EP0731686A1

EP0731686A1 - Use of l-arginine, l-ornithine or l-citrulline and topical preparations with these substances

Info

Publication number: EP0731686A1
Application number: EP95902780A
Authority: EP
Inventors: Joachim Ennen; Gerhard Sauermann; Franz STÄB
Original assignee: Beiersdorf AG
Current assignee: Beiersdorf AG
Priority date: 1993-12-02
Filing date: 1994-12-01
Publication date: 1996-09-18
Also published as: DE4341000A1; JPH09505822A; WO1995015147A1

Abstract

Disclosed is the use of one or more compounds selected from the group of L-arginine, L-ornithine and L-citrulline or their salts, acid addition salts, esters or amides, as needed with the addition of folic acid or its salts and/or one or more compounds selected from the group of flavins, for prophylaxis and/or treatment of neurosensory phenomena.

Description

Use of L-arginine, L-ornithine or L-citrulline and topical preparations with these substances

The present invention relates to the use of L-arginine, L-ornithine and / or L-citrulline and the use of cosmetic and dermatological topical preparations which contain these active ingredients.

The epidermis is richly equipped with nerves and nerve end devices such as Vater-Pacini lamellar bodies, erkel-cell-neurite complexes and free nerve endings for sensation of pain, cold, heat and itching.

In people with sensitive, sensitive or vulnerable skin, a neurosensory phenomenon called "stinging" (English "sting", burn, pain) can be observed. This "sensitive skin" differs fundamentally from "dry skin" with thickened and hardened horny layers. Typical reactions of "stinging" to sensitive skin are redness, tightness and burning of the skin as well

Itching.

Another itchy sensory phenomenon is the itching in atopic skin and itching in skin diseases.

It was therefore an object of the invention to provide active ingredients and topical preparations with active ingredients which prevent neurosensory phenomena or alleviate or quickly fade away after onset, ie are suitable for prophylaxis and / or treatment.

"Stinging" phenomena can be regarded as disorders to be treated cosmetically. On the other hand, severe itching, especially severe itching in the case of atopy, can also be described as a more serious dermatological disorder.

These objects are achieved by using one or more compounds selected from the group consisting of L-arginine, L-ornithine and L-citrulline or their salts, acid addition salts, esters or amides, optionally with the addition of folic acid or its salts and / or one or more compounds, selected from the group of flavins, for the prophylaxis and / or treatment of neurosensory phenomena.

They are preferably used for the prophylaxis and / or treatment of neurosensory phenomena of the skin, in particular "stinging" or atopy (neurodermatitis).

The invention is also the use of cosmetic and dermatological topical ^{'preparations} which active ingredients according to the invention included, for the prophylaxis and / or treatment of neurosensory phenomena.

It was not foreseeable for the person skilled in the art that the active substances according to the invention and that cosmetic or dermatological preparations with effective contents of arginine, citrulline, ornithine, folic acid and flavins according to the invention are outstandingly suitable for the prophylaxis and treatment of neurosensory phenomena.

Preferred salts of L-arginine, L-ornithine and L-citrulline are water soluble salts, e.g. 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.

Suitable esters of these compounds are e.g. those which are formed with short-chain and medium-chain alcohols, preferably mono-alcohols, but especially methanol, ethanol or propanol. The 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.

Combinations of active substances and topical preparations which contain L-arginine and / or its derivatives according to the invention are particularly preferred.

L-arginine and its derivatives are also characterized by a particularly good skin penetration ability. The amino acids according to the invention and / or their

Derivatives are preferably in amounts from 0.01 to 30

% By weight, particularly preferably 0.01 to 10% by weight, in particular 0.1-7.5% by weight, based in each case on the entire preparation, in the cosmetic and dermatological preparations according to the invention. L-arginine, ornithine and citrulline and the

Derivatives can be used singly or in combination, but then preparations comprise particularly preferably L-arginine in quantities of 1 to 10 parts by weight ⁰ /., Based on the total preparation.

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

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

Folic acid or its salts and / or flavins are preferably contained in the preparations according to the invention, preferably 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 Preparations.

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 in the sense of a dermatological treatment or a treatment in the sense of nourishing cosmetics.

