WO2021104775A1

WO2021104775A1 - Active substance combinations of ubichinol and creatine and cosmetic or dermatological preparations containing said active substance combinations

Info

Publication number: WO2021104775A1
Application number: PCT/EP2020/080050
Authority: WO
Inventors: Julia Maxi Weise; Andrea Krueger; Thomas Raschke; Alexandra Vogelsang
Original assignee: Beiersdorf Ag
Priority date: 2019-11-26
Filing date: 2020-10-26
Publication date: 2021-06-03
Also published as: DE102019218243A1; EP4065238A1

Abstract

The invention relates to active substance combinations comprising a) one or more ubiquinols and b) creatine.

Description

Beiersdorf Aktiengesellschaft Hamburg

description

Active ingredient combinations of ubiquinol and creatine and cosmetic or dermatological preparations containing such active ingredient combinations

The present invention relates to cosmetic and dermatological preparations with an effective content of physiologically compatible combinations of active ingredients. In particular, the present invention relates to cosmetic preparations with effective protection against harmful oxidation processes in the skin, but also to protect cosmetic preparations themselves or to protect the constituents of cosmetic preparations from harmful oxidation processes.

The present invention also relates to antioxidants, preferably those which are used in skin-care cosmetic or dermatological preparations. In particular, the invention also relates to cosmetic and dermatological preparations containing such antioxidants. In a preferred embodiment, the present invention relates to cosmetic and dermatological preparations for the prophylaxis and treatment of cosmetic or dermatological skin changes such as skin aging, in particular skin aging caused by oxidative processes.

The present invention also relates to active ingredients and preparations containing such active ingredients for the cosmetic and dermatological treatment or prophylaxis of erythematous, inflammatory, allergic or autoimmune reactive phenomena, in particular dermatoses.

The present invention also relates to active ingredient combinations and preparations which are used for the prophylaxis and treatment of light-sensitive skin, in particular of photodermatoses.

The harmful effects of the ultraviolet part of solar radiation on the skin are well known. While rays with a wavelength smaller than 290 nm (the so-called UVC range) are absorbed by the ozone layer in the earth's atmosphere, rays in the range between 290 nm and 320 nm, the so-called UVB- Area, an erythema, a simple sunburn or even more or less severe burns.

The narrower range around 308 nm is given as a maximum of the erythema effectiveness of sunlight.

To protect against UVB radiation, numerous compounds are known which are derivatives of 3-benzylidene camphor, 4-aminobenzoic acid, cinnamic acid, salicylic acid, benzophenone and also 2-phenylbenzimidazole.

It is also important to have filter substances available for the range between about 320 nm and about 400 nm, the so-called UVA range, since its rays can cause reactions in photosensitive skin. It has been proven that UVA radiation leads to damage to the elastic and collagenous fibers of the connective tissue, which causes the skin to age prematurely, and that it can be seen as the cause of numerous phototoxic and photoallergic reactions. The damaging influence of UVB radiation can be intensified by UVA radiation.

To protect against the rays of the UVA range, use is therefore made of certain derivatives of dibenzoylmethane, the photostability of which (Int. J. Cosm. Science 10, 53 (1988)) is insufficient.

However, UV radiation can also lead to photochemical reactions, in which case the photochemical reaction products intervene in the skin's metabolism.

Such photochemical reaction products are predominantly radical compounds, for example hydroxy radicals. Undefined free radical photo products, which arise in the skin itself, can show uncontrolled secondary reactions due to their high reactivity. But singlet oxygen, a non-radical excited state of the oxygen molecule, can also occur when exposed to UV radiation, as can short-lived epoxides and many others. Singlet oxygen, for example, stands out from the normally present triplet oxygen (more radical Ground state) by increased reactivity. However, there are also excited, reactive (radical) triplet states of the oxygen molecule.

UV radiation also counts as ionizing radiation. There is therefore a risk that ionic species will also be formed when exposed to UV, which in turn are able to intervene oxidatively in the biochemical processes.

In order to prevent these reactions, additional antioxidants and / or radical scavengers can be incorporated into the cosmetic or dermatological formulations.

