WO1997009975A1 - Topical anti-skin-cancer preparations - Google Patents

Abstract

The invention concerns the use of topical cosmetic or dermatological preparations containing one or a plurality of active substances selected from the group of compounds comprising arginine, citrulline, ornithine or their salts, acid addition salts, esters or amides, folic acid or its salts, cysteine, N-acetylcysteine, homocysteine, glutamine, flavins and ceramides, for treating keratosis or skin cancer and for the preventive treatment of the skin to protect it against these diseases.

Description

 description

Topical preparations effective against skin cancer

UV radiation is mutagenic, i.e. it changes the DNA of skin cells. In photo-aged skin, UV-related mutations have been detected in the basal cells of the epidermis, in melanocytes and in the fibroblasts of the dermis. A gene, called P53, has become the focus of attention in recent years when the relationships between cancer risk and mutation frequency are considered: the greater the number of mutations, the greater the risk of degeneration. Proteins, for which the DNA of the P53 gene serves as a blueprint, are increasingly produced with increasing frequency of mutations in terms of their natural function.

These proteins, the synthesis of which is triggered by UV, have the ability in the mutation-free or poor state to arrest cell division or initiate cell death (apoptosis). This makes sense in the case of cells damaged by previous UV radiation, whose error-free DNA repair is questionable or impossible. Sunburn cells are such histologically quantifiable, dead cells. It has already been discussed in the literature that in cell cultures or endogenously determined ceramides can be effective as regulators for apoptosis and growth inhibition (a) Immonology Today, Vol. 6 1995, page 294; b) Proc. Natl. Acad. Be USA Vol. 91, pp. 73-77, January 1994 Cell Biology; c) SCIENCE, VOL. 259, 19 MARCH 1993, page 1769).

Surprisingly, it was found that ceramides and the other active compounds according to the invention, administered topically, trigger apoptosis and / or growth inhibition and are suitable for the prophylaxis and treatment of skin cancer.

The invention relates to the use of cosmetic or dermatological topical preparations containing one or more active substances, selected from the group of the compounds arginine, citrulline, ornithine or their salts, acid addition salts, esters or amides, folic acid or salts thereof , Cysteine, N-acetylcysteine, homocysteine, glutamine, the flavins and ceramides, for the treatment of keratoses or skin cancer and for the prophylactic treatment of the skin against these diseases.

Derivatives of the active compounds according to the invention are also the subject of the invention. The invention also relates to the topical use of the active compounds according to the invention for the prophylaxis and treatment of the skin and of the diseases mentioned.

With preference, photokeratoses, UV-induced forms of cancer, basal cell carcinomas or spinaliomas can be treated or combated prophylactically. The active substances and preparations according to the invention can be used particularly advantageously on photo-aged skin and the skin of children and adolescents.

The active compounds according to the invention are known or can be obtained by known analog processes.

The L forms of arginine, citrulline and ornithine are preferred. Arginine and L-arginine and their salts, acid addition salts, esters or amides are particularly preferred.

Ceramides are also particularly preferred.

The invention also relates to the use of cosmetic or dermatological topical preparations, characterized by a content of a combination of active compounds according to the invention, comprising one or more active compounds selected from group (A) of the compounds arginine, its salts, acid addition salts, esters or Amides in combination with one or more active substances, selected from group (B) of ceramides, for the treatment of keratoses or skin cancer and for the prophylactic treatment of the skin against these diseases.

In the combinations, the weight ratio of the compounds of group (A) to the compounds of group (B) can preferably be 10: 1 to 1:10, particularly preferably 5: 1 to 1: 5, but in particular 1: 1.

Preferred salts of arginine, ornithine and citrulline are water-soluble salts, for example sodium, potassium and ammonium salts. This also applies to the acid addition salts. Suitable acid addition salts are obtained with inorganic and organic acids. The hydrochlorides, sulfates, acetates, caprylates or citrates are preferred. Physiologically acceptable salts and addition salts are preferred. Suitable esters of these compounds are, for example, those which are formed with short-chain and medium-chain alcohols, preferably mono-alcohols, but especially methanol, ethanol or propanol. Ethyl esters are preferred.

