EP4405045A1

EP4405045A1 - Cosmetic compositions containing cannabidiol and zingiber extract

Info

Publication number: EP4405045A1
Application number: EP22793528.5A
Authority: EP
Inventors: Christoph Abels; Michael Soeberdt
Original assignee: Bionorica SE
Current assignee: Bionorica SE
Priority date: 2021-09-22
Filing date: 2022-09-21
Publication date: 2024-07-31
Also published as: WO2023046730A1

Abstract

The present invention relates to cosmetic compositions that contain cannabidiol and Zingiber extract, and to the use of those compositions as cosmetics.

Description

Cosmetic compositions containing cannabidiol and zingiber extract

The present invention relates to cosmetic compositions of cannabidiol (CBD) and an extract of Zingiber, preferably Zingiber officinale Roscoe rhizoma.

State of the art

A large number of people suffer from skin changes that are treated with drugs or where cosmetics are used to improve the appearance of the skin. Both in pharmaceuticals and in cosmetics, active ingredients are used that can be either synthetic or plant-based. In recent years, cannabidiol (CBD), a cannabinoid derived from female hemp (cannabis), in particular, has attracted interest for topical use on the skin due to its anti-inflammatory properties. In most countries, cannabis is classified as a narcotic and its use is heavily regulated or prohibited. The production of synthetic cannabidiol is also expensive.

Various effects of cannabidiol in the medical and cosmetic field have already been described, including analgesic, anti-inflammatory, antimicrobial and sebostatic effects.

Due to the positive experimental studies described above, several clinical studies with topical formulations containing CBD have been initiated in various dermatological indications in recent years. Of particular interest in this regard is a clinical trial of topical CBD in atopic eczema conducted by Botanix, Perth, Western Australia, and Philadelphia, USA. Atopic eczema is a chronic, inflammatory skin disease that cannot be cured. The characteristic symptoms are severe skin dryness combined with scaling and itching and, if the condition worsens, eczema, especially in the bends, with reddening and weeping. This randomized, double-blind, vehicle-controlled, 200-patient phase 2 study was conducted with CBD (BTX 1204) and did not meet the primary endpoint (ClinicalTrials.gov Identifier: NCT03824405): the objective of the study was to evaluate safety, tolerability and efficacy of cannabidiol. After 12 weeks of treatment, there was no statistically significant difference between the patients treated with cannabidiol (4% CBD formulation) and the control group treated with placebo. The clinical development of cannabidiol for the treatment of atopic eczema was then discontinued by Botanix. Another one, also from Botanix A study conducted in moderate acne (5% CBD formulation) in 386 patients also found no difference between the CBD-treated groups and the pooled placebo group (ClinicalTrials.gov identifier: NCT03573518).

Zingiber (ginger) is traditionally used in the treatment of arthrosis and rheumatism and to relieve pain, inflammation and colds.

The endocannabinoid system (ECS) comprises cannabinoid receptors (CB1 and CB2, TRPV1 and possibly also GPR55), arachidonic acid-derived ligands and their regulatory enzymes. The importance of the endocannabinoid system in peripheral tissues has been demonstrated in numerous recent studies (Di Marzo V. Targeting the endocannabinoid system: to enhance or reduce? Nat Rev Drug Discov. 2008 May; 7(5):438-55). While activation of the peripheral endocannabinoid system is commonly associated with anti-inflammatory and immunosuppressive effects, the role of the ECS in the skin is more complex. Activation of the CB2 receptor has been shown to trigger endorphins that have local analgesic effects (Ibrahim MM, Porreca F, Lai J, Albrecht PJ, Rice FL, Khodorova A, Davar G, Makriyannis A, Vanderah TW, Mata HP, Malan TP Jr. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids Proc Natl Acad Sci USA 2005 Feb 22;102(8):3093-8). When studying CB knockout mice, it was observed that the ECS and the CB1 receptor can inhibit the pathogenesis of allergic contact dermatitis (Karsak M, Gaffal E, Date R, Wang-Eckhardt L, Rehnelt J, Petrosino S, Starowicz K, R Steuder, E Schlicker, B Cravatt, R Mechoulam, R Buettner, S Werner, V Di Marzo, T Turing, A Zimmer A. Attenuation of allergic contact dermatitis through the endocannabinoid system.Science.2007 Jun 8;316(5830):1494 -7). Interestingly, it was shown in this study that inhibitors of anandamide (AEA) degradation via fatty acid amide hydrolase (FAAH) could be a promising therapeutic strategy to treat various forms of dermatitis. Overall, the endocannabinoid system is present in the skin, both CB1 and CB2 receptors have been identified in keratinocytes and fibroblasts, and the endocannabinoids are released in the skin where they appear to regulate several signals involved in inflammation. Anandamide exerts strong anti-inflammatory and anti-allergic effects (Leonti M, Casu L, Raduner S, Cottiglia F, Floris C, Altmann KH, Gertsch J. Falcarinol is a covalent cannabinoid CB1 receptor antagonist and induces pro-allergic effects in skin. Biochem. Pharmacol 2010, 79: 1815-1826). Raising the tone of the endogenous cannabinoid system leads to antipruritic effects. Increasing the local concentration of AEA by blocking FAAH or by Palmitoylethanolamide (PEA) by inhibiting N-acylethanolamine-hydrolyzing acid amidase (NAAA) leads to antipruritic effects in various animal models (Toth KF, Adam D, Biro T, Olah A. Cannabinoid Signaling in the Skin: Therapeutic Potential of the "C(ut )annabinoid" System. Molecules. 2019, 24: 918. doi: 10.3390/molecules24050918). For the Physiogel® AI cream containing PEA, antipruritic effects were found in 14 of 22 patients with various itchy skin diseases (StÃ¤nder S, Reinhardt HW, Luger TA. Topical cannabinoid agonists. An effective new possibility for treating chronic pruritus. Hautarzt 2006, 57: 801 -807).

An initial increase in the concentration of 2-arachidonylglycerol in inflamed tissue suggests that 2-AG has an important stimulatory role in sensitization, induction and exacerbation of allergic inflammation (Oka S, Wakui J, Ikeda S, Yanagimoto S, Kishimoto S, Gokoh M, Nasui M, Sugiura T. Involvement of the cannabinoid CB2 receptor and its endogenous ligand 2-arachidonoylglycerol in oxazolone-induced contact dermatitis in mice J Immunol 2006, 177: 8796-8805. As the literature shows, the endocannabinoid system is highly complex. It is therefore not surprising that CBD has a pleiotropic effect, which means that effects and side effects can be triggered through different pathways. For this reason, the mechanism of action of CBD is not yet exactly known.

The object of the present invention was to provide a composition or combination or mixture that combines the positive effects of CBD and a Zzz / gz / v extract on the skin with the lowest possible proportion of CBD in order to keep costs low and narcotics law to avoid problems. Since CBD hardly penetrates the skin and consequently cannot produce any effect in the skin, the present invention provides a composition which surprisingly penetrates the skin with low concentrations of CBD and Zzz/gz/v extract and thus produce an effect can, although a clinical study detailed below showed no effect in much higher concentrations of CBD.

In particular, a cosmetic composition will be made available that has an anti-inflammatory and antipruritic effect with a very low proportion of CBD.

Description of the invention

These objects are solved by the present invention. In particular, it has surprisingly been shown that the composition of the invention with CBD and a Z / z / / Ac / 'extract both an anti-inflammatory and an antipruritic (itch-relieving) effect, for example in people - without being limited to - with neurodermatitis-prone skin or with atopic eczema, although this in the low concentration of CBD was not to be expected due to the disclosed study results on CBD by Botanix, among others, and the unknown mechanism of action. In the present invention, the "Zzzz z/zcz'extract" may be synonymously referred to with the word ..zingibe or "ginger"; Zingiber extract is used in the present invention.

One reason for this could be the chemical structure of the CBD, which (even at high concentrations, 4 and 5% respectively) did not produce the desired effect. The structures of Zingiber's pungent substances, preferably those of gingerol and shogaol derivatives as well as zingiberene and ar-curcumene, show a high structural similarity to CBD. In particular, the aliphatic side chains (C5-C10) and the structural unit connected by the isopropyl/isopropylene function and connected via seven carbons suggest a similar activity and the synergistic effects observed according to the invention were therefore not to be expected, since the above-mentioned study with CBD had no effect had shown. In this respect, no effect of Zzz/z/v extract or a combination of CBD and Zzz/zAcz' extract was to be expected. In addition, it has been shown according to the invention that the skin barrier in subjects with a disturbed skin barrier (very dry skin or skin with a tendency to neurodermatitis or in the case of atopic eczema) is improved.

In the present invention, in particular, an anti-inflammatory effect is achieved by a surprisingly clear synergistic inhibition of the activation of the nuclear factor 'kappa light chain enhancer' of activated B cells (NF-KB) when the combination of CBD and Zzzz z/ v extract. It was not to be expected by the person skilled in the art that the combination of Zzzz z/zcz' extract and CBD would have synergistic anti-inflammatory effects. In particular, it was more than surprising that the combination of the two active ingredients did not lead to increased cytotoxicity. NF-κB is a transcription factor that plays an important role in inflammatory processes in the skin. NF-κB influences the transcription of genes by binding to regulatory sections of DNA. Activation of NF-κB results in increased transcription of pro-inflammatory genes and genes that induce or exacerbate pruritus. The transcribed proinflammatory cytokines include IL-lß, IL-6, IL-8 and TNF-α. Examples of cytokines important for the induction of itching, the transcription of which is mediated via NF-κB, are TSLP and IL-31. Inhibition of activation of NF-κB and the resultant reduced release of pruritogenic cytokines such as TSLP and IL-31 by the combination of CBD and Zzzz z/v extract according to the invention therefore also leads to antipruritic, ie itching-relieving effects, in addition to anti-inflammatory effects.