It has already been proposed to use vitamin E, a substance with a known antioxidant effect, in light protection formulations, but here too the effect achieved remains far below that which was hoped for.

The object of the invention was therefore also to create cosmetic, dermatological and pharmaceutical active ingredients and preparations and light protection formulations which are used for the prophylaxis and treatment of light-sensitive skin, in particular photo dermatoses, preferably PLD.

Further names for polymorphic light dermatosis are PLD, PLE, Mallorca acne and a large number of other names, as they are in the literature (e.g. A. Voelckel et al, Zentralblatt Skin and Sexual Diseases (1989), 156, p.2), are specified.

Erythematous skin symptoms also occur as side effects of certain skin diseases or irregularities. For example, the typical skin rash is usually more or less reddened when acne appears.

Antioxidants are mainly used as protective substances against spoilage of the preparations containing them. Nevertheless, it is known that undesirable oxidation processes can also occur in human and animal skin. Such processes play an essential role in skin aging. In the article "Skin Diseases Associated with Oxidative Injury" in "Oxidative Stress in Dermatology", p. 323 ff. (Marcel Decker Inc., New York, Basel, Hong Kong, editors:

Jürgen Fuchs, Frankfurt, and Lester Packer, Berkeley / California), oxidative damage to the skin and its closer causes are listed.

If human hair is to be colored permanently, only oxidizing hair coloring processes come into consideration in practice. In oxidative hair coloring, the dye chromophore is formed by the reaction of precursors (phenols, aminophenols, more rarely also diamines) and bases (mostly p-phenylenediamine) with the oxidizing agent, mostly hydrogen peroxide. Hydrogen peroxide concentrations around 6% are commonly used.

It is usually assumed that, in addition to the coloring effect, the hydrogen peroxide also has a bleaching effect. In oxidatively dyed human hair, similar to bleached hair, microscopic holes can be detected in the places where melanin granules are present.

The fact is that the oxidizing agent hydrogen peroxide not only reacts with the dye precursors, but also with the hair substance and can cause damage to the hair under certain circumstances.

Antioxidants are substances which prevent oxidation processes or which prevent the auto-oxidation of fats containing unsaturated compounds. Antioxidants, which are also used in the field of cosmetics and pharmacy, are, for example, α-tocopherol, in particular in the form of α-tocopheryl acetate, sesamol, gallic acid derivatives, butylhydroxyanisole and butylhydroxytoluene.

Antioxidants and / or radical scavengers can also be incorporated into cosmetic formulations for the purpose of preventing such reactions.

Some antioxidants and radical scavengers are known. For example, US Patents 4,144,325 and 4,248,861 as well as numerous other documents suggest It has been decided to use vitamin E, a substance with a known antioxidant effect, in sunscreen formulations, but here too the effect achieved remains far below the hoped-for effect.

One object of the present invention was to eliminate the disadvantages of the prior art. In particular, active ingredients or preparations containing such active ingredients should be made available, if they are used, damage to the skin and / or hair due to oxidative influence can at least be reduced, if not completely prevented.

Another object of the present invention was to provide cosmetic preparations which, before or after treatment of the hair with hair coloring preparations, even those with a content of strong oxidizing agents such as hydrogen peroxide, counteract their damaging oxidizing effect.

In particular, active ingredients and preparations containing such active ingredients should be made available for the cosmetic and dermatological treatment and / or prophylaxis of erythematous, inflammatory, allergic or autoimmune reactive phenomena, in particular dermatoses, but also the appearance of "stinging".

It was surprising and could not be foreseen by the person skilled in the art that active ingredient combinations comprising a) one or more ubiquinols and b) creatine or cosmetic or dermatological preparations containing such active ingredient combinations or the use of such active ingredient combinations as an antioxidant and / or as a radical scavenger, in particular in cosmetic or dermatological preparations that represent the solution to these problems and remedy the disadvantages of the prior art.

Ubiquinols or their oxidized form, the ubiquinones, play an important role in the transport of electrons in the respiratory chain of living things. Ubiquinols are characterized by the following chemical structure and act as antioxidants:

In naturally occurring ubiquinols or their oxidized form, the ubiquinones, n can assume values from 0 to 50. In mammals, especially humans, n = 10 predominates (ubidecarenol), which according to the invention is the preferred ubiquinol. Due to the redox character of ubiquinone and ubiquinol, only the reduced form, ubiquinol, can act as an antioxidant (Fig. 1).

