DE4328871A1 - Means against sensitive, hyper-reactive skin conditions, atopic dermatitis, pruritus, psoriasis prurigo, photodermatoses and ichthyosis - Google Patents

Description

The present invention relates to active ingredients and Preparations, in particular for topical use, sensitive to prophylaxis and treatment, hyperreactive and predisposed to dermatitis Skin, deficient age skin and for the treatment of manifest atopic dermatitis such as B. Atopic Dermatitis, eczema, atopic eczema and seborrhoeic dermatitis and light-induced Dermatoses (eg polymorphic photodermatosis, Photodermatitis), prurigo forms, pruritus, Psoriasis forms and Ichtyosis serve.

Various pathological mechanisms that the clinical picture of sensitive, hyperreactive skin, at Atop. Dermatids, prurigo forms, psoriasis, Photodermatoses and ichthyosis are found in the Literature described. However, none of them called dermatoses the causal pathological Mechanisms and their chronology known. The so far  known treatments and administered At best, active ingredients lead to a short-term improvement of the symptoms. For treatment be z. As UV therapy and or chemotherapy (Psoralen, Cyclosporin A etc.) applied with the known negative side effects in repeated Application.

The object of the invention is this unsatisfactory To improve state of the art and cosmetic, dermatological and / or pharmaceutical agents and To provide preparations for prophylaxis and Treatment for sensitive hyperreactive, too Dermatidally prone skin and for prophylaxis and Treatment in the above-mentioned manifest dermatoses Serve without the side effects of known agents, too with permanent use, to induce.

The invention relates to the use of Antioxidants and / or agents that are endogenous Energy metabolism and / or the endogenous enzymatic Antioxidant system, especially that of the skin, on regulate normal level or a normal level maintained, for the prophylaxis and treatment of more sensitive, hyperreactive and for dermatids predisposed skin, deficient age skin and of manifest atopic dermatitis such as B. Atopic Dermatitis, eczema, atopic eczema and Seborrheic dermatitis and light-induced Dermatoses such. B. Polymorphic photodermatosis, Mallorca Acne, photodermatitis, as well as prurigo forms, Pruritus forms, psoriasis forms and ishtyosis.

The invention also provides the use of Preparations, in particular topical preparations, With  Antioxidants and / or agents that are endogenous Energy metabolism and / or the endogenous enzymatic Antioxidant system, especially that of the skin, on regulate normal level or a normal level maintained, for the prophylaxis and treatment of more sensitive, hyperreactive and for dermatids predisposed skin, deficient age skin and of manifest atopic dermatitis such as B. Atopic Dermatitis, eczema, atopic eczema and Seborrheic dermatitis and light-induced Dermatoses such. B. Polymorphic photodermatosis, Mallorca Acne, photodermatitis and prurigo forms, Pruritus forms, psoriasis forms and ishtyosis.

To the endogenous energy metabolism z. B. the Pentose phosphate cycle, the β-oxidation of fatty acids and the citrate cycle.

To the endogenous enzymatic antioxidant systems counts z. B. the glutathione redox system and the Thioredoxin redox system and the superoxide dismutase system and the catalase system.

It was surprising and not for the expert predictable that the active compounds of the invention and Preparations, in particular after topical application on the human skin, for prophylaxis and treatment the above dermatoses and the sensitive, hyperreactive skin predisposed to dermatitis can serve.

Evidence of efficacy in vivo and in vitro was obtained by analyzing the antioxidant status by means of Chemiluminescence Measurement (1) (Free Radical Biology & Medicine, Vol. 3, pp. 329-333, 1987) and by histochemical analyzes of glutathione status (2)  (Cancer Research 46, 6105-6110, December, 1986) at the treated with the preparations according to the invention Skin measured. Oxidative, radical stress is z. As by ozone, UV light, smog, cigarette smoke and caused by oxidative chemical agents. Based on the above measuring methodology could surprisingly after treatment with the Active ingredients and preparations according to the invention Reduction of increased oxidative stress in sensitive hyperreactive skin and at the be detected above dermatoses.

The mechanism of action of the new, inventive Active ingredients and preparations are not yet complete clarified. It is assumed that in the case in question pathological skin conditions an increased oxidative, radical stress as the cause, which is caused by the Treatment with the active compounds according to the invention Relieved or even to the normal level of healthy skin is regulated. It is also advantageous that the The active ingredients used in the invention also the enzymatic antioxidant and repair systems of Skin support so that an additive or even synergistic mechanism of action in the according to the invention used and Preparations is present. These agents can by Penetration through the sebaceous and sweat glands, but also along hair shafts or through the stratum corneum get to the site of action. These can be the Preparations according to the invention Penetrationsförderer such as DMSO, Azone, oleic acid, cis-alkeno fatty acids, Heptadecenoic acid, liposomes, nanosomes etc. added become.

Preferred antioxidants of the invention are:
Amino acids (eg glycine, histidine, tyrosine, tryptophan) and their derivatives, imidazoles (eg urocaninic acid) and their derivatives, peptides such as D, L-carnosine, D-carnosine, L-carnosine and their derivatives (eg B. anserine), carotenoids, carotenes (eg alpha-carotene, beta-carotene, lycopene) and their derivatives, lipoic acid and its derivatives (eg dihydrolipoic acid), aurothioglucose, propylthiouracil and other thiols (e.g. Thioredoxin, glutathione, cysteine, cystine, cystamine and their glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl and lauryl, palmitoyl, oleyl, gamma-linoleyl, cholesteryl and glyceryl esters) and their salts, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and derivatives thereof (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts) and sulfoximine compounds (eg buthionine sulfoximines, homocysteinesulfoximine, buthionine sulfones, pentat, hexa, Heptahioninsulfoximin) in very low tolerated dosages (eg pmol to μ mol / kg), furthermore (metal) chelators (e.g. Alpha-hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin), alpha hydroxy acids (eg, citric acid, lactic acid, malic acid), humic acid, bile acid, bile extracts, bilirubin, biliverdin, EDTA, EGTA and their derivatives, unsaturated fatty acids and their derivatives (eg gamma-linolenic acid, linoleic acid, oleic acid), folic acid and its derivatives, ubiquinone and ubiquinol their derivatives, vitamin C and derivatives (eg ascorbyl palmitates, Mg ascorbyl phosphates, ascorbyl acetates), tocopherols and derivatives (e.g. Vitamin E acetate), vitamin A and derivatives (vitamin A palmitate) and benzylic resin, rutinic acid and its derivatives, ferulic acid and its derivatives, butylhydroxytoluene, butylated hydroxyanisole, nordihydroguaiacetic acid, nordihydroguiaretic acid, trihydroxybutyrophenone, uric acid and its derivatives, mannose and their derivatives Derivatives, zinc and its derivatives (eg Zno, ZnSO₄) selenium and its derivatives (eg selenium methionine), stilbenes and their derivatives (For example stilbene oxide, trans-stilbene oxide) and the derivatives suitable according to the invention (salts, esters, ethers, sugars, nucleotides, nucleosides, peptides and lipids) of these active substances mentioned.