Preferred amides are short and medium chain mono- and di-alkylamides.

Alkyls of the above substituents contain e.g. up to 12, preferably up to 6 carbon atoms.

Particularly suitable salts of folic acid are water-soluble salts, in particular sodium, potassium and ammonium salts.

Preferred compounds from the group of flavins are flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN).

Ceramides are known as commercial products and as natural products and are described in the literature. (e.g. "Römpp Chemie Lexikon", 9th edition, page 623, Georg Thieme Verlag Stuttgart).

The skin ceramides are preferred, in particular ceramide 1, ceramide 2, ceramide 3, ceramide 4/5, ceramide 6 I and ceramide 6 II. They are described in the literature under these names.

Also known in the alkyl chains, e.g. Alkyl chain lengths, varied ceramides and skin ceramides are the subject of the invention.

Ceramide 2 and ceramide 3 and the compounds of these basic types derived therefrom, for example varied in chain lengths, are particularly preferred. Furthermore, the ceramides of the general formulas

-CO-R ¹

HO-CH ₂ T-CH-CH-CH = CHR ² (I)

OH and

H πNiN - CUOU - Rrt ¹

HO-CH ₂ -CH-CH-CH-CH ₂ -R ^"2 OO

OH OH preferred, wherein R ^{1 is} an alkyl radical having 1 to 24, preferably 1 to 10 carbon atoms and R ^{2 is} an alkyl radical having 1 to 22, preferably 1 to 13 carbon atoms.

Further preferred ceramides are N-acyl-sphingosines and acyl-phytosphinosines, for example those with 1 to 19, in particular with 1 to 9 carbon atoms in the alkyl radical of the acyl groups. Be particularly preferred

N-acetyl sphingosine,

N-butyryl sphingosine,

N-hexanoyl sphingosine,

N-octanoyl sphingosine and the corresponding phyto-sphingosine.

Are also preferred

N-octanoyl-D-sphingosine,

N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, N-palmitoyl-sphingosine,

N-palmitoyl-dihydrosphingosine,

N-stearoyl sphingosine,

N-oleoyl sphingosine, (cis-9),

N-lignoceroyl-dihydrosphingosine and

N-nervonoyl sphingosine (cis-15).

The D and DL forms are particularly preferred.

Particularly preferred ceramides are N-acyl-sphingosine, N-acetyl-sphingosine, N-octanoyl-sphingosine, N-oleoyl-sphingosine. Combination Natio ^¬ particularly preferred nen contain arginine and N-acetyl-sphingosine or N-octanoyl-sphingosine. The cosmetic or dermatological topical preparations according to the invention can be based on conventional formulation bases and can be used to treat the skin and diseased skin in the sense of a dermatological treatment or a prophylactic treatment, in particular with cosmetic preparations according to the invention.

For prophylaxis, the active ingredients are administered, e.g. to prevent the diseases or manifestations of the diseases or to reduce their frequency and strength.

The cosmetic or dermatological preparations or formulations according to the invention can be composed as usual and can be used to treat the skin. They contain e.g. B. 0.0001 to 30 wt .-% preferably 0.01 wt .-% to 10 wt .-%, but in particular 0.1 wt .-% to 5 wt .-%, each based on the total weight of the preparations the active ingredients according to the invention.

For use, the cosmetic and dermatological preparations according to the invention are applied in a customary manner to the skin or diseased areas of the skin in a sufficient amount.

The invention also relates to the use of the active compounds mentioned for the production of topical preparations for the stated uses.

The amino acids according to the invention and / or their derivatives are preferably present in amounts of 0.01 to 30% by weight, particularly preferably 0.01 to 10% by weight, in particular 0.1 to 7.5% by weight on the entire preparation, contained in the cosmetic and dermatological preparations according to the invention. Arginine, ornithine and citrulline and the derivatives can be used individually or in combination, but preparations then particularly preferably contain I-arginine in amounts of 1 to 10% by weight, based on the preparation as a whole. Folic acid or its salts and / or flavins are preferably contained in the preparations according to the invention in each case in amounts of 0.0001 to 5% by weight, in particular 0.01 to 1.5% by weight, in each case based on the total weight of the Preparation.

