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Definitions

• the invention relates to the use of certain DNA repair enzymes as inhibitors of collagen-degrading matrix metal proteinase 1 (MMP-1) in cosmetic or pharmaceutical compositions in order to prevent aging, in particular light-induced aging, of human skin.
• MMP-1 collagen-degrading matrix metal proteinase 1
• induction of collagenase MMP-1 can be understood to mean both an increase in the amount of this enzyme and an increase in its activity, and both.
• MMP-1 separates the fibrillary, triple-helical collagen at a defined point on the molecule. The triple helix, split into two parts, dissolves and becomes accessible for degradation through additional collagenases. Macroscopically, the reduction in the amount of collagen is reflected in a reduction in the elasticity of the skin and in the formation of wrinkles.
• the induction of the collagenase MMP-1 by UV radiation is considered the main reason for the macroscopic effects of skin aging.
• an MMP-1 inhibitor is understood to mean a substance which
• MMP-1 synthesis and / or MMP-1 activity is thus an important goal in the development of "anti-aging" skin cosmetics, that is to say cosmetic products which counteract skin aging.
• An ideal "anti-age” active ingredient inhibits the expression of MMP-1 even in low concentrations.
• the substance must not be toxic to cells and must be stable in cosmetic and pharmaceutical formulations.
• MMP-1 matrix metal proteinases
• the anti-aging active ingredients known from the prior art do not meet these conditions, or do so only to an inadequate extent.
• the application WO 98/55075 claims triple combinations of a UV-A blocker, a UV-B blocker and an MMP inhibitor which counteract the aging of the skin by light.
• the compositions must be applied to the skin 7 to 48 hours before UV exposure.
• Retinoic acid (tretinoin) and retinol are preferred as MMP inhibitors.
• Retinoids intervene in the metabolism of the skin cells and, in addition to stimulating the proliferation and differentiation of epidermal keratinocytes, increase the production of collagen by fibroblasts.
• retinol is said to reduce the formation of collagen-digesting enzymes (New Scientist 2031, 42 - 46, 1996).
• retinoic acid has teratogenic properties and may only be used in prescription drugs.
• the use of retinol in cosmetic and pharmaceutical topical preparations is problematic for several reasons.
• Retinol for example, has a relatively high cell toxicity and in particular phototoxicity and can therefore only be used in low concentrations in compositions for use in humans.
• retinol is easily oxidatively degraded under the influence of heat and / or light and is difficult to stabilize in cosmetic and pharmaceutical formulations.
• the object of the invention was to remedy the shortcomings of the prior art and to provide more suitable agents for the cosmetic treatment of sunlight-induced skin aging.
• Another object of the invention was to provide agents suitable for the pharmaceutical treatment of sunlight-induced skin aging.
• T4N5 Photolyase and T4 endonuclease V, the latter hereinafter abbreviated to "T4N5", are already known in the art as so-called DNA repair enzymes.
• DNA repair means the cleavage or removal of UV-induced pyrimidine dimers from the DNA.
• Pyrimidine dimer is the common name in the prior art for dimers which are photochemically, for. B. by UV B rays, are formed from certain pyrimidine bases of DNA. Pyrimidine itself is not a DNA base, but in the following the term “pyrimidine dimer” is used instead of the correct term “pyrimidine base dimer”.
• the dimerization on the pyrimidine base thymine takes place in that neighboring thymine units of a DNA strand dimerize to a tricyclic compound.
• the dimerization product, a cis-syn-cyclobutane dipyrimidine unit can cause errors in the transmission of the genetic code.
• the epidermal keratinocytes are particularly affected by the formation of the pyrimidine dimers.
• Photolyase is the short name for deoxyribodipyrimidine photolyase or DNA photolyase, an enzyme with the classification number EC 4.1.99.3.
• Photolyase was found in low eukaryotes, e.g. B. yeasts detected. It needs light in the wavelength range from 350 to 500 nm to be activated. This light is absorbed by a chromophore group contained in the photolyase molecule, which then transfers electrons to a second chromophore. Further electron transfer to the cyclobutane dipyrimidine unit cleaves it and the two original thymine bases are restored.
• a particularly efficient photolyase comes from Anacystis nidulans, a phototrophic marine microorganism. The A. nidulans photolyase is now obtained in technically relevant quantities from E. coli.
• the enzyme T4 endonuclease V is produced by the e ⁇ V gene of bacteriophage T4 and belongs to the phosphodiesterases that hydrolytically cleave the nucleic acids at the (5 ' -3> bond.
• T4N5 attacks within the nucleic acid strand cut out the DNA areas damaged by UV-induced pyrimidine dimers and polymerase inserted new, correct bases using the complementary strand as a template and linked by ligases to the original DNA strand.
• This excision repair mechanism is a dark reaction that does not require light activation.
• T4N5 is a prokaryote enzyme, but it also works on human cells. It can be produced on an industrial scale from E. coli strains which contain the cfet? V gene.
• DNA repair enzymes represent an interesting active ingredient for cosmetic compositions.
• the cosmetic compositions preferred in the prior art are sunscreens and after-sun products.
• T4N5 liposome encapsulation is described by Ceccoli et al., J. Invest. Dermatol. 93, 190-194, 1989.
• Yarosh US Pat. No. 5,190,762; WO 94/14419 A1
• Gilchrest et al Describe the use of liposome-encapsulated T4N5 or photolyase in cosmetic products. (WO 94/17781 A1). Burmeister et al.
• compositions which contain liposome-encapsulated combinations of DNA repair enzymes with tyrosine, tyrosine derivatives, vitamins or provitamins of the vitamin groups A, C and E, glycoprotein complexes of copper, zinc or magnesium, forskolin, cyclic Contain adenosine monophosphate (c-AMP), bioflavonoids or emulsifiers with an HLB value of 10-14, as well as processes for the production of cosmetic tanning agents and hair care products.
• c-AMP cyclic Contain adenosine monophosphate
• T4N5 causes an increased melanogenesis and can therefore be used in tanning agents is described in the published patent applications EP 0 707 844 A2, WO 94/14419 A1 and WO 94/17781 A1.
• Photolyase has no influence on melanogenesis and can therefore be used in skin lightening agents (S.H. Lee, KR 97032828 A).