The amount of antioxidants (one or more Compounds) in the preparations is preferably 0.001 wt% to 30 wt%, more preferably 0.05-20% by weight, in particular 1-10% by weight, based on the Total weight of the preparation.

Preferred, energy metabolism and endogenous, enzymatic antioxidant systems, in particular in Skin, low-impacting agents and regulating agents are z. Vitamin D, D-biotin, Glucose and glucose derivatives (eg glucose-6-phosphate, Glucose-1,6-phosphate, glucosylcysteine, glucosylcystine, Glycosylcysteine, glycocylsylcystine, glucosylglutathione, Glucosylcystamine, glycosylcycstamine), NADH, NADPH, ATP, GTP and FADH₂, FMN and the suitable derivatives (salts, Sugars, esters, ethers, nucleotides, nucleosides, peptides and lipids) of said active substances.

The amount of these regulatory agents is z. B. 0.0001% by weight to 30% by weight, preferably 0.01% by weight up to 20% by weight, in particular 0.1% by weight to 10% by weight, each based on the total weight of Preparations.

Particularly preferred are combinations of one or several of the compounds from the group of  Antioxidants with one or more compounds the group of energy metabolism regulating Substances.

Preferably, the amount of the invention effective combination of antioxidants with Active substances for the support and regulation of Energy metabolism in the preparations 0.001% by weight to 40% by weight, preferably from 0.01% by weight to 30% Wt .-%, in particular 0.1 wt .-% to 15 wt .-% based on the total weight of the preparation.

Preference is given to the following active substances and Drug combinations. The specified there Weight quantities are particularly preferred Weights. The substances serve, even in the preparations according to the invention, for the treatment of above-mentioned skin symptoms.

• 1. cystine (0.05-15% by weight)
• 2. cystine (1.0-10% by weight), D-biotin (0.01-0.4% by weight), Glucose-6-phosphate (0.001-10 wt.%), Vitamin E acetate (0.01-15 wt.%), oleyl-L-carnosine (0.05-12 % By weight), oleic acid (0.05-0.5% by weight), urea (0.01% by weight), 12% by weight), NADPH (0.001-1% by weight).
• 3. Cystamine (0.01-5.0 wt%), L-histidine (0.01-6 Wt%), beta-carotene (0.01-3 wt%), ascorbyl palmitate (0.01-8.6 wt%), oleyl cysteine (0.01-10 wt%), Bile extract (0.02-4.2% by weight), folic acid (0.01-2.7%) Wt%), rutinic acid (0.05-2.3 wt%), uric acid (0.02-1.0 wt.%), FMN (0.0005-0.25 wt.%).
• 4. L-anserine (0.01-3.2% by weight), palmitoyl-thioredoxin (0.002-0.5 wt%), butylhydroxyanisole (0.05-0.9  Wt%), heptadecenoic acid (0.01-0.9 wt%), linoleyl glutathione (0.01-1.8 wt.%), humic acid (0.01-2.7 Wt%), ATP (0.004-0.5 wt%).
• 5. lycopene (0.01-3, 8 wt .-%), L-carnosine (0.01-15 Wt%), glycine (0.02-1.2 wt%), lipoic acid (0.01-1.8 wt.%), FADH₂ (0.0008-0.5 wt.%), Palmitic acid (0.01-2.5 wt%), Mg ascorbyl phosphate (0.002-5.4 Wt%), ethyl cysteine (0.004-4.5 wt%), Cholesteryl cystine (0.02-2.7 wt%), bilirubin (0.003-1.2 wt.%), NADH (0.001-1.6 wt.%), Manose (0.01-2.0 wt%).
• 6. butylhydroxytoluene (0.01-1.0 wt%), ZnO (0.02- 1.4% by weight), selenium methionine (0.01-0.8% by weight), Ferulic acid (0.02-4.2% by weight), butyl cystine (0.01-1.9 wt.%), Palmitoylglutination (0.01-3.6 wt.%), Ubiquinol (0.003-4.8 wt%), vitamin E palmitate (0.02-8.6 wt.%), Vitamin aoleate (0.02-2.0 wt. %), Konyferylbenzoat (0.05-1.5 wt .-%), liposomes (0.2-2.5 wt.%), GTP (0.001-0.9 wt.%), gamma-linolenic acid from vegetable oils (0.01-15% by weight), Dimethyl isosorbitol (0.02-3.4 wt%).
• 7. cis-urocanic acid (0.005-2.0% by weight), Thiodipropionic acid (0.03-0.5 wt%), phytic acid (0.01-2.7 wt.%), Alpha-carotene (0.05-2.9 % By weight), propylthiouracil (0.0005-0.06% by weight), Thioglucose (0.001-0.9 wt.%), Ascorbyl acetate (0.08-5.8 wt%), linoleic acid (0.05-6.4 Wt%), lactoferrin (0.002-1.0 wt%), Dilauryl thiodipropionate (0.2-2.0 wt.%), Ubiquinone (0.001-2.1 wt%), ZnSO₄ (0.001-2.0 wt%), Azone (0.01-3.0% by weight), N-acetylglutathione (0.004-4.1 Wt%), biliverdin (0.002-2.5 wt%).  
• 8. thiols (0.001-10.wt .-%) such. Glutathione Cysteine, cystine and their esters (eg methyl, ethyl, Butyl, propyl, amyl, sorbitosyl, galactosyl, Manosyl, glucosyl, glycosyl, acetyl, lauryl, Palmitoyl, oleyl, linoleyl, cholesteryl esters) and their salts (eg distearyl thiopropionate, Dioleylcysteinylpropionat).
• 9. According to the invention effective peptide compounds of under 1-8 agents and combinations between the inventively mentioned active systems 1-8.
• 10. According to the invention effective fatty acids and Lipid compounds mentioned under 1-9 Active ingredients (eg lauryl, oleyl, linoleyl, Palmitoyl, stearyl compounds) and combinations between the mentioned active systems 1-9.
• 11. Inventive Nuleinsäure and Nucleotide compounds mentioned under 1-10 Active substances (eg propylthiouracil, ethylthioadenosine, Isopropylguanosylcysteine) and combinations of Inventive active systems 1-11.