The cosmetic use of ubiquinols is known per se, for example from WO 2017/045034, DE 42 28871 and other publications.

The advantageous prophylactic and therapeutic effect of creatine in cosmetic and medical skin care is known per se. Creatine (from Greek to krέaV = "the meat") is characterized by the following structure:

It is found in the muscle juice of vertebrates to 0.05-0.4%, in small amounts also in the brain and blood. As a monohydrate, it is a colorless, crystalline powder. Creatinine is formed in aqueous solution. In the organism it is produced by transamidination of L-arginine on glycine to guanidinoacetic acid and its subsequent methylation by means of S-adenosylmethionine (by guanidinoacetate methyltransferase). You think creatine is you appetite-enhancing component of beef and meat extract. Adding creatine to food increases physical performance.

The prior art on the cosmetic and dermatological uses of creatine is extensive.

DE 10032 964 describes the use of creatine and / or creatine derivatives in cosmetic or dermatological preparations for the treatment and prophylaxis of the symptoms of UV- and / or ozone-induced skin damage and of inflammatory and degenerative skin conditions.

Lenz et al (J Invest Dermatol 124: 443-452, 2005, Fig. 6B) describes that creatine has no antioxidant effect whatsoever. The same was also shown here (Fig. 2).

Surprisingly, it could be shown that the antioxidant effect of ubiquinol (Qh2) is further improved by the combination with creatine (FIG. 2).

However, the person skilled in the art could not have foreseen that the physiologically compatible active ingredient combinations used according to the invention or cosmetic or dermatological preparations containing better antioxidants act better than radical scavengers prevent the binding of harmful photo products to lipids, DNA and proteins better Against skin aging act better protect the skin against photoreactions better inflammatory reactions would prevent than the active ingredients, active ingredient combinations and preparations of the prior art. Furthermore, it could not have been foreseen that the active ingredient combinations in cosmetic or dermatological preparations would have a higher stability than comparable active ingredients, for example as vitamin C. According to the invention, therefore, the use of physiologically compatible combinations of active ingredients as antioxidants and their use for combating and / or prophylaxis of skin aging and inflammatory reactions caused by oxidative stress.

It is advantageous according to the invention to choose the molar ratio of one or more ubiquinols to creatine from the range from 100: 1 to 1: 100, preferably 50: 1 to 1:50, particularly preferably 20: 1 to 1:20.

According to the invention, the preparations are particularly advantageously characterized in that one or more ubiquinols, in particular ubidecarenol, in concentrations of 0.0001-10.00% by weight, preferably 0.005-5.00% by weight, particularly preferably 0.01 3.00% by weight, based in each case on the total weight of the composition, is or are present.

According to the invention, the preparations are particularly advantageously characterized in that creatine in concentrations of 0.001-10.00% by weight, preferably 0.005-5.00% by weight, particularly preferably 0.01-1.00% by weight, in each case based on the total weight of the composition, is or are present.

The cosmetic or dermatological formulations according to the invention can have the usual composition and serve for the treatment, care and cleaning of the skin and / or hair and as a make-up product in decorative cosmetics. They preferably contain 0.01% by weight to 10% by weight, preferably 0.05% by weight to 5% by weight, in particular 0.1-2.0% by weight, based on the total weight of the agent, one or more active ingredient combinations according to the invention.

For use, the cosmetic and dermatological preparations according to the invention are applied to the skin and / or hair in a sufficient amount in the manner customary for cosmetics.

The active ingredient combinations according to the invention can advantageously be incorporated into customary cosmetic and dermatological preparations, which are in various forms may exist. So you can z. B. a solution, an emulsion of the water-in-oil (W / O) type or of the oil-in-water (O / W) type, or a multiple emulsions, for example of the water-in-oil-in-water type (W / O / W) or oil-in-water-in-oil (O / W / O), a hydrodispersion or lipodispersion, a Pickering emulsion, a gel, a solid stick or an aerosol.

