WO1998040082A1

WO1998040082A1 - THE USE OF WATER-SOLUBLE β-GLUCANS AS ACTIVE SUBSTANCES IN THE PRODUCTION OF THERAPEUTIC AGENTS IN SKIN TREATMENT

Info

Publication number: WO1998040082A1
Application number: PCT/EP1998/001202
Authority: WO
Inventors: Ute Griesbach; Elke Wiemann; Heinz Eggensperger
Original assignee: Henkel Kommanditgesellschaft Auf Aktien
Priority date: 1997-03-13
Filing date: 1998-03-04
Publication date: 1998-09-17
Also published as: DE19710368A1

Abstract

The invention relates to the use of water-soluble β-glucans as active substances in the production of therapeutic agents in skin treatment. Said agents strengthen the immune system of the skin and counteract wrinkling and can be used to prevent scaling and psoriasis. Said agents can also be used to produce sun-screening agents.

Description

Use of water-soluble ß-glucans as active ingredients for the production of therapeutic agents for skin treatment

Field of the Invention

The invention relates to the use of water-soluble ß-glucans as active ingredients for combating wrinkles in the skin and skin diseases such as psoriasis, psoriasis or UV erythema.

State of the art

Age-related wrinkling is caused by the breakdown of various macromolecules such as elastin and collagen, for which elastases in the stratum corneum are responsible. A variety of inflammatory skin diseases, such as psoriasis or UV erythema, can also be linked to an increased concentration of elastase in the upper layers of the skin [cf. R. Voegeli et al. in Cosm.Toil. ____, 51 (1996)].

The formation of wrinkles in the skin is usually counteracted not by physiologically effective principles, but by cosmetic means. Many so-called "antiaging products" contain liposomes loaded with water or aqueous active ingredients, which penetrate through the fatty layer of the skin into the epidermis, gradually dissolve there and, due to the continuous release of water, fill the skin depressions and regulate the moisture content of the skin. However, this effect does not result Combat the causes, but only has a so-called "repair effect", which also lasts only for a short time.

In contrast to this purely cosmetic application, cytostatic active ingredients, such as selenium sulfide, cadmium sulfide, zinc pyrithione or corticosteroids, are used to combat psoriasis, the medical effect of which is based, for example, on a reduction in mitotic activity in the basal membrane. However, due to the known side effects, these substances should not be used for extended periods. Furthermore, psoriasis can be reduced by antiseptic agents, such as selenium oxide, salicylic acid, pyrithione derivatives, hexachlorophene or quaternary ammonium compounds or by cell-dissolving and degreasing agents such as benzoyl peroxide or tar extracts, but do not cure them.

The use of special polysaccharides as anti-aging agents is also known from the prior art. For example, US Pat. No. 5,223,491 proposes using a carboxymethylated β-1,3-glucan which has been extracted from the yeast fungus Saccharomyces cerevisiae for topical use. However, the glucan is insoluble in water and can therefore only be formulated with great difficulty.

The use of glucan-containing preparations as antitumor agents is known from German published application DE-OS 2604481 (Ajinomoto). European patent application EP-A1 0463540 (Taito) reports on the use of glucans against viruses. According to the teaching of the two documents DE-A1 3744345 (Lomapharm) and EP-B1 0175667 (noise), glucans are suitable for stimulating macrophage activity. The pharmaceutical effect of various glucans is also known from the two European patent applications EP-A1 0045338 (Debat) and EP-A1 0561408 (Kaken). Finally, soluble phosphorylated glucans are the subject of the European patent EP-B1 0232405 (Tulane Educational Fund).

From the prior art, very different solutions are known for smoothing the skin and strengthening the barrier function, be it from a cosmetic or medical point of view, but they each solve only a subtask and can also be associated with strong side effects. The complex object of the invention was therefore to provide active ingredients which can be used at the same time against wrinkling in the skin (cosmetic effect) and skin diseases (medical effect) and which have a high dermatological and toxicological compatibility.

Description of the invention

The invention relates to the use of water-soluble ß-glucans as active ingredients for the production of therapeutic agents for skin treatment, in particular for the preparation of agents which simultaneously counteract skin aging and wrinkling and erythema. Thanks to their significant contribution to UV protection, the ß-glucans are particularly suitable for use in sunscreens.

