WO2003082284A1

WO2003082284A1 - Use of desoxynojirimycin and the derivatives thereof for the treatment and prophlaxis of degenerative skin infections

Info

Publication number: WO2003082284A1
Application number: PCT/EP2003/003290
Authority: WO
Inventors: Thomas Blatt; Christopher Mummert; Franz STÄB
Original assignee: Beiersdorf Ag
Priority date: 2002-04-02
Filing date: 2003-03-28
Publication date: 2003-10-09
Also published as: DE10214506A1

Abstract

The invention relates to topical compositions having an active content of desoxynojirimycin and/or derivatives thereof for preventing or treating skin irritations.

Description

Use of deoxynojirimycin and its derivatives for the treatment and prophylaxis of degenerative skin conditions

The present invention relates to the use of topical compositions for the prophylaxis and treatment of degenerative skin conditions.

Degenerative skin conditions include age-related changes and inflammatory conditions of the skin, in particular: deficient, sensitive or hypoactive skin conditions or deficient, sensitive or hypoactive conditions of skin appendages, hyper-reactive, intolerant skin conditions as well as atopic eczema, seborrheic eczema, polymorphic light dermatosis, and dermatosis

Appearance of the skin such as sagging skin, age spots, telangiectasias, disturbance of the osmolytic balance, the natural skin pH value and loss of the epidermal and dermal cell layers, the components of the connective tissue, the reticles and capillary vessels of the skin and / or the appendages, environment-related (caused by smoking, smog, reactive oxygen species, free radicals) and in particular light-related negative changes in the skin and appendages, light-related skin damage and UV-induced immunosuppression , reduced skin thickness, sagging skin and skin fatigue,

Disruption of normal skin pH and osmolytic balance, pigmentation disorders, itching,

Horny layer barrier disorders,

Changes in transepidermal water loss and the normal moisture content of the skin, changes in normal lipid peroxidation, hair loss, impaired hair growth and hair structure

Deviations from normal cell-cell communication in the skin,

Changes in normal fibroblast and keratinocyte proliferation,

Changes in normal fibroblast and keratinocyte differentiation, as well as skin with an increased "stinging potential", which is characterized by increased redness, tension and itching.

Inflammatory skin conditions are usually caused by a disturbed barrier function and the resulting drying out of the skin. This barrier function is primarily caused by the epidermis, which as the outermost layer forms the actual protective cover against the environment. The epidermis wears off in contact with the environment and is therefore in a constant process of renewal, whereby fine scales are continuously released to the outside and horny cell and lipid material is reproduced from the inside. In the case of old skin, for example, the regenerative regeneration of the epidermis is slowed down, the water retention capacity of the horny layer in particular diminishing. It therefore becomes inflexible, dry and cracked ("physiologically" dry skin). Barrier damage is the result, and as a result of this barrier damage, the skin becomes ^" susceptible to negative environmental influences such as the invasion of microorganisms, toxins and allergens.

In the case of pathologically dry and sensitive skin, there is a priori barrier damage. Epidermal intercellular lipids appear to be defective or in insufficient quantity or composition. The consequence is increased permeability of the horny layer and inadequate protection of the skin against loss of hygroscopic substances and water.

The barrier effect of the skin can be quantified by determining the transepidermal water loss (TEWL - transepidermal water loss). This is the evaporation of water from the inside of the body without taking into account the loss of water when sweating. The determination of the TEWL value has proven to be extremely useful and can be used to diagnose cracked or chapped skin, to determine the compatibility of chemically differently structured surfactants and the like.

Products for the care, treatment and cleaning of dry and stressed skin that treat or prevent skin irritation are known per se. However, their contribution to the ^• regeneration of a physiologically intact, hydrated and smooth horny layer is often limited in scope and time. The effect of ointments and creams on the barrier function and the hydration of the horny layer is based essentially on the covering (occlusion) of the treated skin areas. The ointment or cream is, so to speak, a second artificial barrier that is supposed to prevent water loss from the skin. This physical barrier can be removed correspondingly easily, for example with cleaning agents, as a result of which the original, impaired state is reached again. Furthermore, can the skin care effect wears off with regular treatment. After stopping the application of the product, the skin quickly returns to the condition before the start of treatment. With certain products, the condition of the skin may even temporarily deteriorate. A sustainable product effect is therefore generally not achieved or only to a limited extent.

The effect of some pharmaceutical preparations on the barrier function of the skin even consists in selective barrier damage, which is intended to enable active substances to penetrate into or through the skin into the body. A disturbed appearance of the skin is sometimes accepted as a side effect.

In addition to steroidal and non-steroidal agents, antibiotics are currently used for the prophylaxis and treatment of atopic eczema and other inflammatory skin conditions. Most of these anti-inflammatory substances, however, require a prescription or pharmacy and are therefore unsuitable for cosmetic use. In addition, these substances have a broad spectrum of side effects.

Products for the care of aged skin are also known. They contain e.g. B. retinoids (vitamin A acid and / or its derivatives) or vitamin A and / or its derivatives. However, their impact on structural damage is limited in scope. In addition, there are often considerable difficulties in product development to sufficiently stabilize the active ingredients against oxidative decay. The use of products containing vitamin A acid frequently also causes severe erythematous skin irritation. Retinoids can therefore only be used in low concentrations.

In addition, the regulatory component of glucose metabolism is neglected in the pathogenesis of the known agents. _t . <■ The prior art lacks preparations which positively influence the barrier function and the hydration of the horny layer and which strengthen or even restore the physicochemical properties of the horny layer and in particular the lamellae from intercellular lipids.