Particularly advantageous preparations are also obtained if the active compounds according to the invention are combined with antioxidants. It was not foreseeable that the active ingredients and combinations with an effective content of

Arginine, ornithine or citrulline and the aforementioned

Cofactors or the combination mentioned with

Antioxidants and neurosensory hypersensitivity

Reduce itching. Furthermore, it could not have been foreseen that they would lead to skin-compatible products or would increase their tolerance and would be healthy

Do not interfere with the skin's own microflora.

This will solve the tasks.

Typical disturbing neurosensory phenomena associated with the terms "stinging" or "sensitive skin" are reddening of the skin, tingling, tingling, tension and burning of the skin and itching. By stimulating environmental conditions e.g. Massage, surfactant, weather influences such as sun, cold, dryness, but also moist heat, heat radiation and UV radiation, e.g. the sun.

According to the invention, the symptoms of sensitive skin and itching in skin diseases, such as e.g. in atopy, mitigated or avoided.

The antioxidants according to the invention can advantageously be selected from the group of customary cosmetic and dermatological antioxidants, in particular from the group consisting of tocopherols and their derivatives, in particular α-tocopherol or α-tocopheryl esters, in particular α-tocopheryl acetate, furthermore sesa ol, bile acid derivatives such as methyl -, ethyl, propyl, amyl, butyl and lauryl gallate, the Konyferylbenzoat of the benzoin, Nordihydroguajakharzäure, Nordihydroguajaretsäure, Butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid,

Citric acid, phosphoric acid, lecithin,

Trihydroxybutyrophenone, carotenes, vitamin A and its

Derivatives, especially retinyl palmitate, ascorbic acid,

Ascorbyl palmitate, dilaur lthiodipropionate,

Distearyl thiodipropionate, monoisopropate,

Thiodipropionic acid, EDTA and EDTA derivatives, cysteine,

Glutathione and esters, uric acid, lipoic acid and

Esters, carotenes, heavy metal complexing agents such as delta-A inolevulinic acid and phytic acid.

The cosmetic or dermatological preparations according to the invention preferably contain 0.01 to 10% by weight, but in particular 0.1 to 6% by weight, based on the total weight of the preparations, of one or more substances from the group of antioxidants.

It is preferred to choose the antioxidants according to the invention from the group of tocopherols and their derivatives.

The preparations also advantageously contain urea. The urea content is, for example, 0.01-30% by weight, in particular 0.1-10% by weight, in each case based on the total weight of the preparations.

For use, the preparations are applied to the skin in a sufficient amount in the manner customary for cosmetics or dermatics.

Skin and hand care preparations, sun protection and after-sun preparations, washing and shower preparations with skin-care function are particularly preferred. Dermatological and cosmetic preparations according to the

Invention can exist in various forms. For example, aqueous, alcoholic or aqueous-alcoholic solutions, emulsions of the type

Oil-in-water (0 / W), water-in-oil emulsions

(W / 0), multiple emulsions e.g. of the water-in type

Oil-in-water (W / O / W), gels, hydrodispersions, solid

Pens or aerosols the above Combinations of active ingredients included.

The topical preparations according to the invention can contain the customary auxiliaries such as emulsifiers and preservatives.

Those cosmetic and dermatological preparations which are in the form of a sunscreen are also preferred. These advantageously additionally contain at least one UVA filter and / or at least one UVB filter and / or at least one inorganic pigment.

However, those preparations which are applied to the skin after exposure to light, ie apres-soleil products, are also extremely advantageous. In the case of such preparations, it is at the discretion of the person skilled in the art whether or not additional UV filter substances are to be used.

Cosmetic preparations according to the invention for protecting the skin from UV rays can be in various forms, such as are usually used for this type of preparation. For example, they can be an aqueous, alcoholic or aqueous alcoholic solution, an emulsion of the water-in-oil (W / 0) or oil-in-water (0 / W) type, or a multiple emulsions, for example of the water type -in-oil-in-water (W / O / W), represent a gel, a hydrodispersion, a solid stick or an aerosol.