These individual components in the respective active systems 1-11 and their concentration data are exemplified without the use of others said active ingredients and their derivatives or their According to the invention effective combinations and To exclude concentrations.

It also proved to be beneficial in the Prophylaxis and treatment of the invention Dermatoses and more sensitive, hyperreactive Skin conditions, the active compounds of the invention and  in particular the active ingredient systems 1-11 with urea (eg 0.01-15% by weight). The usage of urea in cosmetic and dermatological Formulations for the treatment, in particular of dry skin conditions, is the general state of Technology.

Of benefit in the prophylaxis and treatment of According to the invention mentioned dermatoses and deficit Skin conditions using the following combinations A-D, in particular for:

Atopic dermatitis z. B. from the following Single substances and their derivatives composed could be:

Combination A: carnosine 3.0 wt.%, Histidine 0.8 wt. %, Urocaninic acid 1.0%, β-carotene 0.5% by weight, Palmitoyl cystine 0.2% by weight, Mg ascorbyl palmitate 2.0 Wt .-%, vitamin E acetate 3.5 wt .-%, Oleylglutathion 0.2% by weight, glucosylcystamine 0.04% by weight, oleic acid 0.3 Wt%, heptadecenoic acid 0.02 wt%, butylhydroxyanisole 0.5 wt .-%, FADH₂ 0.02 wt .-%, glucose 6-phosphate 0.06 wt%, NADPH 0.05 wt%, ubiquinol 0.5 wt%.

Of particular advantage proved in these Dermatoses also combinations of these Active ingredient composition with the above Active systems 1-4, 7 and 8.

Furthermore, the combination of the mentioned proved single active substances according to the invention and under 1-11 and A-D called active systems with urea as advantageous.  

It is furthermore preferred, in particular for psoriasis, z. B. the following combination B, the z. B. from the following Single substances and their derivatives composed can be:

Combination B: carnosine 2.0% by weight, histidine 0.5% by weight, Rutinic acid 0.8% by weight, oleic acid 0.3% by weight, ethylcysteine 0.5 wt .-%, glutathione 1.0 wt .-%, vitamin E acetate 3.0% by weight, vitamin A palmitate 0.4% by weight.

Of particular advantage was in psoriasis forms also the treatment with these active ingredients in Combination with the active systems 2-5, 8 and 10.

Furthermore, it is preferred, in particular for Prurigo forms and pruritus forms, e.g. For example, the following Combination C, consisting of the following individual substances and whose derivatives may be composed:

Combination C: oleyl carnosine 2.8% by weight, Cholesteryl cystine 0.4% by weight, oleyl cysteine 0.6% by weight, β-carotene 0.8% by weight, citric acid 1.4% by weight, Linoleylglutathione 0.5% by weight, glutathione 2.0% by weight, Vitamin E palmitate 4.5% by weight, lipoic acid 0.5% by weight.

Of particular advantage proved for the treatment of Prurigo forms and pruritus forms too Active ingredients in combination with the active systems 2-4, 6, 7-11.

Furthermore, it is preferred, in particular for Photodermatoses, e.g. As the following combination D, the from the following individual substances and their derivatives can be composed:  

Combination D: N-acetyl glutathione 3.0% by weight, D, L-carnosine 2.7% by weight, palmitoylcysteine 2.1% by weight, L-histidine 2.5% by weight, L-tyrosine 0.2% by weight, vitamin E acetate 4.0% by weight, folic acid 0.5% by weight, manose 0.5 % By weight, malic acid 2.0% by weight, glycine 1.2% by weight, Oleic acid 0.3% by weight, uric acid 0.05% by weight, Selenium methionine 0.02% by weight, NADPH 0.02% by weight, Mg ascorbyl palmitate 3.5% by weight.

Of particular advantage proved to be for prophylaxis and Treatment of photodermatoses also the combinations of these active ingredients with the active systems 3,5-9.

In the above combinations, the given wt .-% - each data on the Total weight of the preparations.

These individual components and their concentrations in a preparation are exemplified, without it the use of other antioxidants and active ingredients excluded.

For prophylaxis, the active ingredients are administered to Manifestations of diseases in frequency and To reduce strength. Treatment in the manifest stage leads to their shortening and mitigation of the Symptoms.

The active compounds according to the invention and their combination and the preparations thus obtained, such as pharmaceutical preparations and topical preparations in Form of creams, lotions, gels and sprays as well Solutions (eg aqueous, alcoholic or aqueous-alcoholic) and other suitable In particular, formulations are prophylactic effective, by being sensitive, for those mentioned  Dermatoses predisposed skin, especially at atopic dermatids, protect or their education reduce. These are the active ingredient-containing Formulations once and several times a day regularly applied. In manifest dermatoses, especially in atopic dermatitis (eg atopic dermatitis, Atopic dermatitis) and psoriasis and pruritus after adequate treatment with the inventive Substances and preparations improve the Skin conditions, especially a decay in the case of these Dermatitis occurring itching. Then you can be further treated prophylactically.

For use, the cosmetic according to the invention and dermatological preparations in the usual Way to the skin, scalp and / or hair in applied sufficient amount.

Furthermore, it is advantageous for the invention Active substances and preparations, including in combination with conventional agents and methods to use for the treatment of the mentioned dermatoses commonly used (eg, cyclosporin A, Psoralen, UV therapy, UVA and / or UVB filters, Urea).