• Liposome encapsulated photolyase is commercially available e.g. B. under the product name Photosome TM, liposome-encapsulated T4N5 z. B. available under the name Ultrasome TM from Applied Genetics, Freeport, USA.
• the interleukins translocate into the dermis and bind to receptors on the fibrobiasts. In response, collagen-degrading MMP-1 is synthesized from the fibroblasts.
• the DNA repair enzymes photolyase and T4N5 are apparently able to cure UV-induced DNA damage even before the cell's own transcription-coupled repair mechanism is activated and the causal chain for the UV-induced MMP-1 synthesis in Gear is set.
• photolyase or T4N5 to inhibit MMP-1 expression and to delay collagen breakdown is new. It opens up new areas of application in the cosmetic treatment of skin aging that go beyond the known possible uses.
• MMP-1 inhibitors can advantageously be used in cosmetics wherever cosmetically desired effects are associated with MMP-1 inhibition. Accordingly, the use of photolyase or T4N5 in anti-wrinkle creams is recommended, especially for the constantly light-exposed skin areas on the face, neck or hands. Concentrated creams, lotions, plasters and patches with photolyase or T4N5 as MMP-1 inhibitors can be produced for local wrinkle treatment. T4N5 can even be used to treat wrinkles after exposure to UV on normally less exposed areas of the body, e.g.
• the DNA repair enzymes according to the invention can be used both for preventive cosmetic treatment and for delaying the macroscopic effects of skin aging, in particular the aging of the human skin induced by sunlight.
• the skin treatment agents according to the invention are suitable for preventing sun-induced skin aging both in the case of sun exposure below the minimum erythemal dose (MED) and for exposure above the MED. They are therefore suitable both for long-term preventive treatment, whereby their daily use protects the skin in the long term even with low sun exposure, as well as for preventing high exposure to sunlight.
• MED minimum erythemal dose
• the MMP-1-inhibiting agents can be used both before and after exposure to sunlight, ie the effect on the skin desired according to the invention is achieved in both cases. It is particularly advantageous that the MMP-1-inhibiting agents according to the invention prevent sunlight-induced skin aging when they are applied topically to the skin only relatively shortly before exposure to sunlight. A relatively short period is understood to mean in particular a period between one and five hours.
• a first subject of the invention is therefore the use of DNA repair enzymes in cosmetic topical skin treatment agents to inhibit the light-induced collagen breakdown.
• Another object of the invention is the use of DNA repair enzymes in cosmetic topical skin treatment agents for inhibiting the expression or the activity of the matrix metal proteinase MMP-1.
• the invention further relates to the use of DNA repair enzymes for the production of pharmaceutical topical skin treatment agents which inhibit the light-induced collagen breakdown.
• the invention furthermore relates to the use of DNA repair enzymes for the production of pharmaceutical topical skin treatment agents which inhibit the expression or the activity of the matrix metal proteinase MMP-1.
• DNA repair enzymes in topical skin treatment agents or anti-aging agents to reduce the loss of elasticity and wrinkling of aging skin.
• the DNA repair enzyme used according to the invention is photolyase. Liposome-encapsulated photolyase is particularly preferred.
• the DNA repair enzyme used according to the invention is T4 endonuclease V. Liposome-encapsulated T4 endonuclease V is particularly preferred. Use of a mixture of photolyase and T4 endonuclease V according to the invention is also preferred, particularly preferably in liposome-encapsulated form , In a further preferred embodiment, the use according to the invention is preventive.
• the amount of the DNA repair enzyme or the DNA repair enzymes used according to the invention is 1 -10 "6 to 5-10 " 2 % by weight, particularly preferably 1 -10 "5 to 1-10 " 2 % By weight, based in each case on the entire skin treatment agent.
• Another object of the invention is a cosmetic or pharmaceutical skin treatment agent containing photolyase and / or T4 endonuclease V and also at least one substance selected from the vitamins, provitamins or vitamin precursors of the vitamin B group or their derivatives and the derivatives of 2-furanone.
• the vitamin B group or the vitamin B complex include, among others
• Vitamin B common name thiamine, chemical name 3 - [(4 ' -Amino-2 ' -methyl- 5 ' -pyrimidinyl) -methyl] -5- (2-hydroxyethyl) -4-methylthiazolium chloride.
• Thiamine hydrochloride is preferably used in amounts of 0.05 to 1% by weight, based on the total agent.
• Vitamin B 2 common name riboflavin, chemical name 7,8-dimethyl-10- (1-D-ribityl) -benzo [g] pteridine-2,4 (3H, 10H) -dione.
• riboflavin comes e.g. B. in whey before, other riboflavin derivatives can be isolated from bacteria and yeast.
• a stereoisomer of riboflavin which is also suitable according to the invention is lyxoflavin which can be isolated from fishmeal or liver and which carries a D-arabityl radical instead of D-ribityl.
• Riboflavin or its derivatives are preferably used in amounts of 0.05 to 1% by weight, based on the total agent.
• nicotinic acid and nicotinamide are often listed under this name. According to the invention, preference is given to nicotinamide which is present in the agents according to the invention is preferably contained in amounts of 0.05 to 1 wt .-%, based on the total agent.
• Vitamin B 5 pantothenic acid and panthenol
• Panthenol is preferably used.
• Derivatives of panthenol which can be used according to the invention are, in particular, the esters and ethers of panthenol and cationically derivatized panthenols.
• derivatives of 2-furanone with the general structural formula (I) can also be used.
• the 2-furanone derivatives in which the substituents R 1 to R 6 independently of one another are a hydrogen atom, a hydroxyl radical, a methyl, methoxy, aminomethyl or hydroxymethyl radical, a saturated or mono- or di-unsaturated, linear or branched C 2 -C 4 - hydrocarbon residue, a saturated or mono- or di-unsaturated, branched or linear mono-, di- or trihydroxy-C 2 -C 4 - hydrocarbon residue or a saturated or mono- or di-unsaturated, branched or linear mono- , Di- or triamino-C 2 -C 4 - represent hydrocarbon radical.