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

If the cosmetic or dermatological preparation is a solution or lotion, the following can be used as solvents:

Water or aqueous solutions; oils, such as triglycerides of capric or

Caprylic acid, but preferably castor oil;

Fats, waxes and other natural and 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;

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, - Onoethyl or monobutyl ether, diethylene glycol monomethyl or monoethyl ether and the like

Products.

Mixtures of the abovementioned solvents are used in particular. Water can also be a component of alcoholic solvents.

Emulsions according to the invention e.g. in the form of a sunscreen cream, a sunscreen lotion or a sunscreen milk 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.

Cosmetic and dermatological preparations for the treatment and care of the skin can be in the form of gels which, in addition to the active ingredients and the solvents usually used for them, also contain organic thickeners, e.g. Gum arabic, xanthan gum, sodium alginate, cellulose derivatives, preferably methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl ethyl cellulose or inorganic thickeners, e.g. B. aluminum silicates such as bentonite, or a mixture of polyethylene glycol and polyethylene glycol stearate or distearate. The thickener is in the gel e.g. in an amount between 0.1 and 30% by weight, preferably between 0.5 and 15% by weight.

Gels according to the invention usually contain alcohols of low C number, for example ethanol, isopropanol, 1, 2-propanediol, glycerol and water or an oil mentioned above in the presence of a thickener which preferred for oily-alcoholic gels

Silicon dioxide or an aluminum silicate, in the case of aqueous-alcoholic or alcoholic gels, is preferably a polyacrylate.

Hydrodispersions are dispersions of a liquid, semi-solid or solid inner (discontinuous) lipid phase in an outer aqueous (continuous) phase.

In contrast to O / W emulsions, which are characterized by a similar phase arrangement, hydrodispersions are essentially free of emulsifiers. Hydrodispersions, like the rest of emulsions, are metastable systems and tend to transition into a state of two interrelated discrete phases. In emulsions, the choice of a suitable emulsifier prevents phase separation.

In the case of hydrodispersions of a liquid lipid phase in an outer aqueous phase, the stability of such a system can be ensured, for example, by building a gel structure in the aqueous phase in which the lipid droplets are stably suspended.

Fixed pins according to the invention can e.g. contain natural or synthetic waxes, fatty alcohols or fatty acid esters. Lip care sticks are preferred.

Suitable propellants for cosmetic or dermatological 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), alone or in a mixture can be used together. Compressed air can also be used advantageously.

Of course, the person skilled in the art knows that there are nontoxic propellant gases which would in principle be suitable for the present invention, but which should nevertheless be dispensed with, in particular fluorocarbons and chlorofluorocarbons (CFCs), because of their harmful effects on the environment or other associated circumstances.

The preparations according to the invention can preferably also contain substances which absorb UV radiation in the UVB range, the total amount of the filter substances e.g. 0.1% by weight to 30% by weight, preferably 0.5 to 10% by weight, in particular 1 to 6% by weight, based on the total weight of the preparation, in order to provide cosmetic preparations which protect the skin from the entire range of ultraviolet radiation. They can also serve as sunscreens.

The UVB filters can be oil-soluble or water-soluble. As oil-soluble substances e.g. to call:

- 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-eth lhexyl) ester, 4-methoxycinnamic acid isopent ester;

- Salicylic acid esters, preferably Salicylic acid (2-ethylhexyl) este,

Salicylic acid (4-isopropylbenzyl) ester,

Salic 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-ethyl exyl) ester;

- 2,4,6-trianilino- (p-carbo-2'-ethyl-1 '-hexyloxy) - -1,3,5-triazine.

As water-soluble substances e.g. to call:

- Salts of 2-phenylbenzimidazole-5-sulfonic acid such as its sodium, potassium or triethanolammonium salt, and 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, e.g. 4- (2-0xo-3-bornylidenemeth) benzenesulfonic acid, 2-meth 1-5- (2-oxo-3-bornylidenemethyl) sulfonic acid and its salts.

The invention also relates to the combination of active ingredients according to the invention with one or more UVB filters or cosmetic or dermatological preparations according to the invention which also contain one or more UVB filters. It may also be advantageous to treat the active ingredients with UVA

To combine filters that were previously usually contained in cosmetic and / or dermatological.