Topical, cosmetic and dermatological preparations can be in different Shapes are present. So they can z. B. a solution, a Emulsion of the water-in-oil (W / O) or type Oil-in-water (O / W), or multiple emulsions, for example of the water-in-oil-in-water (W / O / W) type, a gel, a solid stick or even an aerosol represent. The production takes place in itself known way.  

The topical, cosmetic and dermatological preparations can be cosmetic Excipients contain, as they are usually in such Preparations are used, for. B. Preservatives, bactericides, perfumes, substances for preventing foaming, dyes, pigments, the have a coloring effect, thickener, surface-active substances, emulsifiers, weichma moisturizing and / or moisturizing substances, Fats, oils, waxes or other common ingredients a cosmetic or dermatological formulation such as alcohols, polyols, polymers, foam stabilizers, Electrolytes, organic solvents or Silicone derivatives.

Unless the topical, cosmetic or dermatological Preparing a solution or lotion may be used as solvent:

• - water or aqueous solutions
• - Oils, such as triglycerides of caprine or Caprylic acid, but preferably castor oil;
• - fats, waxes and other natural and synthetic fat bodies, preferably esters of Fatty acids with low C-number alcohols, e.g. B. with isopropanol, propylene glycol or glycerol, or esters of fatty alcohols with alkanoic acids low C number or with fatty acids;
• Alcohols, diols or polyols of low C number, and their ethers, preferably ethanol, Isopropanol, propylene glycol, glycerol, Ethylene glycol, ethylene glycol monoethyl or monobutyl ether, propylene glycol monomethyl,  monoethyl or monobutyl ether, diethylene glycol monomethyl or monoethyl ether and analogues Products.

In particular, mixtures of the above Solvent used. For alcoholic Solvents can be another component of water his.

Emulsions according to the invention z. B. in the form of a Sunscreen cream or a sunscreen milk are preferred and contain z. As mentioned fats, oils, Waxes and other fats, as well as water and a Emulsifier, as he usually does for such a type the formulation is used.

Gels according to the invention usually contain Low C-number alcohols, e.g. For example, ethanol, isopropanol, 1,2-propanediol, glycerol and water or one above called oil in the presence of a thickener, the in oily-alcoholic gels preferably Silica or an aluminum silicate, at aqueous-alcoholic or alcoholic gels preferably a polyacrylate.

Solid pins according to the invention contain z. B. natural and / or synthetic waxes, fatty alcohols and / or fatty acid esters. To be favoured Lip balm.

As blowing agent for inventive, from Aerosol containers sprayable preparations are the usual known volatile, liquefied Propellants, for example hydrocarbons (propane, Butane, isobutane), alone or in admixture  can be used together. Also compressed air is advantageous to use.

Of course, the expert knows that in itself Non-toxic propellant gases exist, which in principle for the present invention would be suitable, however nonetheless because of its harmful effect on the environment or other accompanying circumstances should be waived, in particular fluorohydrocarbons and Chlorofluorocarbons (CFCs).

Preferably, the topical preparations may also Substances containing UV radiation in the UVB range absorb, the total amount of the filter substances z. 0.1 wt.% To 30 wt.%, Preferably 0.5 to 10 Wt .-%, in particular 1.0 to 6.0 wt .-%, based on the total weight of the preparations to provide cosmetic preparations which the skin in front of the whole area of the ultraviolet Protect radiation. They can also be called suns serve as a protective agent.

The UVB filters can be oil-soluble or water-soluble his. As oil-soluble substances z. To name, for example:

• 3-benzylidene camphor derivatives, preferably 3- (4-methylbenzylidene) camphor, 3-benzylidene camphor;
• 4-aminobenzoic acid derivatives, preferably 4- (dimethylamino) benzoic acid (2-ethylhexyl) ester, 4- (dimethylamino) benzoic acid ester;
• - esters of cinnamic acid, preferably 4-methoxycinnamate (2-ethylhexyl) ester, 4-methoxycinnamate;  
• - esters of salicylic acid, preferably Salicylic acid (2-ethylhexyl) ester, Salicylic acid (4-isopropylbenzyl) ester, salicylate;
• - Derivatives of benzophenone, preferably 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxy-4'-methylbenzophenone, 2,2'-dihydroxy-4-methoxybenzophenone;
• Esters of benzalmalonic acid, preferably 4-methoxybenzalmalonate (2-ethylhexyl) ester; 2,4,6-trianilino- (p-carbo-2'-ethyl-1'-hexyloxy) -1,3,5- triazine.

As water-soluble substances z. To name, for example:

• - Salts of 2-phenylbenzimidazole-5-sulfonic acid like her Sodium, potassium or their triethanolammonium salt, as well as the sulfonic acid itself;
• Sulfonic acid derivatives of benzophenones, preferably 2-Hydroxy-4-methoxybenzophenone-5-sulfonic acid and its salts;
• Sulfonic acid derivatives of the 3-benzylidene camphor, such as z. B. 4- (2-oxo-3-bornylidenemethyl) benzenesulfonic acid, 2-methyl-5- (2-oxo-3-bomylidenemethyl) sulfonic acid and their salts.

The list of mentioned UVB filters, in combination be used with the active compounds according to the invention can, of course, not be limiting.  

The invention is also the use of a Combination of the active compounds according to the invention at least one UVA and / or UVB filter in one cosmetic or dermatological preparation.

Cosmetic and dermatological preparations may also contain inorganic pigments that Usually used in cosmetics to protect the skin UV rays are used. It refers to Oxides of titanium, zinc, iron, zirconium, silicon, Manganese, aluminum, cerium and mixtures thereof, as well as Variations in which the oxides are the active agents are. Particularly preferred are pigments based on titanium dioxide. Also these combinations of UVA and / or UVB filters and pigment or Preparations containing this combination are Subject of the invention. It can be for the used amounts mentioned above become.

Cosmetic preparations containing a skin cleanser or shampoo preferably at least one anionic, nonionic or amphoteric surfactant, or else Mixtures of such substances, according to the invention Active ingredients and auxiliaries as they usually are be used. The surface-active substance or the mixtures of these substances can in one Concentration between 1% by weight and 50% by weight in the Shampooning present.