• the substituents R 1 to R 6 independently of one another are a hydrogen atom, a hydroxyl radical, a methyl, methoxy, aminomethyl or hydroxymethyl radical, a saturated or mono- or di-unsaturated, linear or branched C 2 -C 4 - hydrocarbon residue, a saturated or mono- or di-
• Particularly preferred derivatives are the commercially available substances dihydro-3-hydroxy-4,4-dimethyl-2 (3H) -furanone with the common name pantolactone (Merck), 4-hydroxymethyl- ⁇ -butyrolactone (Merck), 3.3 -Dimethyl-2-hydroxy- ⁇ -butyrolactone (Aldrich) and 2,5-dihydro-5-methoxy-2-furanone (Merck), all stereoisomers being expressly included.
• the 2-furanone derivative which is extremely preferred according to the invention is pantolactone (dihydro-3-hydroxy-4,4-dimethyl-2 (3H) -furanone), wherein in formula (I) R 1 for a hydroxyl group, R 2 for a hydrogen atom , R 3 and R 4 represent a methyl group and R 5 and R 6 represent a hydrogen atom.
• the stereoisomer (R) - pantolactone is formed when pantothenic acid is broken down.
• the compounds of the vitamin B 5 type mentioned and the 2-furanone derivatives are preferably present in the compositions according to the invention in a total amount of 0.05 to 10% by weight, based on the overall composition. Total amounts of 0.1 to 5% by weight are particularly preferred.
• Vitamin B 6 which does not mean a uniform substance, but rather the derivatives of 5-hydroxymethyl-2-methylpyridin-3-ol known under the trivial names pyridoxine, pyridoxamine and pyridoxal. Vitamin B 6 is contained in the agents according to the invention preferably in amounts of 0.0001 to 1.0% by weight, in particular in amounts of 0.001 to 0.01% by weight.
• Vitamin B 7 also known as vitamin H or "skin vitamin”.
• Biotin is (3aS, 4S, 6aR) -2-oxohexahydrothienol [3,4-d] imidazole-4-valeric acid.
• Biotin is contained in the agents according to the invention preferably in amounts of 0.0001 to 1.0% by weight, in particular in amounts of 0.001 to 0.01% by weight.
• Panthenol, pantolactone, nicotinamide and biotin are very particularly preferred according to the invention.
• Another object of the invention is a cosmetic or pharmaceutical skin treatment composition containing photolyase and / or T4 endonuclease V and furthermore at least one plant extract.
• Plant extracts are usually produced by extracting the entire plant, but in individual cases also exclusively from flowers and / or leaves and / or seeds and / or other parts of plants. According to the invention, the extracts from the meristem, i.e.
• Algae extracts can also be used to advantage.
• the Algae extracts used according to the invention come from green algae, brown algae, red algae or blue-green algae (cyanobacteria).
• the algae used for the extraction can be of natural origin as well as obtained through biotechnological processes and, if desired, can be changed compared to the natural form.
• the organisms can be changed genetically, by breeding or by cultivation in media enriched with selected nutrients.
• Preferred algae extracts come from seaweed, blue-green algae, from the green algae Codium tomentosum and from the brown algae Fucus vesiculosus.
• a particularly preferred algae extract comes from blue-green algae of the Spirulina species, which were cultivated in a magnesium-enriched medium.
• the extracts from spirulina, green tea, aloe vera, meristem, witch hazel, apricot, marigold, guava, sweet potato, lime, mango, kiwi, cucumber, mallow, marshmallow and violet are particularly preferred.
• the agents according to the invention can also contain mixtures of several, in particular two, different plant extracts.
• u. a Water, alcohols and mixtures thereof can be used.
• alcohols lower alcohols such as ethanol and isopropanol, but especially polyhydric alcohols such as ethylene glycol, propylene glycol and butylene glycol are preferred, both as the sole extracting agent and in a mixture with water.
• Plant extracts based on water / propylene glycol in a ratio of 1:10 to 10: 1 have proven to be particularly suitable.
• steam distillation is one of the preferred extraction processes.
• the plant extracts can be used both in pure and in diluted form. If they are used in dilute form, they usually contain about 2 to 80% by weight of active substance and, as a solvent, the extractant or mixture of extractants used in their extraction. Depending on the choice of extracting agent, it may be preferred to stabilize the plant extract by adding a solubilizer. Suitable solubilizers are, for. B. Ethoxylation products of optionally hardened vegetable and animal oils. Preferred solubilizing agents are ethoxylated mono-, di- and triglycerides of C 8 - 22 - fatty acids having from 4 to 50 ethylene oxide units, for example. B.
• mixtures of several, in particular two, different plant extracts in the agents according to the invention may be preferred.
• Another object of the invention is a cosmetic or pharmaceutical skin treatment agent containing photolyase and / or T4 endonuclease V and at least one further MMP-1 inhibiting substance selected from propyl gallate, precocenes, 6-hydroxy-7-methoxy-2,2-dimethyl -1 (2H) -benzopyran, 3,4-dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1 (2H) -benzopyran (available as a commercial product Lipochroman 6 TM from Lipotec SA) and their mixtures , contain.
• Precocenes are chromium derivatives which occur in plants and are known as hormones (The Merck Index, 12th edition, Merck & Co. 1996).
• the MMP-1-inhibiting effect of these substances is described in the German published patent application DE 10016016 A1. They are used in amounts of 0.1 to 5, preferably 0.5 to 2,% by weight, based in each case on the total agent.
• the skin treatment compositions of the invention additionally contain at least one ester of retinol (Vitamin A ⁇ with a C 2. 18 carboxylic acid.
• retinol retinol, retinyl acetate and retinyl palmitate, retinyl palmitate is particularly preferred.
• the retinol esters are used in amounts of from 0.1 to 5, preferably from 0.5 to 2 wt .-%, each based on the total agent used.
• the skin treatment compositions according to the invention contain at least one surface-active substance as an emulsifier or dispersant.
• emulsifiers cause the formation of water- or oil-stable adsorption layers that counter the dispersed droplets Protect coalescence and thus stabilize the emulsion.
• surfactants emulsifiers are therefore made up of a hydrophobic and a hydrophilic part of the molecule. Hydrophilic emulsifiers preferably form O / W emulsions and hydrophobic emulsifiers preferably form W / O emulsions.
• W / O emulsions which are stabilized without hydrophilic emulsifiers are disclosed in the published documents DE 19816665 A1 and DE 19801593 A1.