Ceramides are preferably present in the preparations according to the invention in quantities of 0.01 to 10% by weight, but in particular 0.1 to 2% by weight, in each case based on the total weight of the preparations.

Cosmetic and dermatological preparations according to the invention can be in the known various forms. So you can e.g. a solution, a cream, a lotion, an anhydrous preparation, an emulsion or microemulsion e.g. of the water-in-oil (W / O) or oil-in-water (O / W) type, a multiple emulsion, for example of the water-in-oil-in-water (W / O / W) type, represent a gel, a powder, an oil, a solid stick, an ointment or an aerosol. It is also advantageous to present the active compounds according to the invention in encapsulated form in a manner known per se. Particularly preferred preparations are sun protection products and apresun products. Such preparations can contain IR, UVA and / or UVB filters and / or pigments.

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

The cosmetic and dermatological preparations according to the invention can contain cosmetic auxiliaries, as are usually used in such preparations, e.g. Preservatives, bactericides, perfumes, substances to prevent foaming, dyes, pigments which have a coloring effect, thickeners, surface-active substances, emulsifiers, softening, moisturizing and / or moisturizing substances, fats, oils, waxes or other customary substances Components of a cosmetic or dermatological formulation such as alcohols, polyols, polymers, foam stabilizers, electrolytes, organic solvents or silicone derivatives.

The preparations preferably also contain antioxidants, for example in amounts of 0.001 to 20% by weight, based on the total weight of the preparations. Emulsions according to the invention are advantageous and contain, for example, the fats, oils, waxes and other fat bodies mentioned, as well as water and an emulsifier, as is customarily used for such a type of formulation. The lipid phase can advantageously be selected from the following group of substances: natural, synthetic and / or partially synthetic oils, such as triglycerides of capric or caprylic acid, but preferably castor oil;

Fats, waxes and other natural synthetic and / or partially synthetic fat bodies, preferably esters of fatty acids with alcohols of low C number, e.g. with isopropanol, propylene glycol or glycerin, or esters of fatty alcohols with low C number alkanoic acids or with fatty acids;

Silicone oils such as dimethylpolysiloxanes, diethylpolysiloxanes, diphenylpolysiloxanes and mixed forms thereof.

saturated compounds such as hydrocarbons of natural or synthetic origin (petroleum jelly, squalane)

The aqueous phase of the preparations according to the invention advantageously contains alcohols, diols or polyols with a low C number, and also 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 similar products, furthermore alcohols of low C number, for example ethanol, isopropanol, 1,2-propanediol, glycerol and in particular one or more thickeners, which one or more can advantageously be selected from the group Silicon dioxide, aluminum silicates, polysaccharides or their derivatives, for example hyaluronic acid, xanthan gum, hydroxypropylmethyl cellulose, particularly advantageously from the group of polyacrylates, preferably a polyacrylate from the group of so-called carbopoles, for example carbopoles of types 980, 981, 1382, 2984 , 5984, or also the types ETD (Easy-to-disperse) 2001, 2020, 2050, each individually or in any combination with one another. In particular, mixtures of the abovementioned solvents are used. Water can also be a component of alcoholic solvents.

Emulsions according to the invention are advantageous and contain e.g. the fats, oils, waxes and other fat bodies mentioned, as well as water and an emulsifier, as is usually used for such a type of formulation.

Gels according to the invention usually contain low C number alcohols, e.g. Ethanol, isopropanol, 1, 2-propanediol, glycerol and water or an oil mentioned above in the presence of a thickener which, in the case of oily-alcoholic gels, preferably silicon dioxide or an aluminum silicate, in the case of aqueous-alcoholic or alcoholic gels, preferably a poly is acrylate.

Suitable propellants for preparations according to the invention which can be sprayed from aerosol containers are the customary, known volatile, liquefied propellants, for example hydrocarbons (propane, butane, isobutane), which can be used alone or in a mixture with one another. Compressed air is also advantageous to use.