Are the cosmetic or dermatological preparations in the form of a lotion that has been rinsed out and z. B. before or after decolorization, before or after Shampooing, between two shampooing steps, is applied before or after the permanent wave treatment,  so it is z. B. aqueous or aqueous-alcoholic solutions which optionally upper surface-active substances, preferably nonionic or cationic surfactant Substances whose concentration is between 0.1 and 10 Wt .-%, preferably between 0.2 and 5 wt .-%, are can. This cosmetic or dermatological accessory Preparations can also be made with aerosols represent used tools.

Preparations for the treatment of the scalp and hair, may be present as emulsions, which are from non-ionic or anionic type. Non-ionic emulsions contain oils in addition to water or fatty alcohols, which include, for example, polyethoxy liert or polypropoxylated, or else Mixtures of the two organic components. These Emulsions optionally contain cationic surface-active substances.

According to the invention, cosmetic preparations for Treatment of the skin, scalp and hair as gels present, in addition to an effective content of Active ingredients according to the invention and usually used solvents, preferably water, still organic thickeners, e.g. Gum arabic, Xanthan gum, sodium alginate, cellulose derivatives, preferably methylcellulose, hydroxymethylcellulose, Hydroxyethyl cellulose, hydroxypropyl cellulose, Hydroxypropylmethylcellulose or inorganic Thickener, z. B. aluminum silicates such For example, bentonite, or a mixture of poly ethylene glycol and polyethylene glycol stearate or distearate. The thickener is in the Gel z. B. in an amount between 0.1 and 30 wt .-%, preferably between 0.5 and 15% by weight.  

According to the invention are as preparations also pharmaceutical preparations, agents or Compositions are provided which are the inventive Compounds or their derivatives or pharmaceutically compatible salts together with a pharmaceutical compatible diluents or carriers.

The compounds of the present invention can be used in the People oral or parenteral z. B. in a dosage from 0.01 to 5000 mg, preferably 1 to 500 mg, per Be applied day, especially in divided doses, for example, twice to four times Every day.

The active compounds according to the invention can be mixed with conventional pharmaceutically acceptable diluents or Carriers and, if necessary, with other aids mixed and, for example, orally or parenterally be administered. You can preferably take in orally Form of granules, capsules, pills, tablets, Film-coated tablets, dragees, syrups, emulsions, Suspensions, dispersions, aerosols and solutions as well as liquids, or as a suppository, Vaginal balls or parenteral z. B. in the form of Administered solutions, emulsions or suspensions become. Orally administered preparations may have a or several additives, such as sweeteners, Flavoring agents, dyes and Preservative included. Tablets can do that Active substance with conventional pharmaceutically acceptable Auxiliaries mixed, for example, inert Diluents such as calcium carbonate, Sodium carbonate, lactose and talc, granulating agents and agents that inhibit the disintegration of the tablets in the case of oral Promote administration such as starch or alginic acid,  Binders such as starch or gelatin, lubricants such as Magnesium stearate, stearic acid and talc.

Suitable carriers are, for example, lactose (Lactose), gelatin, corn starch, stearic acid, ethanol, Propylene glycol, ethers of tetrahydrofurfuryl alcohol and water.

The formulations are prepared, for example by stretching the active ingredients with solvents and / or carriers, optionally using of emulsifiers and / or dispersants, wherein z. B. in the case of using water as Diluent optionally organic Solvent can be used as auxiliary solvent can.

The application is carried out in the usual way, preferably oral or parenteral, especially perlingual or intravenously. In the case of oral use can Tablets of course except those mentioned Excipients, such as sodium citrate, Calcium carbonate and dicalcium phosphate together with various additives, such as starch, preferably Potato starch, gelatin and the like. Furthermore, lubricants such as magnesium stearate, Sodium lauryl sulfate and talc for tableting be used. In the case of aqueous suspensions and / or elixirs intended for oral use are, the active ingredients except with the above Excipients with different flavor enhancers or dyes are added.

In the case of parenteral use, solutions the active ingredients using suitable liquid Carrier materials are used.  

Capsules may contain the active ingredient as the only ingredient or mixed with a solid diluent such as Calcium carbonate, calcium phosphate or kaolin. The injectable preparations are also in themselves formulated in a known manner.

The pharmaceutical preparations can be the active ingredient in in an amount of 0.1 to 90% by weight, especially 1-90% by weight. Be capsules particularly preferred. Single doses contain the Active ingredients preferably in an amount of 0.01mg-500mg.

The invention also pharmaceutical and topical preparations characterized are that they are a combination of inventive Contains antioxidants and regulatory agents as well as the combination of inventive Antioxidants and regulatory agents such as described above.

All quantities, proportions and percentages are, Unless otherwise indicated, on the weight and the Total or on the total weight of Preparations related.

The following examples are intended to illustrate the present Illustrate the invention.

In the examples, the following combinations AD of individual substances with the stated parts by weight are used, which in each case represent the weight ratios of the individual substances in the combination.
Combination A: Carnosine 3.0 parts by weight, histidine 0.8 parts by weight, urocaninic acid 1.0 part by weight, β-carotene 0.5 parts by weight, palmitoyl cystine 0.2 parts by weight T., Mg ascorbyl palmitate 2.0 parts by weight, vitamin E acetate 3.5 parts by weight, oleyl glutathione 0.2 parts by weight, glucosyl cystamine 0.04 parts by weight, oleic acid 0.3 Parts by weight, heptadecenoic acid 0.02 part by weight, butylated hydroxyanisole 0.5 part by weight, FADH₂ 0.02 part by weight, glucose 6-phosphate 0.06 part by weight, NADPH 0.05 part by weight, Ubiquinol 0.5 part by weight.
Combination B: carnosine 2.0 parts by weight, histidine 0.5 parts by weight, rutinic acid 0.8 parts by weight -T. , Oleic acid 0.3% by weight, ethyl cysteine 0.5 part by weight, glutathione 1.0 part by weight, vitamin E acetate 3.0 parts by weight, vitamin A palmitate 0.4 Gew. -T.
Combination C: oleyl carnosine 2.8% by weight, cholesteryl cystine 0.4% by weight, oleyl cysteine 0.6% by weight, β-carotene 0.8% by weight, citric acid 1.4% by weight T., linoleylglutathione 0.5 parts by weight, glutathione 2.0 parts by weight, vitamin E palmitate 4.5 parts by weight, lipoic acid 0.5 parts by weight.
Combination D: N-acetylglutathione 3.0 parts by weight, D, L-carnosine 2.7 parts by weight, palmitoylcysteine 2.1 parts by weight, L-histidine 2.5 parts by weight. , L-tyrosine 0.2 parts by weight, vitamin E acetate 4.0 parts by weight, folic acid 0.5 parts by weight, manose 0.5 part by weight, malic acid 2.0 parts by weight Tg, glycine 1.2 parts by weight, oleic acid 0.3 part by weight, uric acid 0.05 part by weight, selenium methionine 0.02 part by weight, NADPH 0.02 part by weight T, Mg ascorbyl palmitate 3.5 parts by weight.