• An emulsion is to be understood as a droplet-like distribution (dispersion) of a liquid in another liquid with the use of energy to create stabilizing phase interfaces by means of surfactants.
• the selection of these emulsifying surfactants or emulsifiers is based on the substances to be dispersed and the particular external phase as well as the fine particle size of the emulsion.
• Emulsifiers which can be used according to the invention are, for example
• alkyl (oligo) glucosides e.g. B. the commercially available product Montanov ® 68,
• Adducts of 5 to 60 moles of ethylene oxide with castor oil and hardened castor oil Adducts of 5 to 60 moles of ethylene oxide with castor oil and hardened castor oil
• Sterols are understood to mean a group of steroids which carry a hydroxyl group on the C atom 3 of the steroid structure and both from animal tissue (zoosterols) as well as from vegetable fats (phytosterols). Examples of zoosterols are cholesterol and lanosterol. Examples of suitable phytosterols are beta-sitosterol, stigmasterol, campesterol and ergosterol. Sterols, the so-called mycosterols, are also isolated from fungi and yeasts.
• glucose phospholipids especially the glucose phospholipids, which, for. B. as lecithins or phosphatidylcholines from z. B. egg yolk or plant seeds (e.g. soybeans) are obtained,
• polyglycerols and polyglycerol preferably Polyglyceryl-2-dipolyhydroxy- stearate (commercial product Dehymuls ® PGPH) and polyglyceryl-3 diisostearate (Lameform ® TGI commercial product)
• the agents according to the invention preferably contain the emulsifiers in amounts of 0.1 to 25% by weight, in particular 0.5-15% by weight, based on the total agent.
• At least one nonionic emulsifier with an HLB value of 8 and below is according to the 10th edition, Georg Thieme Verlag Stuttgart, New, in the Rompp-Lexikon Chemie (Eds .: J. Falbe, M. Regitz) York, (1997), page 1764, listed definitions of the HLB value.
• a particularly preferred emulsifier of the formula R 1 - O - R 2 is a behen or erucyl derivative in which R 1 represents a linear, terminally substituted alkyl, alkenyl or acyl group having 22 carbon atoms.
• suitable emulsifiers with an HLB value of 8 and below are the addition products of 1 or 2 moles of ethylene oxide or propylene oxide with behenyl alcohol, erucyl alcohol, arachidyl alcohol or else with behenic acid or erucic acid.
• the monoesters of C 16 -C 30 fatty acids are also preferred Polyols such as B. pentaerythritol, trimethylolpropane, diglycerol, sorbitol, glucose or methylglucose. Examples of such products are e.g. B. sorbitan monobehenate or pentaerythritol monoerucate.
• At least one ionic emulsifier selected from anionic, zwitterionic, ampholytic and cationic emulsifiers is contained.
• Preferred anionic emulsifiers are alkyl sulfates, alkyl polyglycol ether sulfates and ether carboxylic acids with 10 to 18 carbon atoms in the alkyl group and up to 12 glycol ether groups in the molecule, sulfosuccinic acid and dialkyl esters with 8 to 18 carbon atoms in the alkyl group and sulfosuccinic acid mono-alkyl polyoxyethyl ester with 8 to 18 carbon atoms in the alkyl group and 1 to 6 oxyethyl groups, monoglyceride sulfates, alkyl and alkenyl ether phosphates and protein fatty acid condensates.
• Zwitterionic emulsifiers carry at least one quaternary ammonium group and at least one -COO " or -SO 3 " group in the molecule.
• Particularly suitable zwitterionic emulsifiers are the so-called betaines such as the N-alkyl-N, N-dimethylammonium glycinate, N-acylaminopropyl-N, N-dimethylammonium glycinate and 2-alkyl-3-carboxymethyl-3-hydroxyethyl-imidazolines each with 8 to 18 carbon atoms in the alkyl or acyl group and the cocoacylaminoethyl hydroxyethyl carboxymethyl glycinate.
• ampholytic emulsifiers contain at least one free amino group and at least one -COOH or -S0 3 H group in the molecule and can form internal salts.
• suitable ampholytic emulsifiers are N-alkylglycines, N-alkylaminopropionic acids, N-alkylaminobutyric acids, N-alkyliminodipropionic acids, N-hydroxyethyl-N-alkylamidopropylglycines, N-alkyltaurines, N-alkyl sarcosines, 2-alkylaminopropionic acids and alkylaminoacetic acids each with about 8 bisacetic acids 24 carbon atoms in the alkyl group.
• the ionic emulsifiers are present in an amount of 0.01 to 5% by weight, preferably 0.05 to 3% by weight and particularly preferably 0.1 to 1% by weight, based on the total agent ,
• the skin treatment compositions according to the invention contain at least one organic or mineral or modified mineral light protection filter.
• the light protection filters are to liquid or crystalline substances at room temperature, which are able to absorb ultraviolet rays and the absorbed energy in the form of longer-wave radiation, e.g. B. to release heat again.
• UVA filters and UVB filters.
• the UVA and UVB filters can be used both individually and in mixtures. The use of filter mixtures is preferred according to the invention.
• the organic UV filters used according to the invention are selected from the derivatives of dibenzoylmethane, cinnamic acid esters, diphenylacrylic acid esters, benzophenone, camphor, p-aminobenzoic acid esters, o-aminobenzoic acid esters, salicylic acid esters, benzimidazoles, 1, 3,5-triazines, monomeric and oligomeric 4,4- Diaryl butadienecarboxylic acid esters and carboxamides, ketotricyclo (5.2.1.0) decane, benzalmalonic acid esters and any mixtures of the components mentioned.
• the organic UV filters can be oil-soluble or water-soluble.
• oil-soluble UV filters are 1- (4-tert-butylphenyl) -3- (4'methoxyphenyl) propane-1, 3-dione (Parsol ® 1789), 1-phenyl-3- (4'-isopropylphenyl ) - propane-1, 3-dione, S - ⁇ - methylbenzylidene ⁇ DL-camphor, 4- (dimethylamino) benzoic acid 2-ethylhexyl ester, 4- (dimethylamino) benzoic acid 2-octyl ester, 4- (dimethylamino) - benzoic acid amyl ester , 2-ethylhexyl 4-methoxycinnamate, propyl 4-methoxycinnamate, isopentyl 4-methoxycinnamate, 2-ethylhexyl 2-cyano-3,3-phenylcinnamate (octocrylene), 2-ethylhexy
• Preferred water-soluble UV filters are 2-phenylbenzimidazole-5-sulfonic acid and its alkali metal, alkaline earth metal, ammonium, alkylammonium, alkanolammonium and glucammonium salts, sulfonic acid derivatives of benzophenones, preferably 2-hydroxy-4-methoxybenzophenone-5 -sulfonic acid and its salts, sulfonic acid derivatives of 3-benzylidene camphor, such as.