Surprisingly, it was found that water-soluble β-glucans, preferably those obtained by extraction of Basidiomycetes and / or Ascomyceten, in the Langerhans cells of the cause deeper skin layers to have an immune modulation that produces special cytokines. ß-Glucans are also toxicologically safe.

Water soluble ß-glucans

The term glucans is understood to mean homopolysaccharides based on glucose. Depending on the steric linkage, a distinction is made between ß-1, 3-, ß-1,4- and ß-1,6-glucans. β-1,3-glucans usually have a helical structure, while glucans with a 1,4-linkage generally have a linear structure. The β-glucans of the invention can be obtained, for example, by extracting higher fungi, such as, for example, the Basidiomycete Schizophyllum Commune or Conolosus versicolor, or by extracting tubular fungi, such as e.g. Prepare ascomycetes of the type Scleroticum glucanium. In these cases, technical mixtures of unsubstituted ß-1,3-, ß-14, and ß-1, 6-glucans are obtained which have excellent water solubility. Typical examples of suitable water-soluble β-glucan mixtures are schizophyllan (I) and krestin (II).

It is particularly preferred to use β-glucans or their technical mixtures which have a proportion of at least 50, preferably 60 to 100 and in particular 70 to 90% by weight of a β-1,3 basic structure. It is also advantageous if the glucans have a triple helix fine structure and Molecular weights in the range above 50,000, preferably 100,000 to 1,000,000 daltons. It can also be advantageous to use glucans which have a branch at C-6, preferably with a further saccharide such as, for example, glucose, arabinose or xylose.

The extraction of the mushrooms can be carried out in a manner known per se by the methods of the prior art and does not require the person skilled in the art to be inventive, especially since extracts based on various yeasts are commercially available under the name “CM-glucan” the extracts are used as aqueous or aqueous-alcoholic solutions with an active substance content in the range from 0.1 to 5, preferably 0.5 to 3.

Industrial applicability

For the purposes of the invention, the water-soluble β-glucans can be used as active ingredients for the production of cosmetic and / or pharmaceutical preparations. Typical examples of such agents are skin care products such as anti-wrinkle creams, anti-cellulite creams or sunscreen lotions and ointments for the treatment of skin diseases such as cradle cap, psoriasis, seborrheic dermatitis, seborrhea sicca, seborrhoe oleosa, psoriasis vulgaris, ichthyosis or UV erythema. Usually the water-soluble ß-glucans in

Amounts of 0.0001 to 5, preferably 0.001 to 1 and in particular 0.01 to 0.1% by weight, based on the composition, are used.

The preparations can contain minor amounts of anionic, nonionic, cationic and / or amphoteric or zwitterionic surfactants that are compatible with the other ingredients. Typical examples of anionic surfactants are soaps, alkylbenzene sulfonates, alkane sulfonates, olefin sulfonates, alkyl ether sulfonates, glycerin ether sulfonates, α-methyl ester sulfonates, sulfo fatty acids, alkyl sulfates, fatty alcohol ether sulfates, glycerol ether sulfates, hydroxymixed ether sulfates, fatty ether sulfate monates dialkyl sulfosuccinates, mono- and Dialkylsulfo- succinamates, sulfotriglycerides, amide soaps, ether carboxylic acids and salts thereof, fatty acid taurides, N-acylamino acids such as acyl lactylates, acyl tartrates, acyl glutamates and acyl aspartates, alkyl oligoglucoside sulfates, protein fatty acid condensates (in particular vegetable products based on wheat) and Alkyl (ether) phosphates. If the anionic surfactants contain polyglycol ether chains, they can have a conventional, but preferably a narrow, homolog distribution. Typical examples of nonionic surfactants are fatty alcohol polyglycol ethers, alkylphenol polyglycol ethers, fatty acid polyglycol esters, fatty acid amide polyglycol ethers, fatty amine polyglycol ethers, alkoxylated triglycerides, mixed ethers or mixed formals, alk (en) yl oligo glycosides, fatty acid N-alkylglucamides, protein hydrolyzates (especially vegetable products based on wheat), polyol fatty acid esters, sugar esters, sorbitan esters, polysorbates and amine oxides. If the nonionic surfactants contain polyglycol ether chains, they can have a conventional, but preferably a narrow, homolog distribution. Typical examples of cationic surfactants are quaternary ammonium compounds and ester quats, in particular quaternized fatty acid trialkanolamine ester salts. Typical examples of amphoteric or zwitterionic surfactants are alkyl betaines, alkyl amido betaines, aminopropionates, aminoglycinates, imidazolinium betaines and sulfobetaines. The surfactants mentioned are exclusively known compounds. With regard to the structure and manufacture of these substances, reference is made to relevant reviews, for example J.Falbe (ed.), "Surfactants in Consumer Products", Springer Verlag, Berlin, 1987, pp. 54-124 or J.Falbe (ed.), "Catalysts, Surfactants and mineral oil additives ", Thieme Verlag, Stuttgart, 1978, pp. 123-217.