example 1 Aqueous preparation (facial toner) PEG-40-hydrogenated castor oil 0.811 dipropylene 2,534 PEG-8 1,521 Na₃EDTA 0.253 Polymer JR 125 0,025 Vitamin E acetate 4.0 L-carnosine 2.0 Vit.-C palmitate 1.0 Water VES, ad 100000

Example 2 Aqueous composition Wt .-% Polyfatty acid esters (Cetiol HE) 16,000 PPG-3 myristyl ether (Witconol APM) 1,000 propylene glycol 3,000 glycerin 40,000 rutinic 1.6 L-cysteine 3.8 heptadecenic 0.5 Water VES, ad 100000

Example 3 Hydrogel (polyacrylate gel) Wt .-% Acrylic acid polymer (Carbopol F934) 1,000 Tris (hydroxymethylamino) methane (Tris) 1,000 glycerin 2,000 propylene glycol 2,000 N-acetylcystine 5.00 Vitamin E acetate 3.00   Vit.-A palmitate 2.60 L-histidine 2.00 oleic acid 0.3 Water VES, ad 100000

Example 4 Flooded preparation (very soft) Wt .-% Ceteareth (Cremophor A 25) 0,100 Cetearyl Alcohol (Lanette 0) 0,400 Vaseline, DAB 9 12,500 Mineral oil, DAB 9 11,000 Ceteareth-6-stearyl alcohol (Cremophor A6) 6,000 Combination A: 32.06 Water VES, ad 100000

Example 5 Flooded preparation (soft) Wt .-% Ceteareth-25 (Cremophor A25) 1,500 Cetearyl Alcohol (Lanette 0) 8,500 Combinations A + C @ A: 26.4 C: 13.2 Water VES, ad 100000

Example 6 Flooded preparation (soft) Wt .-% Ceteareth-25 (Cremophor A25) 2,000 Cetearyl alcohol (Lanette 0) 8,000   Vaseline, DAB 9 10,000 Mineral oil, DAB 9 10,000 Combination D: 31.6 Water VES, ad 100000

Example 7 Flooded preparation (medium solid) Wt .-% Ceteareth-25 3,000 Cetearyl Alcohol (Lanette 0) 17,000 Combination B 24.35 Water VES, ad 100000

Example 8 Slimy lotion Wt .-% Ceteareth-25 (Cremophor A25) 1,000 Ceteareth-6-stearyl alcohol (Cremophor A6) 1,000 Glycerol mono-distearate (Tegin normal) 2,000 cetyl alcohol 1,000 isopropyl 1,450 glycerin 1,000 polyvinylpyrrolidone 0,500 Combination A: 26.00 Water VES, ad 100000

Example 9 Thick lotion Wt .-% Ceteareth 25 (Cremophor A25) 2,000 Cetearyl Alcohol (Lanette 0) 3,000   Mineral oil, DAB 9 5,000 propylene glycol 3,000 polyvinylpyrrolidone 0,500 Combination A, B and D @ A: 14.75 B: 9.52 D 12.50 Water VES, ad 100000

Example 10 W / O Cream Wt .-% Glycerol sorbitan fatty acid ester (Arlacel 481) 6,000 Microcrystalline wax (Lunacera M) 1,000 neutral oil 3,000 paraffin oil 19,000 magnesium stearate 1,000 propylene glycol 3,700 Magnesium sulfate (MgSO₄ * 7H₂O) 0,700 Combination A, B and C @ A: 9.24 B: 10.36 C: 10.50 Water VES, ad 100000

Example 11 W / O emulsion Wt .-% Polyoxyethylene glycerol sorbitan fatty acid ester (Arlacel 988) 3,600 Polyoxyethylene fatty acid ester (Arlacel 989) 1,400 Cetearyl Alcohol (Lanette 0) 2,000   Mineral oil, DAB 9 25,000 Paraben Mix at will Magnesium sulfate (MgSO₄ * 7H₂O) 0,700 Combination A + D @ A: 14,30 D: 7.94 Water VES, ad 100000

Example 12 W / O Lotion Wt .-% Glycerol sorbitan fatty acid ester (Arlacel 481) 1,300 Polyoxyethylene fatty acid ester (Arlacel 989) 3,700 Neutral oil (Miglyol) 6,000 Paraffin oil, DAB 9 14,000 propylene glycol 3,800 Magnesium sulfate (MgSO₄ * 7H₂O) 0,700 lipoic acid 1.50 Combination A + D @ A: 13.85 D: 6.80 Water VES, ad 100000

Example 13 O / W emulsion Wt .-% PEG-100 stearates (Arlacel 165) 5,000 Cetearyl Alcohol (Lanette 0) 3,000 Mineral oil, DAB 9 25,000 Paraben Mix at will Combination C + D @ C: 12.56 D: 7.05 Water VES, ad 100000

Example 14 O / W emulsion Wt .-% Polysorbate-60 (Tween 60) 3,000 Sorbitan Stearate (Arlacel 60) 2,000 Cetearyl Alcohol (Lanette 0) 3,000 Mineral oil, DAB 9 25,000 Paraben Mix at will oleic acid 0.30 Combination A @ A: 24.56 Water VES, ad 100000