• the preferred inorganic light protection pigments according to the invention are finely dispersed metal oxides and metal salts, for example titanium dioxide, zinc oxide, iron oxide, aluminum oxide, cerium oxide, zirconium oxide, silicates (talc), barium sulfate and zinc stearate.
• the particles should have an average diameter of less than 100 nm, preferably between 5 and 50 nm and in particular between 15 and 30 nm. They can have a spherical shape, but it is also possible to use particles which have an ellipsoidal shape or a shape which differs from the spherical shape in some other way.
• the pigments can also be surface-treated, ie hydrophilized or hydrophobicized. Typical examples are coated titanium dioxide, such as. B.
• Titanium dioxide T 805 (Degussa) or Eusolex ® T2000 (Merck). Silicones, and in particular trialkoxyoctylsilanes or simethicones, are particularly suitable as hydrophobic coating agents. So-called micro- or nanopigments are preferably used in sunscreens. Micronized zinc oxide is preferably used.
• the skin treatment agents according to the invention contain at least one protein hydrolyzate or its derivative.
• both vegetable and animal protein hydrolyzates can be used.
• Animal protein hydrolyzates are e.g. B. elastin, collagen, keratin, silk and milk protein protein hydrolyzates, which can also be in the form of salts.
• Vegetable protein hydrolyzates e.g. B. soy, wheat, almond, pea, potato and rice protein hydrolyzates.
• Corresponding commercial products are e.g. B. DiaMin ® (Diamalt), Gluadin ® (Cognis), Lexein ® (Inolex) and Crotein ® (Croda).
• amino acid mixtures obtained in some other way can be used, and also individual amino acids and their physiologically tolerable salts.
• the amino acids preferred according to the invention include glycine, serine, threonine, cysteine, asparagine, glutamine, pyroglutamic acid, alanine, valine, leucine, isoleucine, proline, tryptophan, phenylalanine, methionine, aspartic acid, glutamic acid, lysine, arginine and histidine and zinc salt Acid addition salts of the amino acids mentioned.
• derivatives of protein hydrolyzates e.g. B. in the form of their fatty acid condensation products.
• Corresponding commercial products are e.g. B. Lamepon ® (Cognis), Gluadin ® (Cognis), Lexein ® (Inolex), Crolastin ® or Crotein ® (Croda).
• Cationized protein hydrolyzates can also be used according to the invention, it being possible for the underlying protein hydrolyzate to come from animals, plants, marine life forms or biotechnologically obtained protein hydrolyzates.
• Cationic protein hydrolyzates are preferred, the underlying protein portion of which has a molecular weight of 100 to 25,000 Daltons, preferably 250 to 5000 Daltons.
• Cationic protein hydrolyzates also include quaternized amino acids and their mixtures.
• the cationic protein hydrolyzates can also be further derivatized.
• Typical examples of cationic protein hydrolyzates and derivatives used according to the invention are some of the INCI names in the "International Cosmetic Ingredient Dictionary and Handbook" (seventh edition 1997, The Cosmetic, Toiletry, and Fragrance Association 1101 17 t Street, NW, Suite 300, Washington, DC 20036-4702) and commercially available products: Cocodimonium Hydroxypropyl Hydrolyzed Collagen, Cocodimonium Hydroxypropyl Hydrolyzed Casein, Steardimonium Hydroxypropyl Hydrolyzed Collagen, Steardimonium Hydroxypropyl Hydrolyzed Hair Keratin, Lauryldimonium Hydroxypropyl Hydrolyzed Keratin, Cocodimonium Hydroxice Protein Hydrolyzed Hydroxypropyl Hydrolyzed Silk, Cocodimonium Hydroxypropyl Hydrolyzed Soy Protein, Cocodimonium Hydroxypropyl Hydrolyzed Wheat Protein, Cocodimonium Hydroxypropyl Silk Amino Acids, Hydroxypropyl Arginine
• the agents according to the invention contain the protein hydrolyzates and their derivatives or the amino acids and their derivatives in amounts of 0.01-10% by weight, based on the total agent. Amounts of 0.1 to 5% by weight, in particular 0.1 to 3% by weight, are particularly preferred.
• the skin treatment agents according to the invention contain at least one mono-, oligo- or polysaccharide or their derivatives.
• Suitable monosaccharides according to the invention are e.g. B. glucose, fructose, galactose, arabinose, ribose, xylose, lyxose, allose, old rose, mannose, gulose, idose and talose, the deoxy sugar fucose and rhamnose and amino sugar such as.
• Suitable oligosaccharides according to the invention are composed of two to ten monosaccharide units, for. B. sucrose, lactose or trehalose.
• a particularly preferred oligosaccharide is sucrose.
• honey which predominantly contains glucose and sucrose, is also particularly preferred.
• Polysaccharides suitable according to the invention are composed of more than ten monosaccharide units.
• Preferred polysaccharides are the starches made up of ⁇ -D-glucose units and starch breakdown products such as amylose, amylopectin and dextrins. Chemically and / or thermally modified starches, eg. B. hydroxypropyl starch phosphate,
• Dihydroxypropyldiabophosphat or the commercial products Dry Flo ® Dihydroxypropyldiabophosphat or the commercial products Dry Flo ® .
• Dextrans and their derivatives e.g. B. dextran sulfate.
• nonionic cellulose derivatives such as methyl cellulose, hydroxypropyl cellulose or hydroxyethyl cellulose
• cationic cellulose derivatives e.g. B. the commercial products Celquat ® and Polymer JR ® , and preferably Celquat ® H 100, Celquat ® L 200 and Polymer JR ® 400 (Polyquatemium-10) and Polyquaternium-24.
• Further preferred examples are polysaccharides from fucose units, e.g. B. the commercial product Fucogel ® .