Further proof of synergistic effects is the significantly increased inhibitory effect on the release of the proinflammatory cytokines CCL20, IL-6, IL-8 and TNF-a when the combination of CBD and Zzzz z/zcz' extract according to the invention is administered.

The positive modulation of the endogenous cannabinoids anandamide, palmitoylethanolamide and oleoylethanolamide, which is significantly increased when the combination of CBD and Zzzz z/v extract according to the invention is administered, was completely unexpected for the person skilled in the art. Anandamide, palmitoylethanolamide and oleoylethanolamide have anti-inflammatory and antipruritic effects. At the same time, 2-arachidonylglycerol is negatively modulated. Since an initial increase in the concentration of 2-AG has an important stimulatory role in sensitization, induction and exacerbation of allergic inflammation (Oka S, Wakui J, Ikeda S, Yanagimoto S, Kishimoto S, Gokoh M, Nasui M, Sugiura T. Involvement of the cannabinoid CB2 receptor and its endogenous ligand 2-arachidonoylglycerol in oxazolone-induced contact dermatitis in mice (J Immunol 2006, 177: 8796-8805) is an initial reduction of 2-AG by the combination of CBD and CBD according to the invention Zzzz z/ v extract to be rated positively.

Pruritus (from the Latin prurire, "to itch") is an uncomfortable sensation on the skin that causes an urge to scratch or rub the itchy area called itchiness. Itching agents can both directly stimulate the endings of itch-sensitive nerves in the epidermis (upper skin) and act indirectly on these nerves by triggering an inflammatory response in keratinocytes, the main component of the epidermis. Recent work in cell and molecular biology has also shown that scratching or rubbing also activates the complex network of nervous and immune systems in the skin, which can strengthen the defense against potentially harmful substances. In particular, skin diseases of the epidermis are associated with itching. As already mentioned, the endocannabinoid system in the skin plays an important role in these processes and can be considered as a therapeutic target. For this reason, studies with CBD in topical formulations have been initiated by various companies in recent years, including Botanix (see above). The study in the indication atopic eczema with a topical formulation of 4% CBD has the primary End point missed. One reason for this may be the lipophilic structure of CBD and an interaction with endogenous cannabinoids. All endocannabinoids are lipophilic and therefore enter the cell via both active and passive transport mechanisms. A high concentration of externally supplied CBD could thus lead to a local lipid shift, including components of the endocannabinoid system such as anandamide, on or in the cell and disrupt the homeostasis of the various endocannabinoids that are important for the anti-inflammatory tone of the system , so that if necessary negative effects outweigh the positive effects. In the already cited study by the company Botanix, more patients in the placebo group (without CBD) reached the primary endpoint than in the verum group with CBD (18.9% versus 12.1%).

In addition, due to the effects of the ginger/zzz/ z/zcz rootstock described in the literature, which are primarily achieved by systemic administration (oral) - as also described in the EMA monograph, it is not obvious that these can also be achieved by a topical administration can be achieved, since Zingiber extracts can cause local irritation due to their ingredients. This irritation would lead to a deterioration in the skin condition of patients with skin diseases such as atopic dermatitis or skin prone to neurodermatitis. The synergistic effects with regard to inflammation and itching in the low concentrations used are therefore correspondingly surprising, which can certainly be a reason why the target group with very dry skin prone to neurodermatitis or even atopic eczema or other inflammatory skin diseases ( almost) no intolerance reactions occur. Given the known stimulus-triggering properties of the Zzz/z/zcz extract, this was surprising and not to be expected.

For topical application, the active ingredients contained in the formulation of a drug or cosmetic must first be applied to the skin from the container in the formulation. Thereafter, the active ingredients must be released from the formulation and penetrate through the horny layer, which consists of comeocytes and a lamellar lipid layer, into the epidermis with the keratinocytes and the sensory nerve fibers. As already described, it is only there that an effect can be achieved that reduces itching in inflammatory skin diseases such as e.g. B. atopic eczema, lindem. In the case of lipophilic active substances such as CBD or the substances contained in the Zzzz z/zcz extract, e.g. B. ginger, shogaole, this is a challenge, both in terms of the stability of the formulation, the stability of the active ingredients and in terms of a possible interaction of the active ingredients with each other, which then leads to reduced effectiveness in the epidermis on the keratinocytes or sensory nerve fibers, so that no anti-inflammatory or antipruritic effect occurs. In particular, it is a challenge to transfer the effects observed in vitro, ie in particular the synergistic effects in certain ratios, to the clinical (in vivo) situation. In addition to a suitable formulation, which must also be cosmetically acceptable, the Zingiber extracts used according to the invention, so-called multi-substance mixtures, and the other substances contained therein are also of particular importance. Surprisingly, the present invention was also able to achieve improved penetration and thus a reduction in the active substance concentrations used by using suitable Zingiber extracts or combinations thereof, without the effectiveness being impaired.

The present invention thus relates to a cosmetic composition comprising a) cannabidiol and b) an extract from zingiber, characterized in that the extract from zingiber is a lipophilic extract, an alcoholic extract, a CCE extract or the zingiber from the rhizome of zingiber, preferably originates from Zingiber officinale Roscoe rhizoma. According to the invention, CBD is synthetically produced or of plant origin. In a preferred embodiment, synthetic CBD is used.

CBD is a cannabinoid (CAS 13956-29-1) with the following formula:

CBD can be obtained by methods that are well known, either by extraction from Cannabis sativa (e.g. as described in EP3799877 or US9,950,976), by fermentation (e.g. as described in WO2016/010827) or produced synthetically (e.g. as described in WO2020/229891, WO2020/169135 or WO2020/099283). CBD can also be obtained as a commercially available active ingredient from manufacturers such as CBDepot, Teplice, Czech Republic or Purisys, Athens, GA, USA. Preferably, the composition according to the invention comprises 0.001-3% by weight (wt.%) CBD, more preferably 0.001-0.5 wt.% CBD, more preferably about 0.01-0.5 wt.% CBD, even more preferably 0.05 -0.1% by weight CBD, based on the weight of the total composition. “Ca” means that the value includes a deviation of up to +/-20%.

The Zzrfgz'Zer extract used according to the invention can be a commercially available extract (produced as, for example, in US 2011/280976 or Mesomo MC et al., The Journal of Supercritical Fluids 2013, 80, 44-49). Suitable sources are Zingiber officinale Roscoe, where the extract can be obtained from the underground part of the plant (rootstock/rhizome). Zingiber officinale Roscoe is preferred. The extraction methods are well known and can be used, for example, with organic solvents such as alcohols (alcoholic extracts, e.g. methanol, ethanol, isopropanol), aqueous solutions of alcohols (e.g. methanol, ethanol, isopropanol), alkanes (e.g. pentane, hexane, heptane), chlorinated hydrocarbons (e.g. chloroform, methylene chloride), ketones (e.g. methyl ethyl ketone, acetone), esters (e.g. ethyl acetate), mixtures of alcohols and esters (e.g. methanol and ethyl acetate) or by extraction with supercritical carbon dioxide (CO2). Lipophilic extracts are preferred. A lipophilic extract is preferably prepared using ethanol, acetone, ethyl acetate, heptane or supercritical CO2. Production by means of extraction with ethanol, acetone or supercritical CO2 is particularly preferred. The preparation methods for the extracts mentioned above are known to those skilled in the art and are described, for example, in Moazeni and Kademmolhoseini, J. Parasit Dis. 2016, 40, 662-666, Sharif MF, Bennett MT, Jurnal Teknologi 2016, doi: 10.11113/jt.v78.9943, Li Y et al., Planta Med. 2012, 78, 1549-1555 and Hasan HA, et al ., pharmacist. Anal. Acta 2012, 3, doi: 10.4172/2153-2435.1000184.

According to the invention, extraction with supercritical carbon dioxide is particularly preferred, since natural source carbonic acid can be used and the extract can be obtained gently and in a particularly pure manner. In addition, the solvent CO2 can be easily removed without leaving any residue and recycled in a closed loop system. The Zingiber CO2 extract can be obtained as a commercially available extract from manufacturers such as Mane Kancor Ingredients Private Limited, Kochi, Kerala, India or FLAVEX Naturextracts GmbH, Rehlingen, Germany.

The extract from Zingiber is preferably a lipophilic extract. The extract from zingiber is particularly preferably an extract which is obtained using supercritical CO2. According to the invention, a pungent content of the extract between 1-50%, preferably between 20-50% and particularly preferably between 40-50% (by weight) is also preferred. Pungent substances within the meaning of the invention are ginger oil, shogaol, zingerone, ginger diols, dehydrogingerdiones and paradol. Preferably, the pungent ingredients include [6] gingerol, [8] gingerol, [10] gingerol, [6] shogaol, [8] shogaol, [10] shogaol and zingerone:

[6]-gingerol, CAS 23513-14-6: [8]-gingerol, CAS 23513-08-8:

According to the invention, the composition of the lipophilic Zzzz z/zcz extract used differs significantly from pure essential oil extracts or distillates of this plant (Mahboubi M, Clinical Phytoscience 2019, 5, Article number: 6). A lipophilic extract, preferably obtained by extraction with supercritical CO2, contains above all the so-called spicy substance fraction (HagerROM Hagers Handbuch der Drugs und Arzneistoffe - Zingiber HN: 2033300, page 7) of ginger, which is not volatile in water vapor and is absent in pure essential oil fractions . The characteristic ingredients of the lipophilic extract are primarily the homologous series of gingerol and shogaol, in particular [6]-gingerol, [8]-gingerol, [10]-gingerol, [6]-shogaol, [8]-shogaol, [10 ]-Shogaol as well as Zingeron and Zingiberen. The proportion of pungent substances outweighs that of the essential oil many times over. For example, for Zingiber CO2 extracts, a ratio of essential oil to [6]-gingerol from 1:7-10 (Mahboubi M, Clinical Phytoscience 2019, 5, Article number: 6).