Preparations according to the invention can also advantageously contain substances which absorb UV radiation in the UVB range, the total amount of filter substances being, for example, 0.1% by weight to 30% by weight, preferably 0.5 to 10% by weight. , in particular 1.0 to 6.0% by weight, based on the total weight of the preparations, in order to provide cosmetic preparations which protect the skin from the entire range of ultraviolet radiation. They can also serve as sunscreens for the skin.

If the emulsions according to the invention contain UVB filter substances, they can be oil-soluble or water-soluble. Oil-soluble UVB filters which are advantageous according to the invention are, 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 amyl ester;

Esters of cinnamic acid, preferably 4-methoxycinnamic acid (2-ethylhexyl) ester, 4-methoxycinnamic acid isopentyl ester;

Esters of salicylic acid, preferably salicylic acid (2-ethylhexyl) ester, salicylic acid (4-isopropylbenzyl) ester, salicylic acid homomethyl ester,

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-methoxybenzalmalonic acid di (2-ethylhexyl) ester, 2,4,6-trianilino- (p-carbo-2'-ethyl-1'-hexyloxy) - 1,3,5-triazine.

Advantageous water-soluble UVB filters include:

Salts of 2-phenylbenzimidazole-5-suffonic acid, such as its sodium, potassium or triethanolammonium salt, and also the sulfonic acid itself;

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 4- (2-oxo-3-boronylidene methyl) benzenesurfonic acid, 2-methyl-5- (2-oxo-3-bornylidene methyl) sulfonic acid and their salts. The list of UVB filters mentioned, which can be used in combination with the active substances according to the invention, is of course not intended to be limiting.

The invention also relates to the use of the active compounds according to the invention with at least one UVB filter in a cosmetic or dermatological preparation.

It can also be advantageous to combine active ingredients according to the invention with UVA filters. For example, suitable are those which have hitherto usually been contained in cosmetic preparations. These substances are preferably derivatives of dibenzoylmethane, in particular 1- (4 ^* - tert-butylphenyl) -3- (4'-methoxyphenyl) propane-1, 3-dione and 1-phenyl-3- (4 '- isopropylphenyl) propane-1,3-dione. These combinations or preparations which contain these combinations are also the subject of the invention. The quantities used for the UVB combination can be used.

The invention also relates to the use of a combination of the active compounds according to the invention with at least one UVA filter in a cosmetic or dermatological preparation.

The invention also relates to the use of a combination of the active compounds according to the invention with at least one UVA filter in a cosmetic or dermatological preparation.

Cosmetic and dermatological preparations with an effective content of active ingredients according to the invention can also contain inorganic pigments in the usual amounts which are usually used in cosmetics to protect the skin from UV rays. These are oxides of titanium, zinc, iron, zirconium, silicon, manganese, aluminum, cerium and mixtures thereof, as well as modifications in which the oxides are the active agents. It is particularly preferred to use pigments based on titanium dioxide. Preferred amounts are 0.001-20% by weight.

These combinations of UVA filter and / or UVB filter and pigment or preparations which contain these combinations are also the subject of the invention. dung. The amounts given for the above combinations can be used.

The combinations with UV filters and UV protective substances and preparations therewith have the effects described for the active substances and can be used in the same way.

The active substances according to the invention can be used individually or as a mixture of several active substances and can also be contained individually or as a mixture in the preparations.

It has proven to be advantageous to adjust the pH of the preparations according to the invention e.g. to be set in the range from 4 to 9, but especially in the range from pH5 to pH8.

The invention also relates to the process for the preparation of the preparations according to the invention, which is characterized in that active ingredients according to the invention are incorporated into cosmetic and dermatological formulations in a manner known per se. This can e.g. done by stirring or emulsifying.

Unless otherwise stated, all amounts, proportions and percentages are based on the weight and the total amount or on the total weight of the preparations or the respective mixture.

The following examples are intended to illustrate the invention. The production takes place in a manner known per se, e.g. by mixing or emulsifying the substances, advantageously after separate fat phases and water phases have been produced, possibly also with heating. The preparations show a good activity against the diseases according to the invention and a good prophylactic effect.