• the polysaccharides composed of amino sugar units in particular chitins and their deacetylated derivatives, the chitosans and mucopolysaccharides, are particularly preferred.
• the preferred mucopolysaccharides according to the invention include hyaluronic acid and its derivatives, e.g. B. sodium hyaluronate or dimethylsilanol hyaluronate, and chondroitin and its derivatives, for. B. chondroitin sulfate.
• the skin treatment agents according to the invention contain at least one film-forming, emulsion-stabilizing, thickening or adhesive polymer, selected from natural and synthetic polymers, which can be cationically, anionically, amphoterically charged or non-ionically.
• Cationic, anionic and nonionic polymers are preferred according to the invention.
• Preferred among the cationic polymers are polysiloxanes with quaternary groups, e.g. B. the commercial products Q2-7224 (Dow Corning), Dow Corning ® 929 emulsion (with Amodimethicone), SM-2059 (General Electric), SLM-55067 (Wacker) and Abil ® -Quat 3270 and 3272 (Th. Goldschmidt).
• Preferred anionic polymers which can support the action of the active ingredient used according to the invention contain carboxylate and / or sulfonate groups and, for example, acrylic acid, methacrylic acid, crotonic acid, maleic anhydride and 2-acrylamido-2-methylpropanesulfonic acid as monomers.
• the acidic groups can be present in whole or in part as sodium, potassium, ammonium, mono- or triethanolammonium salt.
• Preferred monomers are 2-acrylamido-2-methylpropanesulfonic acid and acrylic acid.
• anionic polymers contain 2-acrylamido-2-methylpropanesulfonic acid as the sole monomer or as comonomer, it being possible for the sulfonic acid group to be wholly or partly in salt form.
• copolymers of at least one anionic monomer and at least one nonionic monomer are acrylamide, methacrylamide, acrylic acid ester, methacrylic acid ester, vinyl pyrrolidone, vinyl ether and vinyl ester.
• Preferred anionic copolymers are acrylic acid-acrylamide copolymers and in particular polyacrylamide copolymers with monomers containing sulfonic acid groups.
• a particularly preferred anionic copolymer consists of 70 to 55 mol% of acrylamide and 30 to 45 mol% of 2-acrylamido-2-methylpropanesulfonic acid, the sulfonic acid groups in whole or in part as sodium, potassium, ammonium, mono- or triethanolammonium Salt.
• This copolymer can also be crosslinked, the preferred crosslinking agents being polyolefinically unsaturated compounds such as tetraallyloxyethane, allyl sucrose, allylpentaerythritol and methylene bisacrylamide.
• Such a polymer is contained in the commercial product Sepigel ® 305 from SEPPIC.
• Sepigel ® 305 from SEPPIC.
• the use of this compound has proven to be particularly advantageous in the context of the teaching according to the invention.
• ® 600 as a compound with isohexadecane and polysorbate-80, sodium sold under the name Simulgel acryloyldimethyltaurate copolymers have proven effective as in the present invention particularly.
• Other particularly preferred anionic homopolymers and copolymers are uncrosslinked and crosslinked polyacrylic acids. Allyl ethers of pentaerythritol, sucrose and propylene can be preferred crosslinking agents.
• Such compounds are, for example, the commercial products Carbopol ® .
• a particularly preferred anionic copolymer contains 80-98% of an unsaturated, optionally substituted C 3 as monomer. 6- carboxylic acid or its anhydride and, if desired, 2 - 20% substituted acrylic acid esters of saturated C 10 - 3 o-carboxylic acids, it being possible for the copolymer to be crosslinked with the aforementioned crosslinking agents.
• Corresponding commercial products are Pemulen ® and the Carbopol ® types 954, 980, 1342 and ETD 2020 (ex BF Goodrich).
• Suitable nonionic polymers are, for example, polyvinyl alcohols, which can be partially saponified, e.g. B. the commercial products Mowiol ® and vinyl pyrrolidone / vinyl ester copolymers and polyvinyl pyrrolidones, which, for. B. are sold under the trademark Luviskol ® (BASF).
• the action of the agents according to the invention can be further optimized by means of fatty substances.
• Suitable fat substances are for example:
• vegetable oils such as sunflower oil, olive oil, soybean oil, rapeseed oil, almond oil, jojoba oil, orange oil, wheat germ oil, peach seed oil and the liquid components of coconut oil,
• paraffin oils e.g. 1, 3-di- (2-ethyl-hexyl) cyclohexane (Cetiol ® S) or polydecene,
• Di-n-alkyl ethers with a total of 12 to 36, in particular 12 to 24 carbon atoms, for.
• di-n-octyl ether (Cetiol ® OE)
• di-n-n-hexyl-n-octyl ether di-n-octyl-n-decyl ether.
• C 8 saturated and / or unsaturated C 8 .
• C 1 are preferred.
• fatty acids are caproic acid, caprylic acid, 2-ethylhexanoic acid, capric acid, lauric acid, isotridecanoic acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, elaidic acid, petroselinic acid, linoleic acid, Linolenic acid, elaeostearic acid, arachidonic acid, gadoleic acid, behenic acid and erucic acid and their technical mixtures.
• the fatty acid cuts that are obtainable from coconut oil or palm oil are usually particularly preferred; the use of stearic acid is particularly preferred.
• Fatty alcohols especially saturated, mono- or polyunsaturated, branched or unbranched fatty alcohols with 6 - 30, preferably 10 - 22 and very particularly preferably 12 - 22 carbon atoms.
• 6 - 30, preferably 10 - 22 and very particularly preferably 12 - 22 carbon atoms For the purposes of the invention, z. B.
• Esteröle that is, esters of C 6 - 3 o-fatty acids with C. 2 30 fatty alcohols.
• the monoesters of fatty acids with alcohols having 2 to 24 carbon atoms are preferred.
• the above-mentioned substances can be used as alcohol and acid components of the ester oils.
• isopropyl myristate C 16 isononanoic acid alkyl ester, 2-ethylhexyl palmitate, stearic acid 2-ethylhexyl ester, cetyl oleate, glycerol tricaprylate, coconut fatty alcohol caprinate / - caprylate, n-butyl stearate, isopropyl enolate, oleylerolate, oleylerucyl ester Di-n-butyl adipate, myristyl myristate, cetearyl isononanoate and oleic acid decyl ester.