These substances are preferably

Derivatives of dibenzoylmethane, especially around

1- (4'-tert.butylphenyl) -3- (4'-methoxyphen l) propane-1,3-dione and 1-phenyl-3- (4'-isopropylphenyl) propane

1,3-dione. These combinations or preparations containing these combinations are also the subject of

Invention. The quantities used for the UVB combination can be used.

Advantageous preparations are also obtained if the active substances according to the invention are combined with UVA and UVB filters.

Combinations of the active compounds according to the invention with one or more antioxidants and one or more UVA filters and / or one or more UVB filters are also particularly advantageous according to the invention.

The cosmetic or dermatological preparations can also contain inorganic pigments, 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.

The invention also relates to the process for the preparation of the topical preparations according to the invention, which is characterized in that the active ingredients are known in a manner known per se incorporates cosmetic or dermatological formulations.

Unless otherwise stated, all quantities, parts and percentages are based on the weight and the total amount or on the total weight of the preparations.

The following examples are intended to illustrate the present invention without restricting it.

example 1

Sun gel LF 4 (transparent)

Weight

L-arginine hydrochloride 10

Benzophenone-4 0.5

Pheny1benzimidazole sulfonic acid 1.3

Acrylamide / sodium acrylate copolymer 1.6

Ethanol 5.0

Glycerin 15.0

NaOH (5-Xig) q. s.

Perfume, preservative q. s.

Water, VES (fully desalinated) ad 100.0

Example 2

Hydrodispersion

Wt.

L-ornithine hydrochloride 5.0

Phenyltrimethicone 1.0

Carbo er (Carbopol 981) 1.0

Hydroxypropyl methyl cellulose 0.2

Butylene glycol 3.0

Trometha in qs EDTA solution (14-Xig) 0.5

Ethanol 5.0

Perfume, preservative q.s.

Water, VES ad 100.0

Example 3

Sun milk 0 / W

L-arginine hydrochloride 5, 0

Octylmethoxycinna at 5.0

Butyl methoxydibenzoyl methane 1.0

Cetearyl alcohol + PEG-40 castor oil

+ Sodium cetearyl sulfate 2.5

Glyceryl alcoholate 1.0

Laurylmethicone copolyol 0.5

Mineral oil (DAB 9) 5,, 0

Caprylic / capric triglycerides 5,, 0

Acrylamide / sodium acrylate copolymer 0, 3

Cyclomethicone 2, 0

Ti0 ₂ 1,. 0

Glycerin 3, 0

EDTA solution (14-Xig) o., 5th

Ethanol 5 _: .0

Perfume, preservative q. s.

Water, VES ad 100, 0

Example 4

Care lotion W / 0

% By weight

L-arginine hydrochloride 2.5

Folic acid 0.1

Cyclomethicone 3.0

PEG-1 glycerol sorbitan oleostearate 1.7 PEG-7 hydrogenated castor oil 6.3

Mineral oil (DAB 9) 13.0

Caprylic / capric triglycerides 13.0

Glycerin 4.0

MgS0 ₄ 0.7

Perfume, preservative q.s.

Water, VES ad 100.0

Example .5

Nourishing day cream 0 / W

Ge.-X

L-arginine hydrochloride 5.0

L-ornithine 1.0

PEG-5 glyceryl stearate 2.00

Glyceryl stearate 3.00

Cyclomethicone 3.00

Caprylic / capric triglycerides 3.00

Cetyl alcohol 3.00

Octyl methoxycinnamate 2.50

Ethanol 1.00

Hyaluronic acid 0.05

Tocopheryl acetate 0.50

Glycerin 4.00

Perfume, preservative q.s.

Water, VES ad 100.00

Example 6

W / 0 cream

% By weight

L-citrulline 2.5

L-arginine hydrochloride 2.5

FAD 0.1

FMN 0.05 PEG-22 dodecyl glycol copolymer 3.0

Cetyl Dimethicone Copolyol 2.0

Cyclomethicone 4.0

Mineral oil (DAB 9) 4.0

Caprylic / capric triglycerides 4.0

Glycerin 4.00

Perfume, preservative q.s.