Furthermore, the agents can contain, as further auxiliaries and additives, oil bodies, emulsifiers, superfatting agents, stabilizers, waxes, consistency agents, thickeners, cation polymers, silicone compounds, biogenic active ingredients, antidandruff agents, film formers, preservatives, hydrotropes, solubilizers, UV light protection filters, colorants and fragrances .

Guerbet alcohols based on fatty alcohols with 6 to 18, preferably 8 to 10 carbon atoms, esters of linear C6-C2o fatty acids with linear C6-C20 fatty alcohols, esters of branched C6-Ci3-carboxylic acids with linear C6-C20- Fe.talkol.olen, esters of linear C6-Ci8 fatty acids with branched alcohols, especially 2-ethylhexanol, esters of linear and / or branched fatty acids with polyhydric alcohols (such as dimer diol or trimer triol) and / or Guerbet alcohols, triglycerides based on Cθ -Cio fatty acids, vegetable oils, branched primary alcohols, substituted cyclo-hexanes, Guerbet carbonates, dialkyl ethers, silicone oils and / or aliphatic or naphthenic hydrocarbons.

Examples of suitable emulsifiers are nonionic surfactants from at least one of the following groups:

(1) Addition products of 2 to 30 moles of ethylene oxide and / or 0 to 5 moles of propylene oxide with linear fatty alcohols with 8 to 22 C atoms, with fatty acids with 12 to 22 C atoms and with alkylphenols with 8 to 15 C atoms in the Alkyl group;

(2) Ci2 / i8 fatty acid monoesters and diesters of adducts of 1 to 30 moles of ethylene oxide with glycerol;

(3) glycerol monoesters and diesters and sorbitan monoesters and diesters of saturated and unsaturated fatty acids having 6 to 22 carbon atoms and their ethylene oxide addition products; (4) alkyl mono- and oligoglycosides with 8 to 22 carbon atoms in the alkyl radical and their ethoxylated analogs;

(5) adducts of 15 to 60 moles of ethylene oxide with castor oil and / or hardened castor oil;

(6) polyol and especially polyglycerol esters such as e.g. Polyglycerol polyricin oleate or polyglycerol poly-12-hydroxystearate. Mixtures of compounds from several of these classes of substances are also suitable;

(7) adducts of 2 to 15 moles of ethylene oxide with castor oil and / or hardened castor oil;

(8) partial esters based on linear, branched, unsaturated or saturated Ci2 / 22 fatty acids, ricinoleic acid and 12-hydroxystearic acid and glycerin, polyglycerin, pentaerythritol, dipentaerythritol, sugar alcohols (e.g. sorbitol) and polyglucosides (e.g. cellulose);

(9) trialkyl phosphates;

(10) wool wax alcohols;

(11) polysiloxane-polyalkyl-polyether copolymers or corresponding derivatives;

(12) mixed esters of pentaerythritol, fatty acids, citric acid and fatty alcohol according to DE-PS 11 65 574 and

(13) Polyalkylene glycols.

The adducts of ethylene oxide and / or of propylene oxide with fatty alcohols, fatty acids, alkylphenols, glycerol mono- and diesters as well as sorbitan mono- and diesters with fatty acids or with castor oil are known, commercially available products. These are mixtures of homologs, the middle of which Degree of alkoxylation corresponds to the ratio of the amounts of substance of ethylene oxide and / or propylene oxide and substrate with which the addition reaction is carried out. C12 /. _. -Fatty acid monoesters and diesters of adducts of ethylene oxide with glycerol are known from DE-PS 20 24 051 as refatting agents for cosmetic preparations.