According to the invention, the cosmetic composition comprises the components CBD and zzz/z/zcz extract in the weight ratios 1:100 to 1:1; preferably 1:10 to 1:2; particularly preferably 1:5 to 1:2. Furthermore, the composition of the invention preferably comprises 0.001-3% by weight CBD, more preferably 0.001-0.5% by weight CBD, more preferably about 0.01-0.5% by weight CBD, even more preferably 0.05- 0.1% by weight CBD, based on the weight of the total composition, and 0.001 - 5% by weight Zzz/ z/zcz extract, preferably 0.01 - 2% by weight Zzz/ z/zcz extract, particularly preferably 0 0.05-0.5% by weight of Zingi/icv extract, each based on the weight of the total composition, and in the weight ratios CBD:Zzz/z/zcz extract described above.

Zzzzgz7>er CO2 extracts are particularly preferred, which include the following substances: 15-30% by weight [6]-gingerol, 3-10% by weight [8]-gingerol, 3-10% by weight [10 ]-gingerol, 0.5-4% wt. [6]-shogaol, 0.03-1.3% wt. [8]-shogaol, 0.03-1% wt. [10]-shogaol , 0.01-1% by weight Zingeron, with the ginger oil content being 24-50% by weight and the shogaol content being 0.5-6% by weight. Another preferred embodiment of a Zingiber CO2 extract comprises: 25-30% by weight [6] gingerol, 5-10% by weight [8] gingerol, 5-10% by weight [10] gingerol, 1, 5-4 wt% [6] shogaol, 0.3-1.3 wt% [8] shogaol, 0.03-1 wt% [10] shogaol, 0.01-1 wt% Zingeron, , where the proportion of ginger oil is 35-50% by weight and the proportion of shogaole is 1.5-6% by weight. Extracts of this type and their preparation are described in EP 2772245 A1. Another preferred Zzzz z/zcz-CCh extract contains 15-25% by weight [6]-gingerol, 3-5% by weight [8]-gingerol, 3-8% by weight [10]-gingerol, 0, 5-3 wt% [6] shogaol, 0.03-1 wt% [8] shogaol, 0.03-1 wt% [10] shogaol, 0.01-1 wt% zingerone, The proportion of ginger oil is 24-35% by weight and the proportion of shogaole is 0.5-5% by weight.

The pungent content can be determined using known analysis methods. An example is the mass spectrometric determination of the pungent content. Furthermore, the pungent content can be determined chromatographically, e.g. by means of HPLC chromatography, using reference substances.

The composition according to the invention also preferably comprises one or more adjuvants. The excipients are commercially available excipients, particularly those materials known to be employed in topical formulations for application to the skin. Suitable auxiliaries are described, for example, in WO2001/066076 A and DE 10 2005 029 387 A1, preferably solvents such as organic solvents, carriers, gelling agents, detergents, emulsifiers, solubilizers, humectants, fillers, bioadhesives, emollients, preservatives, bactericides, surfactants, perfumes , pearlescent waxes, consistency enhancers, thickeners, superfatting agents, softeners, humectants, oils, fats, waxes, lecithins, phospholipids, biogenic active ingredients, antioxidants, film formers, swelling agents, hydrotropes, water, alcohols, polyols, polymers, foam stabilizers, foaming agents, antifoaming agents, hair coating agents or other suitable components of a cosmetic preparation.

The composition according to the invention can contain preservatives. Examples of preservatives are organic acids such as formic acid, sorbic acid, p-anisic acid and benzoic acid. In addition, esters of p-hydroxybenzoic acid, formaldehyde-releasing agents such as DMDM hydantoin, imidazolidinylurea or methylchloroisothiazolinone, methylisothiazolinone, dibromodicyanobutane, iodopropynylbutylcarbamate, phenoxyethanol or benzyl alcohol can be used as bactericides.

Other dermatologically acceptable adjuvants for the purposes of the present invention can be inorganic or organic substances for topical application to the skin. The pH of the formulation can be stabilized with buffer systems consisting of polyacids and their salts. Examples of such polyacids are citric acid, tartaric acid or malic acid.

The compositions according to the present invention may comprise carriers or solvents, preferably water, alcohols, esters, butylene glycol, dipropylene glycol, pentylene glycol, 1,2-hexanediol, caprylyl glycol, decylene glycol, ethanol, ethoxy di glycol, ethyl acetate, glycerol, propanol, isopropanol, macrogols ,

Propyl Propylene Glycol 2 Methyl Ether, Propyl Propylene Glycol 3 Methyl Ether, Propylene Carbonate, Propylene Glycol, Triethylene Glycol, Isoparaffin, Amyl Acetate, Amyl Benzoate, Benzyl Acetate,

Butyl acetate, butylene glycol, butyl lactate, butooctyl benzoate, butooctyl salicylate, C10-C13 alkanes, C14-C17 alkanes, CI 1-C15 cycloalkanes, caprylyl butyrate, isoparaffins, diacetin, triacetin dicaprylyl ether, dicaprylyl maleate and mixtures thereof. Glycerin, propylene glycol, butylene glycol, dipropylene glycol, pentylene glycol, 1,2-hexanediol, caprylyl glycol and decylene glycol are particularly preferred. In the context of the present invention, the composition is preferably a dermatological or cosmetic composition suitable for topical application to the skin of a mammal, preferably a human.

The cosmetic composition is preferably in the form of an emulsion or microemulsion. Another preferred form is, for example, a cream (oil-in-water (O/W) or water-in-oil (W/O)), a lotion, a spray, shampoo, foam, serums, a face mask, ointment, Tincture or an oil, eye care products, cleansing products or soaked pads, and face or hand creams with sunscreen (such as SPF) and cooling eye care products. Also preferred are an acute cream, a face cream, a hand cream and a body lotion or skin lotion. In principle, the cosmetic composition according to the invention is suitable for rinse-off or leave-on products (cosmetic products that are rinsed off, e.g. shampoo). Leave-on products (products that remain on the skin, e.g. body lotion) are preferred.

According to the invention, the composition is used as a cosmetic. The term "cosmetic" preferably refers to compositions intended to care for the skin, to improve skin conditions, to prevent, prevent or alleviate adverse skin conditions.

The composition according to the invention is preferably used for the application or treatment of sensitive or sensitive skin, rough skin, dry skin and/or irritated skin (e.g. reddened skin after sunburn, abrasions or otherwise irritated skin etc.) with or without itching, but also of aged skin , xerosis cutis, inflammatory conditions of the skin, such as in particular atopic dermatitis (neurodermatitis, atopic eczema), acne, rosacea, psoriasis and the prevention of skin infections or to reduce susceptibility to contact allergies or to prevent the skin conditions mentioned.

It further includes topical application or treatment to improve epidermal barrier functions and barrier integrity, to improve the appearance of the skin, to provide antioxidant effects and/or to increase the skin's moisture or lipid content.

The composition of the present invention is preferably applied topically to the skin of mammals, preferably humans. Typical application sites are in addition to the entire body, face/head (e.g. forehead, chin, neck and scalp), armpit, armpits, palms, soles of feet, back of knees, torso and groin. The composition of the present invention is applied to the skin of a mammal, preferably a human, preferably 1 to 4 times a day, preferably 1 to 2 times a day and more preferably 1 time a day before bedtime (for non-sunscreen products) and is applied in a cosmetic manner acceptable dosage used.

Brief description of the illustrations

Figure 1 shows the multivariate evaluation (principal component analysis, PCA) of a cosmetic screen with 23 plant extracts and CBD. PCI and PC2 are plotted.

Figure 2 shows the anti-inflammatory effect of CBD and Zingiber (CO2 extract with 47.7% pungent substances) with increasing concentrations in percent of the control (TNFa DMSO) after stimulation of HaCaT cells by TNF-α. Mean values and the standard deviation are shown. *p<0.05 vs. TNFa DMSO.

Figure 3 shows the anti-inflammatory effect of CBD and Zingiber (CO2 extract with 47.7% pungent substances) and combinations of CBD and Zingiber with increasing concentrations as a percentage of the control (UVB DMSO) after UVB irradiation of HaCaT cells. Mean values and the standard deviation are shown. *p<0.05 versus UVB DMSO.

Figure 4 shows the anti-inflammatory effect of CBD and Zingiber (CO2 extract with 47.7% pungent substances) and combinations of CBD and Zingiber with increasing concentrations as a percentage of the control (TNFa DMSO) after stimulation of HaCaT cells by TNF-α. Mean values and the standard deviation are shown. *p<0.05 vs. TNFa DMSO.

Figure 5 shows the anti-inflammatory effect of CBD and Zingiber (CO2 extract with 47.7% pungent substances) with increasing concentrations in percent of the control (UVB DMSO) after UVB irradiation of HaCaT cells. Mean values and the standard deviation are shown. *p<0.05 *p<0.05 versus UVB DMSO.