Example 15 Cationic emulsion Wt .-% Distearyldimethylammonium chloride (Genamin DS AC) 5,000 Vaseline, DAB 9 5,000 isopropyl palmitate 2,000 cetyl alcohol 1,000 silicone oil 0,100 Propylparaben 0,100 methylparaben 0,100 glycerin 4,000 Glucose-6-phosphate 0.50 Combination C + D @ C: 16.50 D: 10.00 Water VES, ad 100000

Example 16 Ionic emulsion Wt .-% Sodium Cetearyl Sulfate (Emulgade F) 6,000   Mineral oil, DAB 9 25,000 Paraben Mix at will glucose 2.00 Combination D @ D: 12,00 Water VES, ad 100000

Example 17 Ionic O / W emulsion Wt .-% stearic acid 5,000 Cetearyl Alcohol (Lanette 0) 3,000 Mineral oil, DAB 9 25,000 Paraben Mix at will Combination C @ C: 28,00 cis-urocanic 1.00 urea 10.00 triethanolamine 1,000 Water VES, ad 100000

Example 18 suntan oil Wt .-% Palmitic | 1.00 3- (4'-methylbenzylidene) camphor, ("Eusolex 6300", Merck) 60.0 g Myristyl alcohol, polyoxypropylated with 3 moles of propylene oxide ("Witconol APM", Witco) 608.0 g C₁₂-C₁₅ alcohol benzoate ("Finsolv TN", Witco) glycerol monococoate, polyoxyethylated with 7 mol 152.0 g Ethylene oxide ("Cetiol HE", Henkel KGaA) 100.0 g ethanol 65.0 g   2-Octadodecanol 20.0 g Perfume, corrigents, additives, stabilizers at will Combination A + D @ A: 355 g D: 280 g

The constituents of the sun oil are mixed together and optionally heated to 40 to 50 ° C for homogenization.

Example 19 Sonnengel 2,4,6-Trianilino- (p-carbo-2'-ethylhexyl-1'-oxy) -1,3,5-triazine ("Uvinul" T-150, BASF) | 25.0 g isopropyl 189.0 g C₁₂-C₁₅ alcohol benzoate ("Finsolv TN", Witco) 76.0 g Myristyl alcohol, polyoxypropylated with 3 moles of propylene oxide ("Witconol APM", Witco) 304.0 g Caprylic / Capric Acid Triglyceride ("Miglyol Neutral Oil", Dynamite Nobel) 195.0 g "Bentone-38", Kronos-Titan 150.0 g propylene carbonate 20.0 g ethanol 23.0 g Perfume, corrigents, additives, stabilizers at will Combination C + D @ C: 382.0 g D: 91.0 g

With the mentioned ingredients is in the usual way a sun angel made.

Example 20 hydrogel 2-phenylbenzimidazole-5-sulfonic acid, ("Eusolex 232", Merck) | 27.0 g allantoin 2.0 g Sorbitol fl. ("Karion F", Merck) 22.0 g "Carbopol 934", B.F. Goodrich 15.0 g Tris (hydroxymethyl) aminomethane 27.0 g propylene glycol 10.0 g   ethanol 300.0 g Combination B 294.0 g water 582.0 g Perfume, corrigents, additives, stabilizers at will

With the mentioned ingredients is in the usual way made a hydrogel.

Example 21 Oil-in-water emulsion (sunscreen) Combination D | 563 g 2-phenylbenzimidazole-5-sulfonic acid ("Eusolex 232", Merck) 32.0 g Stearyl alcohol, which is oxyethylated with 2 moles of ethylene oxide ("Brÿ 72", ICI) 30.0 g Stearyl alcohol oxyethylated with 21 moles of ethylene oxide ("Brÿ 721", ICI) 20.0 g Cetylstearylalkohol 25.0 g Myristyl alcohol, polyoxypropylated with 3 moles of propylene oxide ("Witconol APM", Witco) 64.0 g C₁₂-C₁₅ alcohol benzoate ("Finsolv TN", Witco) 16.0 g propylene glycol 35.0 g Tris (hydroxymethyl) aminomethane 14.0 g water 744.0 g Perfume, corrigents, additives, stabilizers at will

The fats are heated to 80 to 85 ° C. The water-soluble ingredients are at 40 ° C in water dissolved, both phases with vigorous stirring each other  mixed and allowed to stir with moderate stirring cooling down.

Example 22 Oil-in-water emulsion (sunscreen) Combination A + D A: 297 g D: 360 g 2,4,6-Trianilino- (p-carbo-2'-ethylhexyl-1'-oxy) -1,3,5-triazine ("Uvinul T-150", BASF) 18.0 g C₁₂-C₁₅ alcohol benzoate ("Finsolv TN", Witco) 47.0 g Cetylstearylalkohol 30.0 g Mixture of stearic acid mono- and diesters of glycerol, and stearic acid esters of polyethylene oxide ("Arlacel 165", ICI) 50.0 g Myristyl alcohol, polyoxypropylated with 3 moles of propylene oxide ("Witconol APM", Witco) 185.0 g water 637.0 g Perfume, corrigents, additives, stabilizers at will

The emulsion becomes according to the above example prepared.

Example 23 Water-in-oil emulsion (sunscreen milk) Combination C | 420 g 1- (4'-tert-butylphenyl) -3- (4'-methoxyphenyl) -propane-1,3-dione ("Parsol 1789", Givaudan) 15.0 g 4-methoxycinnamic acid 2'-ethylhexyl ester, ("Parsol MCX", Givaudan) 35.0 g   Esters of saturated fatty acids with polyethylene oxide ("Arlacel 989", ICI) 37.0 g Esters of unsaturated fatty acids with glycerine and sorbitan ("Arlacel 481", ICI) 13.0 g Myristyl alcohol, polyoxypropoxylated with 3 moles of propylene oxide ("Witconol APM", Witco) 160.0 g C₁₂-C₁₅ alcohol benzoate ("Finsolv TN", Witco) 40.0 g Magnesium sulfate heptahydrate 7.0 g water 673.0 g Perfume, corrigents, additives, stabilizers at will

The emulsion is in the appropriate manner prepared as described in Example 21.