Example 1 W / O cream

% By weight

Paraffin oil 10.00

Petrolatum 4, 00

Wool wax alcohol 1.00%

PEG-7 hydrogenated castor oil 3.00

Aluminum stearate 0.40

N-acetyl-D-sphingosine 2.00

Glycerin 2.00

Water, preservatives and perfume ad 100.00

Example 2 W / O lotion

% By weight

Paraffin oil 20.00

Petrolatum 4.00

Glucose Seqiisostearate 2.00

Aluminum stearate 0.40

N-octanoyl-D-sphingosine 4.00

L-arginine 2.00

Vitamin E acetate 2.00

Vitamin C palmitate 0.20

Glycerin 5.00

Water, preservatives and perfume ad 100.00 Example 3 O / W Lotion

% By weight

Paraffin oil 8.00

Isopropyl palmitate 3.00

Petrolatum 4.00,

Cetearyl alcohol 2.00

PEG-40 castor oil 0.50

Sodium cetearyl surfate 0.50

Sodium carbomer 0.40

N-oleoyl sphingosine 4.00

L-arginine 3.00

Glycerin 3.00 α-tocopherol 0.20

Octyl methoxycinnamate 5.00

Butyl methoxydibenzoyl methane 1.00

Water, preservatives and perfume ad 100.00

Example 4 O / W cream

% By weight

Paraffin oil 7.00

Avocado oil 4.00

Glyceryl monostearate 2.00

Sodium stearate 1, 00

L-arginine 2.00

Glutamine 1,00

N-acetylcysteine 2.00

Titanium dioxide 1.00

Sodium lactate 3.00

Glycerin 3.00

Water, preservatives and perfume ad 100.00

Example 5

lipstick

% By weight

Hydrogenated castor oil 4.00

Ceresin 8.00

Beeswax 4.00

Carnauba wax 2.00

Petrolatum 40.00

N-acetyl-phytosphingosine 2.00 ß-carotene 0.10

Paraffin oil, pigments and dyes ad 100.00 Example 6

Gel containing liposomes

% By weight

Lecithin 6.00

Ski butter 3.00

L-arginine 2.00

N-acetyl-D-sphingosine 2.00

Vitamin A palmitate 0.20

Biotin 0.08

Sodium citrate 0.50

Glycine 0.20

Urea 0.20

Sodium PCA 0.50

Hydrolyzed collagen 2.00

Xanthan gum 1.40

Sorbitol 3.00

Water, preservatives and perfume ad 100.00

Example 7

Massage cream

% By weight

Stearyl alcohol 2.00

Lecithin 6.00

Petrolatum 4.00

Dimethicone 2.00

N-acetyl-D-sphingosine 2.00

Isopropyl palmitate 6.00

Cetearyl alcohol 4.00

PEG-40 hydrogenated castor oil 2.00

L-arginine 2.00

Glycerin 3.00

Water, preservatives and perfume ad 100.00

Claims

claims 1. The invention relates to the use of cosmetic or dermatological topical preparations containing one or more active substances, selected from the group of the compounds arginine, citrulline, ornithine or their salts, acid addition salts, esters or amides, folic acid or salts thereof , Cysteine, N-acetylcysteine, homocysteine, glutamine, the flavins and ceramides, for the treatment of keratoses or skin cancer and for the prophylactic treatment of the skin against these diseases. 2. Use of cosmetic or dermatological topical preparations according to claim 1, characterized in that they contain a combination comprising one or more active substances selected from group (A) of the compounds arginine, its salts, acid addition salts, esters or amides in combination with one Active ingredient or several active ingredients selected from group (B) of the ceramides. 3. Use according to claim 1, characterized in that arginine or a ceramide are contained as active substances. 4. Use according to claim 1 or 2, characterized in that one or more active substances from the group N-acyl-sphingosine, N-acetyl-sphingosine, N-octanoyl-sphingosine, N-oleoyl-sphingosine are used. 5. Use of the combinations arginine and N-acetyl-sphingosine or N-octanoyl-sphingosine according to claim 2. 6. Use according to claim 1 or 2, characterized in that the preparations contain IR, UVA and / or UVB filters.