Figure 6 shows the anti-inflammatory effect of CBD (1 pg/ml) and Zingiber (CO2 extract with 47.7% pungent substances) (5 pg/ml) and a 1:5 combination of CBD and Zingiber (1 pg/ml and 5 pg /ml) in percent reduction compared to the control (TNFa DMSO) after stimulation of HaCaT cells by TNF-α. Mean values and the standard deviation are shown. *p<0.05 vs. TNFa DMSO.

Figure 7 shows the anti-inflammatory effect of CBD (5 pg/ml) and Zingiber (CO2 extract with 47.7% pungent substances) (10 pg/ml) and a 1:2 combination of CBD and Zingiber (5 pg/ml and 10 pg/ml) in percent reduction compared to the control (TNFa DMSO). Stimulation of HaCaT cells by TNF-α. Mean values and the standard deviation are shown. *p<0.05 vs. TNFa DMSO.

Figure 8 shows the anti-inflammatory effect of CBD (5 pg/ml) and Zingiber (CO2 extract with 47.7% pungent substances) (5 pg/ml) and a 1:1 combination of CBD and Zingiber (5 pg/ml and 5 pg /ml) in percent reduction compared to the control (TNFa DMSO) after stimulation of HaCaT cells by TNF-α. Mean values and the standard deviation are shown. *p<0.05 vs. TNFa DMSO.

Figure 9 shows the amount of 1-arachidonylglycerol (1-AG) in cell pellets from HaCaT keratinocytes and the concentration of 1-AG in the cell supernatant. Values are shown for CBD (5 pg/ml) and Zingiber (CO2 extract with 47.7% pungent substances) (20 pg/ml) and for a 1:4 combination of CBD and Z/z/g/Ac/' extract (5 pg/ml and 20 pg/ml) compared to the control (TNFa DMSO) after stimulation of HaCaT cells by TNF-α. Non-stimulated cells and their supernatant were examined as a negative control (Crtl DMSO).

Figure 10 shows the amount of 2-arachidonylglycerol (2-AG) in cell pellets from HaCaT keratinocytes and the concentration of 2-AG in the cell supernatant. Values are shown for CBD (5 pg/ml) and Zingiber (CO2 extract with 47.7% pungent substances) (20 pg/ml) and for a 1:4 combination of CBD and Z/'/zg/Ac/' extract (5 pg/ml and 20 pg/ml) compared to the control (TNFa DMSO) after stimulation of HaCaT cells by TNF-α. Non-stimulated cells and their supernatant were examined as a negative control (Crtl DMSO).

Figure 11 shows the amount of anandamide (AEA) in cell pellets from HaCaT keratinocytes and the concentration of AEA in the cell supernatant. Values are shown for CBD (5 pg/ml) and Zingiber (CO2 extract with 47.7% pungent substances) (20 pg/ml) and for a 1:4 combination of CBD and Zzzzgz/zcz extract (5 pg/ml and 20 pg/ml) compared to the control (TNFa DMSO) after stimulation of HaCaT cells by TNF-α. Non-stimulated cells and their supernatant were examined as a negative control (Crtl DMSO).

Figure 12 shows the amount of oleoylethanolamide (OEA) in cell pellets from HaCaT keratinocytes and the concentration of OEA in the cell supernatant. Values are shown for CBD (5 pg/ml) and Zingiber (CO2 extract with 47.7% pungent substances) (20 pg/ml) and for a 1:4 combination of CBD and Zzzzgz/zcz extract (5 pg/ml and 20 pg/ml) compared to the control (TNFa DMSO) after stimulation of HaCaT cells by TNF-α. Non-stimulated cells and their supernatant were examined as a negative control (Crtl DMSO). Figure 13 shows the amount of palmitoylethanolamide (PEA) in cell pellets from HaCaT keratinocytes and the concentration of PEA in the cell supernatant. Values are shown for CBD (5 pg/ml) and Zingiber (CO2 extract with 47.7% pungent substances) (20 pg/ml) and for a 1:4 combination of CBD and zzz/ z/zcz extract (5 pg/ ml and 20 pg/ml) compared to the control (TNFa DMSO) after stimulation of HaCaT cells by TNF-α. Non-stimulated cells and their supernatant were examined as a negative control (Crtl DMSO).

Figure 14 shows the anti-inflammatory effect (release of CCL20, IL-6, IL-8 and TNF-a) of Zingiber (CO2 extract with 47.7% pungent substances) with increasing concentrations in percent of the control (poly(EC)) after stimulation of normal human epidermal keratinocytes (NHEK) using poly(EC). Mean values and the standard deviation are shown. *p<0.05 vs. Poly(EC).

Figure 15 shows the anti-inflammatory effect (CCL20, IL-6, IL-8 and TNF-α release) of CBD with increasing concentrations in percent of control (Poly(LC)) after stimulation of normal human epidermal keratinocytes (NHEK) with Poly (LC). Mean values and the standard deviation are shown. *p<0.05 vs. Poly(LC).

Figure 16 shows the anti-inflammatory effect (release of CCL20, IL-6, IL-8 and TNF-a) for a combination of Zingiber (CO2 extract with 47.7% pungent substances) and CBD in a 4:1 ratio with increasing percentage concentrations the control (Poly(LC)) after stimulation of normal human epidermal keratinocytes (NHEK) with Poly(LC). Mean values and the standard deviation are shown. *p<0.05 vs. Poly(LC).

Figure 17 shows the anti-inflammatory effect (release of CCL20, IL-6, IL-8 and TNF-a) for a combination of Zingiber (CO2 extract with 47.7% pungent substances) and CBD in a ratio of 4: 1 (4 pg/ml and 1 pg/ml) compared to the effects of Zingiber (CO2 extract with 47.7% pungent substances, 4 pg/ml) and CBD (1 pg/ml) in percent reduction compared to the control (poly(LC)) after Stimulation of normal human epidermal keratinocytes (NHEK) using poly(I:C). Mean values and the standard deviation are shown. *p<0.05 vs. Poly(LC).

FIG. 18 shows the results of the subjective assessment of the itching by the subjects in a clinical cosmetics study of adults who were treated with a cream according to the invention containing 0.5% by weight of Zingiber CO2 extract and 0.1% by weight of CBD. The difference in the evaluation of the itching (NRS-11 Scale) in % compared to Day 1. Shown are mean values and the standard error of the mean based on N=44 subjects (Day 7 N=33 subjects).

Figure 19 shows the results of the subjective evaluation of the itching by the subjects in a clinical cosmetics study of adults who were treated with a body lotion according to the invention with 0.2% by weight of Zingiber CO2 extract and 0.05% by weight of CBD. Ratings on day 1 and day 29 are plotted. Means and standard error of the mean based on N=22 subjects are shown; paired t-test two-tailed, a=0.05; p<0.0001.

FIG. 20 shows the results of the subjective assessment of the itching by the subjects in an application study with subjects who were treated with a face cream according to the invention with 0.1% by weight Zingiber CO2 extract and 0.05% by weight CBD. Ratings on day 1 and day 15 are plotted. Means and standard error of the mean based on N=33 subjects are shown; paired t-test two-tailed, a=0.05; **p=0.0019.

Figure 21 shows the results of the subjective assessment of the itching by the subjects in an application study with subjects who were treated with a hand cream according to the invention with 0.2% by weight of Zingiber CO2 extract and 0.05% by weight of CBD. Ratings on day 1 and day 15 are plotted. Means and standard error of the mean based on N=33 subjects are shown; paired t-test two-tailed, a=0.05; **p=0.0098.

examples

Example 1: Cosmetic screen with CBD and 23 plant extracts

In order to be able to select a suitable plant extract for the cosmetic composition with CBD, 23 extracts from different plants, which were produced with extractants of different polarity from aqueous to alcoholic to supercritical CO2, were examined in a cosmetic screen.

For this purpose, epidermal proliferation, differentiation pathways and moisturizing activity were determined by studies of cellular toxicity, proliferation in fibroblasts and keratinocytes, and glucose uptake in keratinocytes.

Antioxidant tests were performed with isoprostane in fibroblasts, ROS in keratinocytes and NO in RAW macrophages. The biology of dennis, skin tightening and anti-wrinkle activity was studied with MMP1, MMP9 and TIMP1 in keratinocytes. Inflammatory characteristics of the skin were examined by measuring PGE2, IL-6, IL-8 in fibroblasts and NF-κB in HEK293t cells, skin lightening via melanin synthesis in melanocytes.

Due to the large number of individual results for the 23 plant extracts and CBD, the results were evaluated multivariably.

The multivariate evaluation of the anti-inflammatory and antioxidant effects of the plant extracts tested is shown in Figure 1. The results for the release of IL-6, IL-8, PGE2 and isoprostane from NHDF, NO from RAW macrophages, ROS in HaCaT and the activation of NF-kB in HEK293t cells were included in the evaluation.

Different effects of the same extract in different concentrations:

Only extracts were taken into account that did not show a positive (mean value > 120) and a negative effect (mean value < 80) in any variable at different concentrations. Only extracts that show no positive (mean > 120) and no negative effect (mean < 80) at different concentrations in any variable were considered. An aggregation over concentrations (mean of means) was performed for 21 extracts and CBD with 7 variables.

Principal component analysis (PCA) showed the cumulative proportion of variance of PCI and PC2 to be 65%. The CBD, Rumex and Zzzz z/zcz extract were clearly separated from the large number of other extracts and showed only minor differences on the PC2. CBD, Rumex and Zzzz z/zcz extract were shifted towards higher activity on both axes (Figure 1). Multivariate analysis of these trials suggested that Rumex, CBD and Zzzz z/v extract might be suitable for providing a cosmetic composition. In the course of further tests with Rumex and CBD, however, it turned out that the combination of Rumex and CBD or even Rumex alone had no effect in the subsequent tests, despite the positive and very similar results from these tests. Rumex was thus unsuitable for the cosmetic composition.