Water, VES ad 100.00

Example 7

W / 0 cream

Ge.-X

L-ornithine hydrochloride 2.5

L-citrulline 2.5

L-arginine hydrochloride 2.5

FAD 0.1

FMN 0.05

PEG-22 dodecyl glycol copolymer 3.0

Cetyl Dimethicone Copolyol 2.0

Cyclomethicone 4.0

Mineral oil (DAB 9) 4.0

Caprylic / capric triglycerides 4.0

Glycerin 4.00

Perfume, preservative q.s.

Water, VES ad 100.00

Example 8

After sun lotion

% By weight L-arginine hydrochloride 5.0

Folic acid 0.1

Urea 2.5 Cetearyl alcohol + PEG-40 castor oil

+ Sodium cetearyl sulfate 2.50

Glyceryl stearate SE 0.60

Mineral oil (DAB 9) 4.00

Caprylic / capric triglycerides 2.00

Ski butter 2.00

Avocado oil 2.00

Tocopheryl acetate 3.00

Acrylamide / sodium acrylate copolymer 0.30

Glycerin 4.00

Hyaluronic acid 0.05

Bisabolol 0.05

Perfume, preservative q.s.

Water, VES ad 100.00

Example 9

Shower milk

% By weight

L-arginine hydrochloride 10.0

Folic acid 1.0

Sodu Laureth Sulfate 12

Cocamidopropyl betaine 5

Cocamide DEA 1

PEG-8 1

Soybean Oil 1

Citric acid 0.1

Sodium chloride 0.2

Fragrance 0.1

Water, demin. ad 100.00 In game 10

W / 0 cream

Weight -2.

L-ornithine hydrochloride 2.5

L-citrulline 2.5

L-arginine hydrochloride 2.5

FAD 0.1

FMN 0.05

Folic acid 0.1

Tocopheryl acetate 1.0

Urea 2.5

PEG-22 dodecyl glycol copolymer 3.0

Cetyl Dimethicone Copolyol 2.0

Cyclomethicone 4.0

Mineral oil (DAB 9) 4.0

Caprylic / capric triglycerides 4.0

Glycerin 4.00

Perfume, preservative qs water, VES ad 100.00

Test report

The following test report demonstrates the excellent action of the active compounds according to the invention. For this purpose, the lotion of Example 4, but with an active ingredient content of 5% by weight of L-arginine and without folic acid and perfume, is used in a "Stinging test" with 5% by weight of lactic acid in water as a "Stinger" analogous to Frosch and Klig (Peter J. Frosch and Albert M. Kligman: "A method for appraising the stinging capacity of topically applied substances", J. Soc. Cosmet. Chem. 28, 197-209, 1977).

After a week of contralateral product application (twice a day), the stinging potential of 5% lactic acid is determined after a single application on the cheeks. First on one cheek and about 1 hour later, after the stimulus has subsided, on the other cheek. The stinging potential of 5% lactic acid is significantly reduced on the cheeks previously treated with 5% L-arginine.

Claims

claims

Use of one or more compounds selected from the group consisting of L-arginine, L-ornithine and L-citrulline or their salts, acid addition salts, esters or amides, optionally with the addition of folic acid or its salts and / or one or more compounds from the group of flavins, for the prophylaxis and / or treatment of neurosensory phenomena.

Use of cosmetic and dermatological topical preparations containing one or more compounds selected from the group consisting of L-arginine, L-ornithine and L-citrulline or their salts, acid addition salts, esters or amides, optionally with the addition of folic acid or its salts and / or one or more compounds selected from the group of the flavins, for the prophylaxis and / or treatment of neurosensory phenomena.

Use according to claim 2, characterized in that the preparations contain L-arginine.

Use according to claim 2, characterized in that the preparations contain folic acid and / or one or more compounds selected from the group of flavins

5. Use according to claim 2, characterized in that the preparations contain at least one antioxidant.

6. Use according to claim 2, characterized in that the preparations contain urea.

7. Use according to claim 2, characterized in that the preparations contain at least one UVA filter and / or at least one UVB filter and / or at least one inorganic pigment.

8. Use according to claim 2, characterized in that the preparations L-arginine, folic acid, one or more compounds selected from the group of flavins, at least one antioxidant, urea and optionally at least one UVA filter and / or at least one UVB Contain filters and / or at least one inorganic pigment.