C8 / i8 alkyl mono- and oligoglycosides, their preparation and their use as surface-active substances are known, for example, from US 3,839,318, US 3,707,535, US 3,547,828, DE-OS 1943689, DE-OS 2036472 and DE-A1 3001064 and EP-A 0077167. They are produced in particular by reacting glucose or oligosaccharides with primary alcohols with 8 to 18 carbon atoms. With regard to the glycoside residue, both monoglycosides in which a cyclic sugar residue is glycosidically bonded to the fatty alcohol and oligomeric glycosides with a degree of oligomerization of up to about 8 are suitable. The degree of oligomerization is a statistical mean value which is based on a homolog distribution customary for such technical products.

Zwitterionic surfactants can also be used as emulsifiers. Zwitterionic surfactants are surface-active compounds that contain at least one quaternary ammonium group and at least one carboxylate and one sulfonate group in the molecule. Particularly suitable zwitterionic surfactants are the so-called betaines such as the N-alkyl-N, N- dimethylammonium glycinate, for example the cocoalkyldimethylammonium glycinate, N-acylamino-propyl-N, N-dimethylammonium glycinate, for example the cocoacylaminopropyldimethylammonium glycinate, and 2-alkyl-3-carboxylmethyl-3-hydroxyethylimidazolines each with 8 to 18 C-atoms or acyl group in the C-atom group as well as the cocoacylaminoethyl hydroxyethyl carboxymethyl glycinate. The fatty acid amide derivative known under the CTFA name Cocamidopropyl Betaine is particularly preferred. Suitable emulsifiers are ampholytic surfactants. Ampholytic surfactants are surface-active compounds which, in addition to a Cs-alkyl or -acyl group, contain at least one free amino group and at least one -COOH or -SO3H group in the molecule and are capable of forming internal salts. Examples of suitable ampholytic surfactants are N-alkylglycines, N-alkylpropionic acids, N-alkylaminobutyric acids, N-alkyliminodipropionic acids, N-hydroxyethyl-N-alkylamidopropylglycines, N-alkyltaurines, N-alkylsarcosines, 2-alkylaminopropionic acids and alkylaminoacetic acids, each with about 8 to 18 carbon atoms in the alkyl group. Particularly preferred ampholytic surfactants are N-cocoalkylaminopropionate, cocoacylaminoethylaminopropionate and Ci2 / ιs-acylsarcosine. In addition to the ampholytic emulsifiers, quaternary emulsifiers are also suitable, those of the esterquat type, preferably methyl-quaternized difatty acid triethanolamine ester salts, being particularly preferred.

Substances such as lanolin and lecithin as well as polyethoxylated or acylated lanolin and lecithin derivatives, polyol fatty acid esters, monoglycerides and fatty acid alkanolamides can be used as superfatting agents, the latter simultaneously serving as foam stabilizers. As consistency agents, primarily fatty alcohols with 12 to 22 and preferably 16 to 18 carbon atoms come into consideration. A combination of these substances with alkyl oligoglucosides and / or fatty acid N-methyl glucamides of the same chain length and / or polyglycerol poly-12-hydroxystearates is preferred. Suitable thickeners are, for example, polysaccharides, in particular xanthan gum, guar guar, agar agar, alginates and tyloses, carboxymethyl cellulose and hydroxyethyl cellulose, and also higher molecular weight polyethylene glycol mono- and diesters of fatty acids, polyacrylates, polyvinyl alcohol and polyvinylpyrrolidone, surfactants such as, for example ethoxylated fatty acid glycerides, esters of fatty acids with polyols such as pentaerythritol or trimethylolpropane, fatty alcohol ethoxylates with a narrow homolog distribution or alkyl oligoglucosides as well as electrolytes such as table salt and ammonium chloride.