Example 2: Anti-inflammatory effects of CBD and Zzzzgz/zcz extract in HaCaT cells

1. Cytotoxicity Assays

Resazurin assay: The resazurin assay, which was performed in parallel plates to the NF-κB test, was used to investigate the toxic potential in UVB-based inflammatory response screening. Resazurin is reduced by vital cells to resorufin, which can be detected by fluorescence measurements (extinction 560 nm, emission 590 nm) can be quantified. Cytotoxic substances reduce the metabolic activity of the cells, which leads to a slowdown in resazurin turnover and thus a reduction in the fluorescence signal, which is proportional to the metabolic activity of the culture.

The media residue was removed after treatment and the cells were washed with prewarmed DPBS (Dulbecco's phosphate-buffered saline). 100 µl medium with 2% FBS (fetal bovine serum) and 10% resazurin solution (working stock concentration 0.15 mg/ml in DPBS) was added and stored for 3 h (confluent cells) or 4 h (proliferative cells) at 37°C, 5% CO2 and 90% humidity incubated. The fluorescence signal was measured with a plate reader at an excitation-excitation wavelength of 540 nm/590 nm. All experiments were performed in the form of technical and biological triplicates.

Unless otherwise stated, the metabolic activity of the HaCaT NF-κB cells was determined 24 h after the induction of inflammation.

Lactate dehydrogenase (LDH) release test:

An LDH test was used to monitor cell toxicity in TNF-α-based inflammatory response screening. The lactate dehydrogenase release assay quantitatively measures lactate dehydrogenase (LDH) in the medium, a stable cytosolic enzyme that is released during cell lysis (the LDH half-life is approximately 9 hours). The LDH test was carried out using the non-radioactive cytotoxicity test CytoTox 96® from Promega (Gl 780) according to the manufacturer's instructions. 50 µl of supernatant from each sample was transferred to a Sarstedt 96-well plate. Then 50 μl of reconstituted substrate mixture were added and incubated for 30 minutes at room temperature with the exclusion of light. Positive and negative controls were always measured (LDH positive control, Promega G181 A; lysis solution 10x, Promega G182A). After the incubation time of 30 minutes, 50 μl of stop solution were added and the absorbance signal was read at 490 nm using the microplate reader.

2. Inflammation Assays

A HaCaT NF-KB reporter cell line was used for the inflammation assay. Treatment with extracts was carried out after exposure to UVB. The cells were irradiated with 0.15 J/cm ² UVB light and then treated with the extract for 24 hours. The reporter cell line HaCaT was also used for cytokine induction screening of NF-κB. In this screening setup, NF-κB activation was induced using 0.75 ng/ml TNF-α. The cytotoxicity was examined with the LDH assay. DMSO concentrations up to 0.5% on the HaCaT cells had no effect on the inflammation assay. Consequently, concentration differences below the threshold of 0.5% DMSO were not separately corrected and balanced.

The assays were performed as follows:

One day before the treatment, 17,000 cells per well were seeded, which provided a confluent cell lawn for the treatment. NF-κB luciferase reporter cells were then either irradiated with UVB via Vilber BIO-SUN or treated with TNF-α. Subsequent to the treatment, the cells were washed with PBS and lysed with 40 μl of cold lysis buffer (250 mM Tris-HCl pH=7.5, 2% Triton X-100) at RT for 3 min. Then 150 μl assay buffer (6.85 ml H2O dist., 2.5 ml 0.1 M glycylglycine, pH=7.8, 0.5 ml 0.1 M ATP and 150 μl 1 M MgSO4) were added and mixed. The luminescence signal was measured with a plate reader with injector function (Mithras LB940, Berthold Technologies LLC). The measurement program of the plate reader injected 50 μl injection buffer (3.9 ml H2O dist., 1 ml 0.1 M glycylglycine pH=7.8, 100 μl 4 mM luciferin) per well, mixed the plate for 2 seconds and then detected the luminescence signal in relative light units (RLU) .

Results: Cytotoxic effect of CBD and Zzzzgz/zcz extract:

The cytotoxic effect of CBD and Zzzzgz/zcz extract was evaluated 24 hours after the start of treatment. The HaCaT cells were treated with the test substances for 24 hours, then the cells were washed and their viability assessed.

For further investigations, CBD was used in non-toxic concentrations of 1, 2, 3, 4, 5 and 6 pg/ml and Zingiber (CO2 extract with 47.7% pungent substances) in non-toxic concentrations of 2.5, 5, 10 , 15, 20 and 25 pg/ml and 20, 40 and 60 pg/ml are used. The Zzzzgz/zcz extract prepared with 70% ethanol was used in further investigations in non-toxic concentrations of 50, 100 and 150 pg/ml. The non-toxic concentrations of the Zzzzgz/w extracts prepared with methanol, acetone, ethyl acetate and heptane selected for further investigations were 20, 40 and 60 pg/ml.

Anti-inflammatory effect after inflammation induction by TNF-α: The anti-inflammatory effect was evaluated 6 hours after treatment of the HaCaT cells with CBD. For this purpose, the inflammatory induction was carried out by adding TNF-α, after which the cells were incubated with CBD for a period of 6 h. Control cells were treated with the same amount of DMSO that served as the solvent for CBD. A significant anti-inflammatory effect could already be demonstrated from a concentration of 4 pg/ml. Even at a CBD concentration of 20 pg/ml, there was a 49% reduction in reporter activity (Figure 1). This effect showed classic dose dependence. The maximum effect was 54%. The simultaneous determination of the viability of the cells showed no reduction in viability in the control group after treatment with TNF-α. The addition of CBD only led to a slight reduction in cell viability at concentrations of 5 and 6 pg/ml, but this was still over 80%.

The anti-inflammatory effect was evaluated 6 hours after treatment of the HaCaT cells with Zingiber (CO2 extract with 47.7% pungent substances). For this purpose, the inflammatory induction was carried out by adding TNF-α, after which the cells were incubated with the extract for a period of 6 h. The control cells were treated with the same amount of DMSO that served as the solvent for the Zingiber extract. A significant anti-inflammatory effect could already be demonstrated from a concentration of 10 pg/ml. Even a Zingiber extract concentration of 20 pg/ml reduced the reporter activity by 42% (Figure 1). This effect showed classic dose dependence. The maximum effect was 56%. The simultaneous determination of the viability of the cells showed no reduction in viability in the control group after treatment with TNF-α. The addition of the Zingiber extract had no additional impact on cell viability.

The anti-inflammatory effect of the alcoholic and lipophilic extracts from Zingiber was evaluated 6 hours after treatment of the HaCaT cells. The CO2 extract with 47.7% pungent substances was carried along for comparison. Significant, dose-dependent anti-inflammatory effects were demonstrated for all extracts. The maximum effect was between 68.8 and 77.4%. A 93.2% reduction in reporter activity was observed for the Zingiber (CO2 extract with 47.7% pungent substances) extract at a concentration of 60 pg/ml (Table 1). The simultaneous determination of the viability of the cells showed no reduction in viability in the control group after treatment with TNF-α. The addition of the Zingiber extracts had no additional impact on cell viability. Table 1: Anti-inflammatory effects of extracts from Zingiber officinale Roscoe rhizome

Stimulation with TNF-α

The extraction agent, the concentrations of the Zingiber extracts used, the inhibition of the activation of NF-κB and the standard deviation (SD) are shown.

All Zzzz z/zcz extracts had a comparable effect on inhibition of NF-κB activation. The CCE extract showed the best effect.

Anti-inflammatory effect after inflammation induction by UVB radiation:

The anti-inflammatory effect of CBD was evaluated by a 24-hour treatment with CBD following inflammation induction by UVB irradiation. The Control cells were treated with the same amount of DMSO that served as the solvent for CBD. A dose-dependent anti-inflammatory effect could be demonstrated. A significant reduction in reporter activity by 23% was detected even at a concentration of 3 pg/ml (Figure 2). This effect increased with increasing concentration of CBD. A 40% reduction in reporter activity was achieved for 6 pg/ml CBD. The simultaneous determination of the viability of the cells showed a reduction to approx. 70% in the control group after irradiation with UVB (UVB DMSO). The addition of CBD had no additional impact on cell viability.

The anti-inflammatory effect of Zingiber (CO2 extract with 47.7% pungents) was evaluated by treatment with extract for 24 hours, following inflammation induction by UVB irradiation. The control cells were treated with the same amount of DMSO that served as the solvent for the extract from Zingiber. A dose-dependent anti-inflammatory effect could be demonstrated. A significant reduction in reporter activity by 32% was detected even at a concentration of 15 pg/ml (Figure 2). This effect increased with increasing concentration of zingiber extract. A 55% reduction in reporter activity was achieved for 25 pg/ml extract from Zingiber. The simultaneous determination of the viability of the cells showed a reduction to approx. 70% in the control group after irradiation with UVB (UVB DMSO). The addition of Zingiber extract had no additional impact on cell viability.

Example 3: Synergistic and additive anti-inflammatory effects of CBD and Zingiber extract in HaCaT cells

In a follow-up experiment, combinations of CBD and Zingiber (CO2 extract with 47.7% pungent substances) were examined for anti-inflammatory effects after stimulation of HaCaT cells with TNF-α or irradiation with UVB. Concentrations of 1, 3 and 5 pg/ml were selected for CBD and concentrations of 5, 10 and 20 pg/ml for the extract from Zingiber. NF-κB activation and cell viability were determined as described in Example 1.