Emulsions according to the invention for the purposes of the present invention, e.g. B. in the form of a cream, a lotion, a cosmetic milk are advantageous and contain z. B. fats, oils, waxes and / or other fatty substances, as well as water and one or more emulsifiers, as they are usually used for such a type of formulation.

It is also possible and advantageous for the purposes of the present invention to incorporate the active ingredient combinations according to the invention into aqueous systems or surfactant preparations for cleaning the skin and hair.

It is of course known to the person skilled in the art that sophisticated cosmetic compositions are mostly inconceivable without the customary auxiliaries and additives. These include, for example, consistency enhancers, fillers, perfumes, dyes, emulsifiers, additional active ingredients such as vitamins or proteins, light stabilizers, stabilizers, insect repellants, alcohol, water, salts, antimicrobial, proteolytic or keratolytic substances, etc.

Mutatis mutandis, corresponding requirements apply to the formulation of medical preparations.

Medical topical compositions for the purposes of the present invention generally contain one or more medicaments in effective concentrations. For the sake of simplicity, reference is made to the legal provisions of the Federal Republic of Germany (e.g. Cosmetics Ordinance, Food and Drugs Act) to clearly distinguish between cosmetic and medicinal use and corresponding products. It is also advantageous to add the active ingredient combinations according to the invention as an additive to preparations which already contain other active ingredients for other purposes.

Accordingly, cosmetic or topical dermatological compositions for the purposes of the present invention, depending on their structure, can be used, for example, as skin protection cream, cleansing milk, sun protection lotion, nutritional cream, day or night cream, etc. It is optionally possible and advantageous to use the compositions according to the invention as a basis for to use pharmaceutical formulations.

For use, the cosmetic and dermatological preparations are applied according to the invention to the skin and / or hair in a sufficient amount in the manner customary for cosmetics.

Those cosmetic and dermatological preparations which are in the form of a sunscreen agent are particularly preferred. These can advantageously also contain at least one further UVA filter and / or at least one further UVB filter and / or at least one inorganic pigment, preferably an inorganic micropigment.

According to the invention, the cosmetic and dermatological preparations can contain cosmetic auxiliaries such as are usually used in such preparations, for example preservatives, bactericides, perfumes, substances to prevent foaming, dyes, pigments that have a coloring effect, thickeners, moisturizing and / or or moisture-retaining substances, fats, oils, waxes or other common constituents of a cosmetic or dermatological formulation such as alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents or silicone derivatives.

An additional content of customary antioxidants is generally preferred. According to the invention, all antioxidants suitable or customary for cosmetic and / or dermatological applications can be used as favorable antioxidants. The amount of the aforementioned antioxidants (one or more compounds) in the preparations is preferably 0.001 to 30% by weight, particularly preferably 0.005-20% by weight, in particular 0.01-10% by weight, based on the total weight the preparation.

If the cosmetic or dermatological preparation for the purposes of the present invention is a solution or emulsion or dispersion, the following solvents can be used:

Water or aqueous solutions

Oils, such as triglycerides of capric or caprylic acid, but preferably castor oil; Fats, waxes and other natural and synthetic fatty substances, preferably esters of fatty acids with alcohols of low carbon number, e.g. with isopropanol, propylene glycol or glycerine, or esters of fatty alcohols with alkanoic acids of low carbon number or with fatty acids;

Alcohols, diols or polyols with a low carbon 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. In the case of alcoholic solvents, water can be another component.

Water or aqueous solutions

Alcohols, diols or polyols with a low carbon number, as well as their ethers, preferably Etha nol, 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.

Suitable propellants for cosmetic and / or dermatological preparations that can be sprayed from aerosol containers in the context of the present invention are the customary, highly volatile, liquefied propellants, for example hydrocarbons (propane, butane, isobutane), which can be used alone or in a mixture with one another. It is also advantageous to use compressed air.

Of course, the person skilled in the art knows that there are propellant gases which are nontoxic per se, which would be suitable in principle for the implementation of the present invention in the form of aerosol preparations, but which should nevertheless be avoided because of their harmful effects on the environment or other accompanying circumstances, in particular fluorocarbons and Chlorofluorocarbons (CFCs).