• Hydroxycarboxylic acid alkyl esters the full esters of glycolic acid, lactic acid, malic acid, tartaric acid or citric acid being preferred, but also esters of ß-hydroxypropionic acid, tartronic acid, D-gluconic acid, sugar acid, mucic acid or glucuronic acid are suitable and particularly preferably the esters of C 12 - C ⁇ 5 fatty alcohols, for. B. are the commercial products Cosmacol ® from EniChem, Augusta Industriale,
• Dicarboxylic acid esters such as di-n-butyl adipate, di- (2-ethylhexyl) adipate, di- (2-ethylhexyl) succinate and di-isotridecylacelate as well as diol esters such as ethylene glycol dioleate, ethylene glycol di-isotridecanoate, propylene glycol di (2-ethylhexanoate), propylene glycol di-isostearate, propylene glycol di-pelargonate, butanediol di-isostearate, neopentyl glycol dicaprylate, - Symmetrical, asymmetrical or cyclic esters of carbonic acid with fatty alcohols, e.g. B. glycerol carbonate or dicaprylyl carbonate (Cetiol ® CC),
• Mono, - di- and trifatty acid esters of saturated and / or unsaturated linear and / or branched fatty acids with glycerol e.g. B. Monomuls ® 90-O18, Monomuls ® 90-L12 or Cutina ® MD,
• - waxes in particular insect waxes such as beeswax and bumblebee wax, vegetable waxes such as candelilla wax and carnauba wax, fruit wax, Ozo- Cherith, microcrystalline wax, ceresin, paraffin, triglycerides of saturated and optionally hydroxylated C 16-3 o-fatty acids such.
• Syncrowachs ® or polyols with 2 - 6 C atoms, esters of optionally hydroxylated C 2 .
• 4- carboxylic acids with lanolin alcohols and C 12 -- ⁇ 8 - fatty alcohols cholesterol or lanosterol esters of C 10 - 3 o-fatty acids, ethoxylated Ci 2 - 2 o-fatty acid glycol esters, fatty acid monoalkanolamides with a C 12 - 22 - acyl residue and one C 2 . 4 -alkanol residue, synthetic fatty acid fatty alcohol esters, e.g. Stearyl stearate or cetyl palmitate as well as fatty acids and synthetic Esterwachse from natural C 20-0 fatty alcohols (INCI name C20-40 alkyl stearates),
• Silicone compounds selected from decamethylcyclopentasiloxane, dodecamethylcyclohexasiloxane and silicone polymers, which can, if desired, be cross-linked, e.g. B. polydialkylsiloxanes, polyalkylarylsiloxanes, ethoxylated polydialkylsiloxanes, preferably the substances with the INCI name Dimethicone Copolyol, and polydialkylsiloxanes containing amine and / or hydroxy groups.
• the amount of fatty substances used is 0.1-50% by weight, preferably 0.1-20% by weight and particularly preferably 0.1-15% by weight, in each case based on the total composition.
• agents according to the invention can contain further active ingredients, auxiliaries and additives, for example:
• Vitamins, provitamins and vitamin precursors from groups A, C, E and F in particular 3,4-didehydroretinol (vitamin A 2 ), ß-carotene (provitamin des Vitamin A, ascorbic acid (vitamin C), and the palmitic acid esters, glucosides or phosphates of ascorbic acid, tocopherols, in particular ⁇ -tocopherol, and its esters, e.g. B. the acetate, nicotinate, phosphate and succinate; also vitamin F, which is understood to mean essential fatty acids, in particular linoleic acid, linolenic acid and arachidonic acid;
• Antioxidants for example imidazoles (e.g. urocanic acid) and their derivatives, peptides such as D, L-carnosine, D-camosine, L-carnosine and their derivatives (e.g. anserine), chlorogenic acid and its derivatives, lipoic acid and their derivatives (e.g. dihydroliponic 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, ⁇ -linoleyl, cholesteryl and glyceryl esters) and their salts, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and their derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts ) and sulfoximine compounds (e.g.
• buthioninsulfoximines homocysteine sulfoximine, butioninsulfones, penta-, hexa-, heptathioninsulfoximine
• very low tolerable dosages e.g. pmol to ⁇ mol / kg
• metal chelators e.g. B. ⁇ -hydroxy fatty acids, palmitic acid, phytic acid, Lac toferrin
• humic acid bile acid, bile extracts, bilirubin, biliverdin, EDTA, EGTA and their derivatives, unsaturated fatty acids and their derivatives (e.g. B.
• ZnO, ZnSO 4 selenium and its derivatives (e.g. selenium methionine), stilbene and their derivatives (e.g. stilbene oxide, trans-stilbene oxide) and the derivatives suitable for use as antioxidants (salts, esters, ethers, sugars, nucleotides, nucleosides, peptides and lipids) of these active substances,
• Ceramides and pseudoceramides Triterpenes, especially triterpenic acids such as ursolic acid, rosmaric acid, betulinic acid, boswellic acid and bryonolic acid,
• Monomeric catechins especially catechin and epicatechin, leucoanthocyanidins, catechin polymers (catechin tannins) and gallotannins,
• - Thickeners e.g. B. gelatin, vegetable gums such as agar agar, guar gum, alginates, xanthan gum, gum arabic, karaya gum or locust bean gum, natural and synthetic clays and layered silicates, e.g. B. bentonite, hectorite, montmorillonite or Laponite ® , fully synthetic hydrocolloids such.
• B. polyvinyl alcohol, and also Ca, Mg or Zn soaps of fatty acids,
• Structurants such as maleic acid and lactic acid
• Solvents, swelling and penetration substances such as ethanol, isopropanol, ethylene glycol, propylene glycol, propylene glycol monoethyl ether, glycerin and diethylene glycol, carbonates, hydrogen carbonates, guanidines, ureas and primary, secondary and tertiary phosphates
• Substances for adjusting the pH e.g. B. ⁇ - and ß-hydroxycarboxylic acids, complexing agents such as EDTA, NTA, ß-alaninediacetic acid and phosphonic acids,
• Opacifiers such as latex, styrene / PVP and styrene / acrylamide copolymers, pearlescent agents such as ethylene glycol mono- and distearate and PEG-3 distearate,
• Blowing agents such as propane-butane mixtures, N 2 O, dimethyl ether, CO 2 and air.