Whitaferin A (TNF-α) and kojic acid (UVB) were used as positive controls.

The data obtained from the studies was analyzed with SynergyFinder 2.0. The analysis took place with duplicates of three biological replicates (n=6). Data were normalized to the induction control for NF-κB and to the control for viability. Analysis Parameters: A four parameter logistic regression (LL4) is a default option for the curve fitting algorithm used to fit dose-response curves of single compounds. The Detect Outliers option is enabled to allow automatic detection of outliers. The synergy was calculated using the ZIP model (Zero Interaction Potency).

Evaluation:

Less than -10: The interaction between the two active substances is probably antagonistic.

From -10 to 10: The interaction between the two active ingredients is probably additive.

Greater than 10: The interaction between the two active ingredients is probably synergistic.

The anti-inflammatory effect was evaluated 6 hours after treatment of the HaCaT cells with CBD and/or Zingiber (CO2 extract with 47.7% pungent substances). For this purpose, the inflammatory induction was carried out by adding TNF-α, after which the cells were incubated with CBD and/or extract for a period of 6 h. Control cells were treated with the same amount of DMSO that served as the solvent for CBD and the Zingiber extract. A significant anti-inflammatory effect was found for the individually tested test substances CBD (5 pg/ml) and Zingiber extract (5, 10 and 20 pg/ml), which confirms the results from example 1. All combinations of CBD and Zingiber extract also showed a significant reduction in NF-κB activation. Dose-dependent effects are shown for each combination of a concentration of CBD with the extract from Zingiber. The effect size for the combination is larger than the effect size for CBD alone (Figure 3). The difference between the groups 1 pg/ml CBD/1 pg/ml CBD + 20 pg/ml extract from Zingiber is statistically significant (p<0.05). The same applies to 3 pg/ml CBD and all combinations thereof with the Zingiber extract and 5 pg/ml CBD and all combinations thereof with the Zingiber extract.

Analysis with SynergyFinder 2.0 revealed that only some combinations showed synergistic effects on NF-κB activation (Table 2). These synergy values are in bold. Antagonistic effects were not found.

The simultaneous determination of the viability of the cells showed no reduction in viability in the control group after treatment with TNF-α (4.97% reduction compared to the DMSO control). The addition of CBD, the extract from Zingiber or the combination had no significant impact on cell viability (inhibition between 0.10 and 7.66% reduction compared to DMSO control). The results are shown in Table 3. Effects for CBD and extract of Zingiber alone and in combination in the ratios 1:1, 1:2 and 1:5 are shown in Figures 5, 6 and 7.

Table 2: Anti-inflammatory effects of the combination of CBD and Zingiber officinale Roscoe Rhizome CCE extract and analysis of synergy after stimulation with TNF-α

The concentrations of CBD and the Zingiber extract used, the inhibition of the activation of NF-κB, the standard deviation (SD) and the synergy determined in SynergyFinder 2.0 are shown. Table 3: Effects of the combination of CBD and Zingiber officinale Roscoe Rhizome CO2 extract on cell viability and analysis of synergy after stimulation with TNF-α

The concentrations of CBD and the Zzzz z/w extract used, the inhibition of cell viability, the standard deviation (SD) and the synergy determined in SynergyFinder 2.0 are shown.

The anti-inflammatory effect of CBD and/or Zingiber (CO2 extract with 47.7% pungent substances) was evaluated by a 24-hour treatment with the test substances or combinations thereof, following inflammation induction by UVB irradiation. The control cells were treated with the same amount of DMSO that served as the solvent for the test substances. A significant anti-inflammatory effect was found for the individually tested test substances CBD (1, 3 and 5 pg/ml) and Z/z/ /Ac/' extract (10 and 20 pg/ml), which confirms the results from Example 1. All combinations of CBD and Zingiber extract also showed a significant reduction in NF-κB activation. Dose-dependent effects are shown for each combination of a concentration of CBD with the extract from Zingiber. The effect size for the combination of 1 pg/mL CBD with 10 or 20 pg/mL extract from Zingiber (39 or 57% reduction, respectively) is larger than the effect size for CBD alone (34% reduction). The same applies to the combination of 3 pg/ml CBD with 10 or 20 pg/ml extract from Zingiber (66 or 80% reduction) versus 54% reduction for CBD alone. For all combinations with 5 pg/ml CBD and extract from Zingiber will observe larger effects than for CBD alone (78, 80 and 87% reduction vs. 71% reduction for CBD alone) (Figure 4). The difference between the groups 1 pg/ml CBD, 3 pg/ml CBD and 5 pg/ml CBD and the respective combination with Zingiber extract is statistically significant (p<0.05).

Analysis with SynergyFinder 2.0 revealed that some combinations showed synergistic effects on NF-κB activation (Table 4). These synergy values are in bold. Antagonistic effects were not found. Table 4: Anti-inflammatory effects of the combination of CBD and Zingiber officinale Roscoe Rhizome CCE extract and analysis of synergy after UVB irradiation

The concentrations of CBD and the Zzzz z/w extract used, the inhibition of the activation of NF-κB, the standard deviation (SD) and the synergy determined in SynergyFinder 2.0 are shown. Example 4 Influencing the concentration of endocannabinoids by CBD and Zzz?gzZ>er extract (COg extract with 47.7% pungent substances) and a combination of CBD and Zzzzgz/zcz' extract in HaCaT cells after stimulation with TNF-q

The inflammation assay was performed as described in Example 2. After the incubation, the cells were centrifuged off and separated from the cell supernatant. The concentration of the endocannabinoids 1-arachidonylglycerol (1-AG), 2-arachidonylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) was measured by LC-MS in the cell pellet and in the cell supernatant.

Results:

The effect on the concentration of endocannabinoids was evaluated 4, 8 and 24 hours after stimulation of HaCaT cells with TNF-α. The stimulation with TNF-a (TNF-a DMSO) led to an increase in the concentration of 1-AG in the cell pellet after 8 and 24 hours compared to the unstimulated control (Crtl DMSO). After 4 hours of stimulation with TNF-α, the concentration of 1-AG in the supernatant was lower than in the unstimulated control (Figure 8). The stimulation with TNF-a (TNF-a DMSO) led to an increase in the concentration of 2-AG in the cell pellet after 8 hours compared to the unstimulated control (Crtl DMSO) (Figure 9). The stimulation with TNF- had no influence on the concentration of AEA and OEA (Figures 10 and 11). The concentration of PEA in the cell pellet was increased after 8 and 24 hours after stimulation with TNF-. Less PEA was found in the supernatant after 4 hours and more after 8 hours than in the unstimulated control (Figure 12).

The effect of CBD on the concentration of endocannabinoids was evaluated 4, 8 and 24 hours after treatment of HaCaT cells with CBD (5 pg/ml). CBD showed a reduction in 1-AG (8 hours and 24 hours) and 2-AG (8 hours) in the cell pellet compared to the stimulated control (TNF-DMSO) (Figures 8 and 9). No effects were observed on the concentrations in the supernatants for 1-AG and 2-AG and the supernatants and cell pellets for AEA and OEA (Figures 8-11). The concentration of PEA in the cell pellet was reduced after 4, 8 and 24 h compared to the stimulated control. More PEA was found in the supernatant after 4 hours and less after 8 hours than in the stimulated control (Figure 12).

The effect of Zzz/gz/zcz extract on the concentration of endocannabinoids was evaluated 4, 8 and 24 hours after treatment of HaCaT cells with Zzzzgz/zcz extract (20 pg/ml). Zzzzgz/zcz extract showed a reduction in 1-AG (8 hours and 24 hours) and 2-AG (8 hours) in the cell pellet and for 1-AG and 2-AG im compared to the stimulated control (TNF-a DMSO). Supernatant (4 hours, Figures 8 and 9). The concentrations of AEA and OEA were increased at all time points in the cell pellet and in the supernatant compared to the stimulated control (TNF-a DMSO) (Figures 10 and 11). The concentration of PEA in the cell pellet was reduced after 4, 8 and 24 hours compared to the stimulated control. More PEA was found in the supernatant after 4 and 24 hours and less after 8 hours than in the stimulated control (Figure 12).

The effect of the mixture of CBD and Zzz/gz/zcz extract on the concentration of endocannabinoids was measured 4, 8 and 24 hours after treatment of HaCaT cells with CBD (5 pg/ml) and Zzz/gz/zcz extract (20 pg /ml) evaluated. The mixture of CBD and Zingiber extract showed a reduction in 1-AG (8 hours and 24 hours) and 2-AG (8 hours) in the cell pellet as well as for 1-AG and 2 compared to the stimulated control (TNF-a DMSO). - AG in the supernatant (4 hours, Figures 8 and 9). The concentrations of AEA and OEA were increased at all time points in the cell pellet and in the supernatant compared to the stimulated control (TNF-a DMSO) (Figures 10 and 11). The concentration of PEA in the cell pellet was reduced after 4 hours compared to the stimulated control. More PEA was found in the supernatant after 4 and 24 hours than in the stimulated control (Figure 12).

Surprisingly, the effects of the composition of CBD and Zzzzgz/zcz extract according to the invention on the concentration of AEA in the cell pellet and in the supernatant were significantly more pronounced at all times than for CBD and Zzzzgz/zcz extract alone. This became particularly clear after 24 hours in the cell supernatant (Figure 10). The effects on the concentration of OEA for the mixture of CBD and zzz/gz/zcz extract at the 4 and 8 hour time points differed little from those for the zzz/gz/zcz extract alone. However, after 24 hours significantly higher concentrations of OEA were found in the pellet and in the supernatant (Figure 11). A similar picture emerges for PEA. Again, the concentration in the supernatant after 24 hours is significantly greater for the composition of CBD and zzzzgz/zcz' extract than for the zzz/gz/zcz extract alone.