Cosmetic preparations within the meaning of the present invention can also be in the form of gels which, in addition to an effective content of active ingredient combinations according to the invention and solvents usually used for this, preferably water, also organic thickeners, e.g. gum arabic, xanthan gum, sodium alginate, cellulose derivatives, preferably methyl cellulose, hydroxymethyl cellulose , Hydroxy ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose or inorganic thickeners, e.g. B. aluminum silicates such as bentonite, or a mixture of polyethylene glycol and polyethylene glycol stearate or distearate contain. The thickening agent is contained in the gel, for example, in an amount between 0.1 and 30% by weight, preferably between 0.5 and 15% by weight.

It is advantageous according to the invention, in addition to the combinations according to the invention, to use further oil-soluble UVA filters and / or UVB filters in the lipid phase and / or further water-soluble UVA filters and / or UVB filters in the aqueous phase. According to the invention, the light protection formulations can advantageously contain further substances which absorb UV radiation in the UVB range, the total amount of the filter substances, for example 0.1% by weight to 30% by weight, preferably 0.5 to 10% by weight, in particular, is 1 to 6% by weight, based on the total weight of the preparations, in order to provide cosmetic preparations which protect the skin from the entire range of ultraviolet radiation. They can also serve as sunscreens.

Proof of effectiveness:

The increased antioxidant effect of the active ingredient combinations according to the invention was determined as follows:

2,2-Diphenyl-1-picrylhydrazyl (DPPH ·) is a stable, commercially available radical with an absorption maximum at 524 nm. In the presence of antioxidants, DPPH · is reduced to the corresponding hydrazine derivative. Depending on the antioxidative capacity and the concentration of the examined antioxidant, this reaction leads to a discoloration of the DPPH ·. The resulting change in absorption can be followed spectrophotometrically. "Trolox" - a vitamin E derivative - is included as a high standard. The respective solvent control was defined as 100%. The lower the percentage result of the measurement, the better the antioxidant effect of the substance tested.

The following test solutions were created:

Final concentrations in the DPPH assay:

25 mM Trolox

25 pM (0.002%) or 50 pM (0.004%) ubiquinone 25 pM (0.002%) or 50 pM (0.004%) ubiquinol 100 pM (0.0015%) creatine

The results are shown graphically in Figures 1-2.

FIG. 1 shows that only the reduced form of Q10, ubiquinol (Qh2), has an antioxidant effect. FIG. 2 shows that, surprisingly, it was possible to show that the combination of ubiquinol (Qh2) with creatine increases the antioxidant effect of ubiquinol even though creatine itself does not have an antioxidant effect.

The following examples are intended to illustrate the present invention without restricting it. Unless otherwise stated, all amounts, proportions and percentages are based on the weight and the total amount or on the total weight of the preparations.

pH 6.8-7.8

pH 6.5-7.5

pH 6.0 -7.0

pH 6.8-7.8

pH 6.0 -7.0

Claims

1. Active ingredient combinations comprising a) one or more ubiquinols and b) creatine

2. Cosmetic or dermatological preparations with a content of such active ingredient combinations according to claim 1.

3. Active ingredient combinations according to claim 1 or preparations according to claim 2, in which the molar ratio of one or more ubiquinols to creatine is in the range from 100: 1 to 1: 1000, preferably 50: 1 to 1: 100, particularly preferably 20: 1 until 1:50 is selected.

4. Preparations according to claim 2 or 3, characterized in that one or more ubiquinols, in particular ubidecarenol, in concentrations of 0.0001-10.00% by weight, preferably 0.005-5.00% by weight, are particularly preferred 0.001-3.00% by weight, based in each case on the total weight of the composition, is or are present.

5. Preparations according to one of the preceding claims, characterized in that creatine in concentrations of 0.001-10.00% by weight, preferably 0.005-5.00% by weight, particularly preferably% by weight, each based on the total weight the composition, is or are present.

6. Use of active ingredient combinations according to claim 1 or 3 as antioxidants and / or as free radical scavengers, in particular in cosmetic or dermatological preparations.