Suitable cationic polymers are, for example, cationic cellulose derivatives, cationic starch, copolymers of diallylammonium salts and acrylamides, quaternized vinylpyrrolidone / vinylimidazole polymers such as, for example, Luviquat® (BASF AG, Ludwigshafen / FRG), condensation products of polyglycols and amines, and quaternized hydroxylated collagen polypeptides hydrolyzed collagen (LamequatΘL, Grünau GmbH), quaternized wheat polypeptides, polyethyleneimine, cationic silicone polymers such as Amidomethicone or Dow Corning, Dow Corning Co./US, copolymers of adipic acid and dimethylaminohydroxypropyldiethylenetrimamine (Cartaretine®, Sandoz / CH), polyaminopolyamides as described for example in FR-A 22 52 840 and their crosslinked water-soluble polymers, cationic chitin derivatives such as quaternized chitosan, optionally microcrystalline, condensation products from dihaloalkylene such as dibromobutane with bisdialkylamines such as bis- Dimethylamino-1, 3-propane, cationic guar gum such as Jaguar® CBS, Jaguar® C-17, Jaguar® C-16 from Celanese / US, quaternized ammonium salt polymers such as Mirapol® A-15, Mirapol® AD- 1, Mirapol® AZ-1 from Miranol / US.

Suitable silicone compounds are, for example, dimethylpolysiloxanes, methylphenylpolysiloxanes, cyclic silicones and amino-, fatty acid-, alcohol-, polyether-, epoxy-, fluorine- and / or alkyl-modified silicone compounds, which can be both liquid and resinous at room temperature. Typical examples of fats are glycerides, waxes include Beeswax, paraffin wax or micro waxes, optionally in combination with hydrophilic waxes, e.g. Cetylstearyl alcohol in question. Mono and difatty acid esters of polyalkylene glycols, partial glycerides or esters of fatty alcohols with polyvalent carboxylic acids or hydroxycarboxylic acids can be used in particular as pearlescent waxes. Metal salts of fatty acids such as e.g. Magnesium, aluminum and / or zinc stearate can be used. Biogenic active substances are understood to mean, for example, bisabolol, allantoin, phytantriol, panthenol, AHA acids, plant extracts and vitamin complexes. Climbazole, octopirox and zinc pyrethione can be used as antidandruff agents. Common film formers are, for example, chitosan, microcrystalline chitosan, quaternized chitosan, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers, polymers of the acrylic acid series, quaternary cellulose derivatives, collagen, hyaluronic acid or its salts and similar compounds. Hydrotropes such as ethanol, isopropyl alcohol, propylene glycol or glucose can also be used to improve the flow behavior. Suitable preservatives are, for example, phenoxyethanol, formaldehyde solution, parabens, pentanediol or sorbic acid.

Typical examples of UV light protection filters are 4-aminobenzoic acid and its esters and derivatives (e.g. 2-ethylhexyl p-dimethylaminobenzoate or p-dimethylaminobenzoic acid octyl ester), methoxycinnamic acid and its derivatives (e.g. 4-methoxycinnamic acid 2-ethylhexyl ester), benzophenones (e.g. Oxybenzone, 2-hydroxy-4-methoxy-benzophenone), dibenzoylmethane, salicylate ester, 2-phenylbenzimadozole-5-sulfonic acid, 1- (4-tert-butylphenyl) -3- (4'-methoxyphenyl) propane-1, 3-dione, 3- (4'-methyl) benzylidene-bornan-2-one, methyl-benzylidene camphor and the like. Finely dispersed metal oxides or salts, such as titanium dioxide, zinc oxide, iron oxide, aluminum oxide, cerium oxide, zirconium oxide, silicates (talc) and barium sulfate, are also suitable. Finally, secondary light stabilizers of the antioxidant type can also be used, such as superoxide dismutase, tocopherols (vitamin E) and ascorbic acid (vitamin C). The dyes which can be used are those substances which are suitable and approved for cosmetic purposes, as compiled, for example, in the publication "Cosmetic Dyes" by the Dye Commission of the German Research Foundation, Verlag Chemie, Weinheim, 1984, pp. 81-106. These dyes are usually used in concentrations of 0.001 to 0.1% by weight, based on the mixture as a whole.

The total proportion of auxiliaries and additives can be 1 to 50, preferably 5 to 40,% by weight, based on the composition. The agents can be produced by customary cold or hot processes; the phase inversion temperature method is preferably used.