These results are surprising in that CBD showed no effects on AEA, OEA and PEA (supernatant). A significant increase in the effect of the zzz/gz/zcz extract by adding CBD was therefore not obvious. An increase in the concentration of the endocannabinoids AEA, PEA and OEA leads to anti-inflammatory and anti-purity effects. These are mediated via the cannabinoid receptors CB1 and CB2 and the transient receptor potential cation channel of subfamily V 1 (TRPV1) for AEA and via activation of the peroxisome proliferator-activated receptor alpha (PPAR-a) for PEA and OEA.

Example 5: Anti-inflammatory effects of CBD and Zzz?gzZ>er extract extract with 47.7% pungent substances) and a combination of CBD and Zzz?gzZ>er extract in normal human epidermal keratinocytes (NHEK)

1. Inflammation Assays

The keratinocytes were seeded in 24-well plates and cultured in culture medium for 24 hours. The medium was then replaced with culture medium containing or not (control) the extracts, the combination or the reference (bafilomycin tested at 100 nM) and the cells were pre-incubated for 24 hours. After the pre-incubation, the medium was replaced, the treatments were renewed and the TLR3 agonist (poly(I:C) tested at 1 pg/ml) was added to all conditions except the unstimulated control. The cells were then incubated for 24 hours.

The effects of the test substances and the combination were then examined on the following aspects:

- CCL20 release with a specific ELISA kit (Human CCL20/MIP-3 alpha DuoSet, ref. DY360; R&D Systems) and

- the release of TNF-a, IL-8 and IL-6 (Human TNF Flex Set, Bead D9, Ref. 558273; Human IL-8 Flex Set, Bead A9, Ref. 558277; Human IL-6 Flex Set, Bead A7, Ref. 558276; BD-Biosciences) with the CBA system. All experimental conditions were carried out in n=3 replicates.

Results:

Anti-inflammatory effect after inflammation induction by poly(LC):

The anti-inflammatory effect was evaluated 24 hours after treatment of the NHEK cells with Zingiber (CO2 extract with 47.7% pungent substances). For this purpose, the inflammatory induction was carried out by adding poly(LC) and the cells were incubated with Zingiber (CO2 extract with 47.7% pungent substances) for a period of 24 h. Treatment with Zzzzgz/v' extract showed a dose-dependent reduction in poly(I:C)-stimulated release of the cytokines CCL20, IL-6, IL-8 and TNF-α. For CCL20, the results of all concentrations used differed significantly from those of the control (poly(EC). For IL-6 and IL-8, this was only the case at the two higher concentrations (10 and 15 gg/ml). In the case of TNF-α showed a statistically significant reduction in cytokine release at the two highest concentrations of Zzz/gz/icz extract, however, a statistically significant increase in cytokine release was observed at the lowest concentration (Figure 13).

The anti-inflammatory effect was evaluated 24 hours after treatment of the NHEK cells with CBD. For this purpose, the inflammatory induction was carried out by adding poly(LC) and the cells were incubated with CBD for a period of 24 h.

Treatment with CBD showed a dose-dependent reduction in poly(LC)-stimulated release of the cytokines CCL20, IL-6, IL-8 and TNF-α. For IL-6, IL-8 and TNF-α, the results of all concentrations used differed significantly from those of the control (Poly(LC). In the case of CCL20, only the highest concentration of CBD (1.5 gg/ml) showed one statistically significant effect on the release of the cytokine (Figure 14).

The anti-inflammatory effect was evaluated 24 hours after treatment of the NHEK cells with a combination of CBD and Zingiber (CO2 extract with 47.7% pungent substances) 1:4. For this purpose, the inflammatory induction was carried out by adding poly(LC) and the cells were incubated for a period of 24 h with a combination of CBD and Zingiber (CO2 extract with 47.7% pungent substances) 1:4.

Treatment with the combination of CBD and Zingiber (CO2 extract with 47.7% pungent substances) 1:4 showed a dose-dependent reduction in poly(LC)-stimulated release of the cytokines CCL20, IL-6, IL-8 and TNF-α .

For IL-8, the results of all concentrations used differed significantly from those of the control (poly(LC)). For IL-6 and CCL20, this was only at the two higher concentrations (0.75 gg/mL CBD/3 gg/mL Zzzzgz/w extract and 1 gg/mL CBD/4 gg/mL Zzz/gzAcz extract, respectively) the case. In the case of TNF-α, the two highest concentrations of Zzz/gzAcz' extract showed a statistically significant reduction in cytokine release. However, for the lowest concentration (0.5 gg/ml CBD/2 gg/ml Zzz/gz/icz extract), a statistically significant increased release of the cytokine was observed (Figure 15).

Surprisingly, the activity of the combination of CBD and Zingiber (CO2 extract with 47.7% pungent substances) 1:4 for all measured cytokines is significantly better than that of the individually tested substances. This was not to be expected, since the two extracts in the comparative concentrations sometimes had no or weak effects (CBD: CCL20, Zingiber extract: IL-6 and IL-8) or even a negative effect (Zzzz z/zcz extract: TNF-a) showed (Table 5). Even a further reduction in concentration shows better activities than the individual extracts. Since Zzzz z/zcz extract has no positive effects on the

release of IL-6, IL-8 and TNF-a, it was not obvious to the person skilled in the art that a further reduction in the concentration of Zzzz z/zcz extract to 0.75 pg/ml in combination with CBD would lead to anti-inflammatory effects that are more potent than CBD (3 pg/mL) alone (Table 6 and Figure 16). Table 5: Effects of the individual extracts and effects of the combination of CBD and Zingiber officinale Roscoe Rhizome CCL extract on the release of cytokines from NHEK in % of the control (poly(LC))

Table 6: Effects of CBD and effects of the combination of CBD and Zingiber officinale Roscoe Rhizome CCL extract on the release of cytokines from NHEK in % of the control (poly(LC)) Example 6: Clinical cosmetic study to evaluate the skin tolerance and effectiveness of a cosmetic agent after five days of use in people with atopic dermatitis

The aim of this exploratory study was to determine the tolerability and effectiveness of the composition according to the invention in the form of a cream containing 0.1% by weight CBD and 0.5% by weight Zingiber officinale Roscoe Rhizome CCE extract in subjects with atopic dermatitis after 5 days of application to investigate. For this study, children aged 6 months to 14 years and adults 18 years and older with a history of atopic dermatitis and pruritic skin were included.

Efficacy was assessed by rating itch using a Numerical Rating Scale (NRS).

At least 44 subjects (22 children and 22 adults) were recruited for this test, so that a total of about 40 subjects should participate in the study. Subjects who withdrew from the study after randomization were not replaced.

Results:

No adverse reactions occurred during the study. This result confirms the good tolerability, especially in this group of subjects with atopic dermatitis, since this group is generally more prone to intolerance reactions, including allergies, in contrast to people with healthy skin.

Subjective rating of itching on NRS-11:

The subjective assessment of the itching using the NRS-11 showed a continuous decrease in the itching values in the course of the study compared to the initial value for the cream according to the invention (FIG. 18).

Example 7: Clinical cosmetic study to evaluate the skin tolerance and effectiveness of a cosmetic agent after four weeks of use in people with atopic dermatitis

The aim of this exploratory study was to determine the tolerability and effectiveness of the cosmetic composition according to the invention in the form of a body lotion with 0.05% by weight CBD and 0.2% by weight Zingiber officinale Roscoe Rhizome CCE extract in volunteers with atopic dermatitis after four weeks of use. Children aged 6 months to 14 years with acute lesions in atopic dermatitis and adults 18 years and older with a history of atopic dermatitis were included for this study.

The SCORAD score was also used to assess the children's tolerance of the test product. Objective and subjective dermatological assessments were carried out to assess tolerability in adults.

Results: No adverse reactions occurred during the study. All subjects tolerated the tested product very well.

Results of the subjective dermatological evaluation (adults):

Itching to a severe intensity was noted in all or nearly all subjects at baseline. At the end of the study, the number of people affected decreased significantly and the intensity also decreased significantly (Figure 19). Compared to the initial value, significantly lower mean values for the parameter itching were determined for the body lotion according to the invention on day 29.

Example 8 Application Test: Evaluation of Dermatological Tolerance

The aim of this exploratory study was to assess the skin tolerance and product acceptance of two cosmetic compositions according to the invention, which were used by the subjects at home over a period of 2 weeks.

The subjects were divided into two equal groups, each group receiving a composition according to the invention either in the form of a face cream with 0.05% by weight CBD and 0.1% by weight Zingiber officinale Roscoe Rhizome CCE extract or in the form of a hand cream with 0 .05% wt CBD and 0.2% wt Zingiber officinale Roscoe Rhizome CO2 extract was used. The products were tested on female and male test subjects with very dry skin on the face and hands. About half of the subjects in each group had skin prone to atopic dermatitis. An objective and subjective dermatological assessment was carried out at the beginning and end of the study.

Results: No adverse reactions were documented.

Results of the dermatological assessment of the skin: Subjective rating:

For both compositions tested, almost all subjects reported a sensation of itching at baseline assessment on Day 1. A statistically significant decrease in case numbers and intensity was observed after treatment with the compositions of the present invention. (Figures 20 and 21).