Example 24 Water-in-oil emulsion (sunscreen milk) Combination B, C, D B: 210 g C: 96 g D: 114 g 4-methoxycinnamic acid 2'-ethylhexyl ester, ("Parsol MCX", Givaudan) 15.0 g 3- (4'-methylbenzylidene) camphor ("Eusolex 6300", Merck) 3.0 g Esters of unsaturated fatty acids with glycerol and ("Arlacel 481", ICI) 60.0 g Microwax ("Lunacera 11", Fuller) 10.0 g Caprylic / Capric Acid Triglyceride ("Miglyol Neutral Oil", Dynamite Nobel) 20.0 g Myristyl alcohol, polyoxypropylated with 3 moles of propylene oxide ("Witconol APM", Witco) 145.0 g C₁₂-C₁₅ alcohol benzoate ("Finsolv TN", Witco) 37.0 g magnesium stearate 10.0 g   propylene glycol 37.0 g Magnesium heptahydrate 7.0 g water 641.0 g Perfume, corrigents, additives, stabilizers at will

The emulsion is in the appropriate manner prepared as described in Example 21.

Example 25 Water-in-oil emulsion (sunscreen milk) FADH₂ | 9.0 g Glucose-1,6-phosphate 133.0 g D-Biotin 22.0 g D-carnosine 115.0 g Vit.-C palmitate 25.0 g Vit. E acetate 35.0 g phytic acid 17.0 g urocanic 13.0 g L-cysteine 157.0 g Dithiopropylgallat 40.0 g 4-Methoxycinnamic acid 2'-ethylhexyl ester ("Parsol MCX", Givaudan) 15.0 g 3- (4'-methylbenzylidene) camphor ("Eusolex 6300", Merck) 3.0 g Esters of unsaturated fatty acids with glycerine and sorbitan ("Arlacel 481", ICI) 60.0 g Microwax ("Lunacera 11", Fuller) 10.0 g Caprylic / Capric Acid Triglyceride ("Miglyol Neutral Oil", Dynamite Nobel) 20.0 g Myristyl alcohol, polyoxypropylated with 3 moles of propylene oxide ("Witconol APM", Witco) 119.0 g C₁₂-C₁₅ alcohol benzoate ("Finsolv TN", Witco) 30.0 g   magnesium stearate 10.0 g propylene glycol 37.0 g Magnesium sulfate heptahydrate 7.0 g water 499.0 g Perfume, corrigents, additives, stabilizers at will

The emulsion is prepared in the same manner as described in Example 21.

Example 26 Cationic emulsion for rinsing the hair NADH | 16.5 g Glucose-6-phosphate 122.0 g Dimethyldistearylammonium chloride ("Arosorf TA 100", Rewo) 50.0 g vaseline 50.0 g isopropyl palmitate 20.0 g cetyl alcohol 10.0 g water 833.5 g glycerin 4.0 g Perfume, corrigents, additives, stabilizers at will Combination C 217 g

With the specified ingredients becomes common Way a hair conditioner made.

For the preparation of the topical preparations, the Active ingredients and drug combinations in the aqueous Phase or dissolved in the fat phase and in known Way further processed.  

Production of capsules

Capsules having the following Contain ingredients are known Working methods produced. These are for the treatment the aforementioned diseases in Dosage amounts of one capsule once or several times a day.

Example 27 ingredients % By weight (mg) Vit. E 50 Vit. C 50 DL-carnosine 250 Combination A 100 Combination D 50

test report

The experimental proof of the effectiveness of Active ingredients and active systems according to the invention were carried out by means of chemiluminescence measurement in vivo on the previously 2 For weeks with verum (preparations with active ingredients according to the invention) or contralaterally with the treated vehicle back of the hand. The oxidative, radical processes in the treated Skin areas were treated by UVA irradiation (dose 500 mJ / cm²). The thereby emitted by the skin Photons are taken with one for in vivo measurements suitable chemiluminescence meter counted (counts / 2 min). A reduction of the emitted photon counts Verum treated areas in comparison to those with  Vehicle treated areas serves as evidence for the in vivo efficacy of the invention Preparations. With these measuring systems can be after the same measuring principle measurements on active ingredients and Preparations in vitro. to Illustrations are the measured values (arithmetic Mean values of the preparation according to the invention Example 10 listed: Verum 3054 counts / 2 min; Vehicle: 27278 counts / 2 min.

The effect according to the invention on the regulation and Reconstitution of glutathione status was e.g. B. in the Skin treated according to the invention on the basis of fresh obtained skin biopsies using the literature described fluorescence detection method with the indicator monochlorobimanes determined histologically. The quantitative evaluation was made on histological Preparations by means of a microscope-coupled Image analysis system.

Claims (4)

1. Use of antioxidants and / or Active substances that limit the endogenous energy metabolism and / or the endogenous enzymatic Antioxidant system, especially that of the skin, on to regulate a normal level or a normal one Maintained level, for prophylaxis and Treatment of more sensitive, hyperreactive and for dermatitis of predisposed skin, deficient Aging skin and manifest atopic Dermatides such. B. Atopic dermatitis, Atopic dermatitis, atopic eczema and seborrheic Dermatitis and light-induced dermatoses like z. B. Polymorphic photodermatosis, Mallorca acne, Photodermatitis, as well as prurigo forms, Pruritus forms, psoriasis forms and ishtyosis. 2. Use of preparations, in particular topical preparations, with antioxidants and / or agents that are endogenous Energy metabolism and / or the endogenous enzymatic antioxidant system, in particular the of the skin, regulate to a normal level or to maintain a normal level, to Prophylaxis and treatment of more sensitive, hyperreactive and for dermatids predisposed skin, deficient age skin and of manifest atopic dermatitis such as B. Atopic dermatitis, neurodermatitis, atopic Eczema and seborrhoeic dermatitis and light-induced dermatoses such. B. polymorphs Light dermatosis, Mallorca acne, photodermatitis  as well as prurigo forms, pruritus forms, Psoriasis forms and Ichtyosis. 3. Pharmaceutical and topical preparations, characterized in that it is a combination of antioxidants and regulatory agents according to claim 1 included. 4. The combination of antioxidants and regulating active ingredients according to claim 1.