0.4

Benzethonium chloride - - 0, 1

 Ethylhexylglycerol 0, 1

 Methylparaben 0.2

Carbomer 0.25 0.2 0.2 0.2

Acrylates / C10-30 Alkyl Acrylate Crosspolymer 0.2 - 0.15

Ammonium acryloyldimethyltaurate / VP

Copolymer 0.25

 Sodium polyacrylate 0.3

 Xanthan gum 0.15

Ethanol 3.0 3.0

 Butylene glycol 2.0 2.0

Coumarin 0.05 0.05

 Hexylcinnamal 0.005 0.001 0.05

Hexyl salicylate 0.05 0.05

Perfume 0.15 0.2 0.25 0.3

Sodium hydroxide q.s. q.s. q.s. q.s.

Withaferin 1, 0 2.0 0.5 1, 0

Water ad 100 ad 100 ad 100 ad 100 Formulation examples 49 50 51 52

Chemical name Wt.% Wt.% Wt.% Wt.%

Potassium cetyl phosphate 0.20 0.20 0.20 0.25 0.20

C12-15 alkyl benzoate 2.5 2.5 2.0 2.0

Isopropyl Palmitate 2.5 2.5 3.0

Isopropyl stearate 2.0

 Caprylic Acid / Capric Acid Triglycerides 2.5 2.5 1, 5 2.0

Glyceryl Stearate 1, 0 1, 0 1, 25 1, 5

Octyldodecanol 1, 5

 Paraffin Liquidum 1.0

Glycerol 5.0 7.0 9.0 6.0

Bis-Ethylhexyloxyphenol Methoxyphenyl

Triazines _ 1, 0 _ 1, 0

TitanDioxide + Trimethoxycaprylylsilane - 1, 0 1, 0

Phenylbenzimidazole sulfonic acid 1, 0 1, 0

Butyl methoxydibenzoylmethane 1.0 2.0 2.0

Disodium phenyl dibenzimidazole tetrasulfonate 1.5 1, 0 -

Ethylhexyltriazone 1.0

 Ethylhexyl methoxycinnamate + BHT 2.0

 Carbomer 0.15 0.2 0.3

Acrylates / CI O-30 Alkyl Acrylate Crosspolymer 0.3 0, 1 0, 15

 Xanthan gum 0.15 0.1

Methylisothiazolinone 0.05

 Phenoxyethanol 0.5 0.5 0.4 0.4

Methylparaben - 0.1

 Ethyl hexyl salicylate - 0.3

 Butylene glycol 3.0 3.0

Benzethonium chloride 0.1

Diethylhexyl butamide triazone 1 0.5 0.3 2

Perfume 0, 1 0.3. 0.2 0.3

BHT (tert-butylhydroxytoluene) 0.05 - -

Tocopheryl acetate - 0.1 - -

Sodium hydroxide q.s. q.s. q.s. q.s.

Oridonin 1, 0 1, 0 2.0 0.5

Water ad 100 ad 100 ad 100 ad 100

Recipe Examples 53 54

Chemical name% by weight% by weight

Polyglyceryl-3 diisostearate 1, 5 1, 5

PEG-40 Sorbitan Perisostearate 2.5 2.5

Lanolin alcohol 0.5 0.5

Mineral oil 8 8

Cera Microcrystallina 2.5 2.5

Cyclomethicone 4 4

Isohexadecane 2 2

Isopropyl palmitate 5 5 Iodopropynyl Butyl carbamate 0, 1

Magnesium sulfate 0.5 0.5

Potassium sorbate 0, 1

 Benzyl salicylate 0, 1

 Glycerol 7 7

Ethylhexyltriazone 1 2

Oridonine 1, 0 2.0

Water ad 100 ad 100

Claims

claims

1 . Use of polycyclic alcohols to stabilize circadian physiology.

2. Use of polycyclic alcohols for day-specific modulation of Klf9 gene expression to stabilize the circadian physiology of skin functions.

3. Use according to claim 1 or 2, characterized in that an effective amount of one or more polycyclic alcohols in a cosmetic preparation during the evening civil twilight is applied to the skin.

4. Use according to one of the preceding claims, characterized in that the polycyclic alcohols are selected from Withaferin and Oridonin.

5. Use according to one of the preceding claims, characterized in that the polycyclic alcohols having a content of 0.00001 - 50.0 wt .-%, in particular 0.001 - 20.0 wt .-%, based on the total weight of the composition in cosmetic or dermatological compositions.

6. Use according to one of the preceding claims, characterized in that the tetracyclic alcohols with 0.002 - 10 wt .-%, particularly preferably 0.002 - 5.0 wt .-%, most preferably 0.005 - 3.0 wt .-%, each based on the total weight of the composition in cosmetic or dermatological compositions.