The studies described using compositions according to the invention with different formulations and different ratios of CBD and Zzz?gzZ> he extract, based on the preclinical studies, show on the one hand an excellent compatibility of the cosmetic composition according to the invention with these active ingredients, which is due to the ingredients of the extracts, in particular the Zingiber extract, was not to be expected. The reduction in itching occurs after just a few days and does not lose its effectiveness over a period of up to 4 weeks, i.e. the effects of the compositions according to the invention with the combination of CBD and Zzz/zAcz extract do not weaken. On the other hand, the compositions used show a significant improvement in the itching, which was not to be expected, despite a significantly lower concentration of CBD and Zzz/zAcz extract used compared to the prior art.

9. Examples of compositions/formulations according to the present invention:

To produce the compositions/formulations according to the invention (batch size: 300 g), water, glycerol and pentylene glycol are initially introduced and allantoin is stirred in for at least 30 minutes (phase 1). Xanthan is sprinkled in with homogenization and the mixture is stirred until smooth with homogenization (16,000, 1 min). Ceramide NP is pre-dissolved in the triglycerides at 80°C (phase 2). To do this, the ingredients in the fat phase container are weighed out, heated to 75°C and the ceramide mixture is added. Phase 2 is added to phase 1 with stirring and the mixture is homogenized (18,000, 3 min). Phase 3 is added and stirred in at 35-40°C. Phase 4 is added at 30° C. and homogenized (19,000, 2 min). Zingiber officinale Roscoe Rhizome CCE extract and cannbidiol are added separately and briefly homogenized (19,000, 1 min; 19,000, 1.5 min). The pH is measured.

Body Lotion with CBD and Zingiber officinale Roscoe Rhizome CCE Extract: INCI overview ingredients Cream with CBD and Zingiber officinale Roscoe Rhizome CCh extract:

INCI overview ingredients Face Cream with CBD and Zingiber officinale Roscoe Rhizome CCh Extract:

INCI overview ingredients Hand Cream with CBD and Zingiber officinale Roscoe Rhizome CCh Extract:

INCI overview ingredients

Claims

patent claims

1. Cosmetic composition comprising a) cannabidiol (CBD) and b) an extract of zingiber, characterized in that the extract of zingiber is a lipophilic extract, an alcoholic extract, a CCE extract or the zingiber from the rhizome of zingiber, preferably from Zingiber officinale Roscoe rhizoma.

2. Cosmetic composition according to claim 1, characterized in that cannabidiol is a synthetic cannabidiol or a vegetable cannabidiol.

3. Cosmetic composition according to one of the preceding claims, characterized in that the extract from zingiber has a pungent content of between 1-50%, preferably between 20-50% and particularly preferably between 40-50% (by weight), the pungent substances being preferably gingerbread , shogaols, zingerone, gingerdiols, dehydrogingerdiones or paradol, particularly preferably [6]gingerol, [8]gingerol, [10]gingerol, [6]shogaol, [8]shogaol, [10]shogaol and/or or Zingeron.

4. Cosmetic composition according to one of the preceding claims, characterized in that the zzz/z/zcz extract comprises the following substances: 15-30% by weight of [6]-gingerol, 3-10% by weight of [8]-gingerol , 3-10% wt.% [10]-gingerol, 0.5-4% wt.% [6]-shogaol, 0.03-1.3% wt.% [8]-shogaol, 0.03- 1% wt. [10]-Shogaol, 0.01-1% wt. , particularly preferred: 25-30% by weight [6] gingerol, 5-10% by weight [8] gingerol, 5-10% by weight [10] gingerol, 1.5-4% by weight [6 ]-Shogaol, 0.3-1.3% by weight [8]-Shogaol, 0.03-1% by weight [10]-Shogaol, 0.01-1% by weight Zingeron, , the proportion of ginger oil is 35-50% by weight and the proportion of shogaol is 1.5-6% by weight.

5. Cosmetic composition according to one of the preceding claims, characterized in that the composition contains the components cannabidiol and Zzzz z/zcz extract in the weight ratios of 1:100 to 1:1; preferably 1:10 to 1:2, particularly preferably 1:5 to 1:2.

6. Cosmetic composition according to one of the preceding claims, characterized in that the composition contains 0.001-3% by weight cannabidiol, preferably 0.001-0.5% by weight cannabidiol, particularly preferably approx. 0.01-0.5, more preferably 0 0.05-0.1% by weight of cannabidiol, based on the weight of the total composition, and 0.001-5% by weight of Zzzz z/zcz' extract, preferably 0.01-2% by weight of Zzz/ z/zcz extract , more preferably about 0.05-0.5% by weight of Zzz/ z/zcz extract, each based on the weight of the total composition and each in the ratio according to claim 5.

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7. Cosmetic composition according to one of the preceding claims, which is preferably in the following form: emulsion, microemulsion, cream (oil-in-water (O/W)) or water-in-oil (W/O)), lotion, spray , shampoo, foam, serums, face mask, ointment, tincture, oil, eye care product, cleansing product, soaked pads, face or hand creams with or without sun protection (such as SPF), cooling eye care product, acute cream, face cream, hand cream, body lotion or skin milk or as a rinse -off or leave-on product.

8. Cosmetic composition according to one of the preceding claims, further comprising one or more adjuvants, preferably solvents, organic solvents, carriers, gelling agents, detergents, emulsifiers, solubilizers, humectants, fillers, bioadhesives, emollients, preservatives, bactericides, surfactants, perfumes, pearlescent waxes , consistency enhancers, thickeners, superfatting agents, softeners, humectants, oils, fats, waxes, lecithins, phospholipids, biogenic agents, antioxidants, film formers, bulking agents, hydrotropes, water, alcohols, polyols, polymers, foam stabilizers, foaming agents, antifoams, hair coating agents.

9. Cosmetic composition according to one of the preceding claims, comprising one or more preservatives, preferably organic acids such as formic acid, sorbic acid, p-anisic acid and benzoic acid, esters of p-hydroxybenzoic acid, formaldehyde-releasing agents, preferably DMDM hydantoin, imidazolidinyl urea or methylchloroisothiazolinone, methylisothiazolinone, Dibromodicyanobutane, iodopropynylbutylcarbamate, phenoxyethanol or benzyl alcohol and/or one or more buffer systems, which preferably consist of polyacids and their salts, citric acid, tartaric acid or malic acid being particularly preferred.

10. Cosmetic composition according to one of the preceding claims, comprising one or more carriers or solvents, preferably water, alcohol, ester, butylene glycol, dipropylene glycol, pentylene glycol, 1,2-hexanediol, caprylyl glycol, decylene glycol, ethanol, ethoxy di glycol, ethyl acetate, glycerol , Propanol, Isopropanol, Macrogols, Propylpropylene glycol 2-methyl ether, Propylpropylene glycol 3-methyl ether, Propylene carbonate, Propylene glycol, Triethylene glycol, Isoparaffin, Amyl acetate, Amyl benzoate, Benzyl acetate, Butyl acetate, Butylene glycol, Butyl lactate, Butooctyl benzoate, Butooctyl salicylate, C10-C13 alkanes, C14 -C 17- alkanes, Cl 1-C15-cycloalkanes, caprylyl butyrate, isoparaffin, diacetin, triacetin dicaprylyl ether, dicaprylyl maleate or mixtures thereof, particularly preferably glycerol, propylene glycol, butylene glycol, dipropylene glycol, pentylene glycol, 1,2-hexanediol, caprylyl glycol and/or decylene glycol.

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11. Cosmetic composition according to one of the preceding claims, consisting of water > 50%, vegetable oil 5-10%, glycerol stearate 1-5%, glycerol tearate citrate 1-5%, oil 1-5%, caprylic / capric acid triglyceride 1-5%, Shea butter 1-5%, pentylene glycol 1-5%, niacinamide 1-5%, castor oil 1-5%, jojoba oil 1-5%, cetearyl olivate 0.1-1%, sorbitan olivate 0.1-1%, glycerol linoleate 0.1-1%, caprylyl glycol 0.1-1%, lacquer tree berry peel wax 0.1-

1%, Xanthan Gum 0.1-1%, Zingiber Officinale Root Extract 0.1-1%, Vitamin E 0.1-1%, Zinc PCA 0.1-1%, Allantoin 0.1-1%, Shea Butter Extract 0.1-1%, cannabidiol 0.05-0.1%, caprylic hydroxamic acid <0.1%, glycerol linolenate <0.1%, sunflower seed oil

<0.1%, ceramide NP <0.1%, ascorbyl palmitate <0.1%.

12. Composition according to any one of the preceding claims for use as

Cosmetic.

13. Composition according to one of the preceding claims for topical use on the skin of a mammal, preferably a human, preferably on the entire body or face, head, forehead, chin, neck and scalp, armpit, armpits, palms, soles, back of the knees, torso or groin.

14. Composition according to any one of the preceding claims for use in the treatment of sensitive or sensitive skin, rough skin, dry skin and / or irritated skin, reddened skin after sunburn, abrasions or otherwise irritated skin, with or without itching, aging skin, xerosis cutis , inflammatory conditions of the skin, in particular atopic dermatitis, neurodermatitis, atopic eczema, acne, rosacea, psoriasis and to prevent skin infections or to reduce susceptibility to contact allergies, to improve epidermal barrier functions, epidermal barrier integrity, to improve the appearance of the skin , to provide antioxidant effects and/or to increase the moisture or lipid content of the skin or to prevent the skin conditions listed in this claim.

15. Composition for use according to any one of the preceding claims, characterized in that the composition is preferably 1 to 4 times a day, preferably 1 to 2 times a day and more preferably 1 time a day before bedtime (for compositions without photoprotection) in a cosmetically acceptable dosage is used.