• the skin treatment compositions according to the invention are advantageously in the form of a liquid or solid oil-in-water emulsion, water-in-oil emulsion, multiple emulsion, microemulsion, PIT emulsion or Pickering emulsion, a hydrogel, a lipogel, a single or multiphase solution, a foam, a powder or a mixture with at least one suitable as a medical adhesive Polymer before.
• the agents can also be presented in an anhydrous form, such as an oil or a balm.
• the carrier can be a vegetable or animal oil, a mineral oil, a synthetic oil or a mixture of such oils.
• the agents are in the form of a microemulsion.
• microemulsions are understood to mean not only the thermodynamically stable microemulsions but also the so-called “PIT” emulsions.
• PIT phase inversion temperature
• These emulsions are systems with the 3 components water, oil and emulsifier, which are available as an oil-in-water emulsion at room temperature. When these systems are warmed up, microemulsions form in a certain temperature range (referred to as phase inversion temperature or “PIT”), which convert to water-in-oil (W / O) emulsions when heated further.
• PIT phase inversion temperature
• O / W emulsions are again formed, but these are also present at room temperature as microemulsions or as very fine-particle emulsions with an average particle diameter below 400 nm and in particular from about 100-300 nm. According to the invention, those micro- or “PIT” emulsions can be preferred which have an average particle diameter of approximately 200 nm. Details regarding these "PIT emulsions" e.g. B. the publication Angew. Chem. 97, 655-669 (1985).
• the effect of liposome-encapsulated DNA repair enzymes on the inhibition of MMP-1 was examined on a multi-layer in-vitro skin model.
• the skin model is a human skin equivalent that consists of a dermis with fibroblasts and an epidermis of keratinocytes.
• This multi-layer structure is created in a special cultivation process.
• dermal equivalents were produced by pipetting a suspension of 2 ⁇ 10 5 / cm 2 fibroblasts from human foreskin in a culture medium onto a matrix consisting of chitosan, collagen and glycosaminoglycans (matrix described by Collombel, C. et al .: Biomaterials with a base of collagen, chitosane and glycosaminoglycans, process for preparing them and their application in human medicine, US Patent 5166187).
• the culture medium consisted of Dulbecco's Modified EagkVs Medium (DMEM) supplemented with 10% fetal calf serum (FCS), 25 ⁇ g / ml gentamycin, 100 ⁇ l / ml penicillin, 1 ⁇ g / ml amphotericin B, 50 ⁇ g / ml sodium ascorbate and 4 mM L -glutamine.
• DMEM Dulbecco's Modified EagkVs Medium
• FCS fetal calf serum
• FCS fetal calf serum
• penicillin 100 ⁇ l / ml
• 1 ⁇ g / ml amphotericin B 50 ⁇ g / ml sodium ascorbate
• 4 mM L -glutamine 4 mM L -glutamine.
• keratinocytes from human foreskin were sown at a density of 200,000 cells / cm 2 on the 14 day old DEs and under submerged conditions in a medium consisting of 60% DMEM, 30% HAM F12 and 10% FCS, supplemented with 25 ⁇ g / ml gentamycin, 100 ⁇ l / ml penicillin, 1 ⁇ g / ml amphotericin B, 50 ⁇ g / ml sodium ascorbate, 4 mM L-glutamine, 10 ng / ml epidermal growth factor (EGF), 0.4 ⁇ g / ml hydrocortisone, 0.12UI / ml insulin, 10 "9 M cholera toxin, 5 ng / ml transferrin and 180 ⁇ M adenine, incubated for a further 7 days.
• a medium consisting of 60% DMEM, 30% HAM F12 and 10% FCS, supplemented with 25 ⁇ g / ml
• DMEM-HAM F12 modified keratinocyte medium
• this model corresponds much better to the in vivo situation, since keratinocytes and fibroblasts are in close contact with one another and, like in vivo, can exchange signal substances.
• the upper layers of skin have a filter function, for example for UVB rays.
• the skin models were first irradiated with UVB radiation in order to generate the pyrimidine dimers. This was followed by irradiation with UVA radiation in order to activate the photolyase so that this irradiation could have an effect on the repair of keratinocyte DNA and on the inhibition of MMP-1 in the fibroblasts.
• the skin models were incubated for 24 hours under standard conditions (37 ° C., 5 vol.% CO 2 and 90% atmospheric humidity) in the air-liquid interphase nutrient medium.
• the MTT test provides information about cell proliferation and cytotoxicity.
• the metabolic activity of living cells is determined in the test.
• the tetrazolium salt 3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide (MTT) is reduced in living cells and converted into a water-insoluble formazan salt.
• the formazan salt is extracted and quantified photometrically.
• the amount of formazan salt formed is a measure of the number of living cells in the sample examined.
• the exact execution of the test is in J. I munol. Methods ⁇ , 55, 1983 (T. Mosmann), to which explicit reference is made here.
• the skin models were transferred to the dish and incubated for 3 hours at 37 ° C. in an atmosphere of CO 2 / air (5% / 95%, v / v) and 90% humidity. After the incubation had ended, the skin models were transferred to centrifuge tubes and the formazan salt formed was extracted on the shaker with 4 ml of extracting agent (292 ml of isopropanol + 8 ml of 1M HCl) for 1.5 hours.
• the optical density of an aliquot of 200 ⁇ l was measured in a 96-well plate at a wavelength of 540 nm (Titertek Multiscan MCC 340, Flow Laboratories).
• RNA of the cells was analyzed according to the R.E. Singer et al. (1997), Preparation and Analysis of RNA in "Current Protocols in Molecular Biology", eds. F.M. Ausubel et al., John Wiley and Sons Inc., Chapter 4.
• the expression of the MMP-1 gene was analyzed in a Northern blot experiment. A radioactive gene probe specific for the MMP-1 mRNA was used. The production of the mRNA is the first and therefore the most important step in the MMP-1 synthesis. Substances that have an effect on mRNA production automatically have an effect on the amount of protein and the enzyme activity of the MMP-1.
• MMP-1 was determined in the following skin model samples:
• Photosome TM Cream Sample No. 4 no UVB radiation, no cream treatment
• Table 2 Composition of the test cream according to the invention

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