Examples

A panel consisting of 15 female volunteers between the ages of 35 and 50 years was exposed to a daily exposure to various glucans over a period of 28 days. For this purpose, O / W skin creams of the following composition were prepared by mixing phases I and II at 95 ° C:

Phase I: cetylstearyl alcohol 8.0% by weight Phase II: glycerin 6.0% by weight ceteareth-12 1.5% by weight glucan * 20.0% by weight ceteareth-20 1.5% by weight % Water 38.0% by weight cetearyl isononanoate 15.0% by weight paraffin oil, viscous 5.0% by weight Baysilonöl M 300 5.0% by weight *) 1% by weight AS in water

36.0% by weight: 64.0% by weight

The subjects applied the skin creams daily before going to bed. The following morning, the number, depth and length of the skin folds were determined every 7 days using profilometry of a selected area of skin, namely a vertical stripe 2 cm wide and 5 cm long, the upper left and right boundaries of which result when one draws a horizontal line from the root of the nose, removes 2 or 4 cm from this towards the right eye and extends the two resulting points at an angle of 270 ° each 2 cm. The dimensionless product of the depth, number and length of the skin folds on the day before the start of exposure was set as the standard (= 100%) and all subsequent measurements were based on it. At the same time, the subjects' skin roughness was assessed subjectively on a scale from 0 = "unchanged" to 3 = "greatly improved". The results are summarized in Table 1. Examples 1 to 3 are according to the invention, examples V1 to V4 are used for comparison.

It can be seen that the water-soluble β-glucans of the invention not only have the advantage of being easier to formulate, but also have a higher activity than known glucans of the prior art. Table 1:

Skin aging and roughness

Legend: 1) ß-1, 3- / ß-1, 6-glucan, extract from Schizophyllum Commune

2) ß-1, 3- / ß-1, 4- / ß-1, 6-glucan protein (30%) complex, extract from Conolossus versicoior

3) ß-1, 3- / ß-1, 6-glucan, extract from Sclereoticum glucanium

4) Carboxymethylated β-1,3-glucan, extract from Saccharomyces cervisiae

5) α-Mannes with branches, extract from Saccharomyces cervisiae

6) + 7) ß-1,3 / ß-1,4-glucan + α-1,3- / α-1,4-glucan mixture, extract from Cetraria isiandica (lichen extract)

Claims

claims

1. Use of water-soluble ß-glucans as active ingredients for the production of therapeutic agents for skin treatment.

2. Use of water-soluble ß-glucans as active ingredients for the production of agents which counteract skin aging.

3. Use of water-soluble ß-glucans as active ingredients for the production of sunscreens.

4. Use according to claims 1 to 3, characterized in that extracts of Basidiomycetes and / or Ascomycetes are used as water-soluble β-glucans.

5. Use according to claims 1 to 4, characterized in that extracts of the fungi Schizophyllum Commune, Conolosus versicoior and / or Scleroticum glucanium are used as water-soluble ß-glucans.

6. Use according to claims 1 to 5, characterized in that Schizophyiian and / or Krestin are used as water-soluble β-glucans.

7. Use according to claims 1 to 6, characterized in that the ß-glucans are used in cosmetic and / or pharmaceutical preparations.

8. Use according to claim 7, characterized in that one uses the ß-glucans in amounts of 0.0001 to 5 wt .-% - based on the agent.

CHANGED CLAIMS

[Received at the International Office on August 28, 1998 (August 28, 1998); original claims 1-8 by; new claims 1-7 replaced (1 page)]

1. Use of water-soluble ß-glucans as active ingredients for the production of agents that counteract skin aging.

2. Use of water-soluble ß-glucans as active ingredients for the production of sunscreens.

3. Use according to claims 1 to 3, characterized in that extracts of Basidiomycetes and / or Ascomycetes are used as water-soluble β-glucans.

4. Use according to claims 1 to 4, characterized in that extracts of the fungi Schizophyllum Commune, Conolosus versicoior and / or Scleroticum glucanium are used as water-soluble ß-glucans.

5. Use according to claims 1 to 5, characterized in that Schizophyiian and / or Krestin is used as the water-soluble β-glucans.

6. Use according to claims 1 to 6, characterized in that the ß-glucans are used in cosmetic and / or pharmaceutical preparations.

7. Use according to claim 7, characterized in that one uses the ß-glucans in amounts of 0.0001 to 5 wt .-% - based on the agent.