The present invention was therefore based on the object of providing a means for preventing or treating degenerative skin conditions which have a long-term positive influence on the barrier function and irritation of the horny layer, are sufficiently stable against oxidative decay, and have as few side effects as possible.

The object is achieved by using a topical composition containing deoxynojiriπiycin and / or its derivatives and / or salts to prevent or treat skin irritation. Miglitol is particularly preferably used. The topical compositions according to the invention restore the barrier properties of the skin, counteract skin dehydration, thus act better against skin aging and protect the skin very well from environmental influences.

Deoxynoj irimycin and / or its derivatives are compounds of the formula (I)

where R ^{1 are} each, independently of one another, H, alkyl, aryl, alkylaryl and arylalkyl substituents which can optionally be substituted, and R ^{2 is} H or an alkyl, aryl, alkylaryl and arylalkyl substituent which is optionally substituted.

R is preferably H in each case

Alkyl group or a hydroxy-substituted C ^ Cg alkyl group.

R ² is preferably H, a C _{j ^} -C _j alkyl group or a hydroxy-substituted Ci-Cg alkyl group. Most preferred is R 2-hydroxyethyl.

Salts of these compounds are formed, for example, by the addition of Lewis acids to the nitrogen atom of the 6-membered ring.

Miglitol has the formula:

Their manufacture is described in DE-OS 23 47 782.

Deoxynojirimycin derivatives, especially miglitol, were previously only known as α-glucosidase inhibitors for the treatment of diabetes. Miglitol suppresses the postprandial increase in blood sugar and the increase in gastrointestinal polypeptides and serum insulin after sucrose loading in a dose-dependent manner.

Surprisingly, it has been shown that deoxynoj irimycin and / or its derivatives, such as miglitol, are active for the prophylaxis against or for the treatment of skin irritations such as atopic eczema, inflammatory skin conditions and pigment disorders and counteract the drying out of the skin by restoring the barrier properties of the skin.

With the use of the topical compositions according to the invention Settlement containing deoxynojirimycin and / or its derivatives is also an effective treatment and prophylaxis of deficient, sensitive or hypoactive skin conditions or deficient, sensitive or hypoactive conditions of skin appendages, of signs of premature aging of the skin (e.g. wrinkles, age spots, telangicentasias) , of environmental (smoking, smog, reactive oxygen species, free radicals) and especially light-related skin damage, pigmentation disorders, dry skin conditions and horny layer barrier disorders, of hair loss and for improved hair growth, and in particular of inflammatory skin conditions and atopic eczema, seborrheic eczema, polymorphic Light dermatosis, psoriasis, and Vitigilo possible. However, the topical compositions according to the invention containing deoxynojirimycin and / or its derivatives also serve, surprisingly, to soothe sensitive or irritated skin, to stimulate the synthesis of collagen, hyaluronic acid and elastin, to stimulate the ceramide synthesis of the skin, to stimulate the intracellular DNA synthesis, especially in deficient or hypoactive skin conditions, to increase cell renewal and regeneration of the skin, to increase the skin's own protection and repair mechanisms (e.g. for dysfunctional enzymes, DNA, lipids, proteins) and for pre- and post-treatment in topical use of laser and abrasive treatments, which serve, for example, to reduce skin wrinkles and scars in order to counteract the resulting skin irritation and to promote the regeneration processes in the injured skin.

Derivatives of deoxynojirimycin are understood to mean, in particular, its ethers, esters and partial ethers and partial esters such as palmitates, acetates etc. and amides. Salts and acid adducts of these compounds are also included. Preferred derivatives of deoxynojirimycin are N-substituted deoxynojirimycin derivatives. The substituent on the N atom can be an alkyl, aryl, cycloalkyl, akylaryl, arylalkyl substituent which can optionally carry further substituents such as alcohol groups, ester groups, ether groups, halogen groups. The substituents preferably have 1 to 20 carbon atoms, preferably 1 to 10 Carbon atoms and in particular 1 to 5 carbon atoms, for example 1 to 2 carbon atoms. Most preferred are alcohols of substituted alkyl substituents such as 2-hydroxyethyl (miglitol).

The content of deoxynojirimycin and / or its derivatives, based on the total composition, is preferably 0.001 to 10% by weight and preferably 0.01 to 1% by weight and in particular 0.1 to 1% by weight.

The topical compositions are preferably in the form of a solution, an emulsion, a hydrodispersion, a lipodispersion or a gel. The topical composition is preferably in the form of an emulsion such as a water-in-oil (W / O) or oil-in-water (0 / W) type or in the form of a multiple emulsion, for example a water-in type -Oil-in-water (W / O / W) or oil-in-water-in-oil (θ / W / 0). Emulsions according to the invention contain, for example, fats, oils, waxes and / or fat bodies as well as water and one or more emulsifiers, as are usually used for such a type of formulation. It is also possible to use the topical compositions in aqueous systems e.g. Add surfactant preparations to clean the skin and hair.

The compositions according to the invention preferably also contain antioxidants. The .antioxidants are preferably selected from the group consisting of amino acids such as glycine, histidine, tyrosine and tryptophan and their derivatives, imidazoles such as urocanic acid and their derivatives, peptides such as D, L-carnosine, D-carnosine, L-carnosine and their derivatives such as Anserine, carotenoids, carotenes such as α-carotene, β-carotene, lycopene and their derivatives, aurothioglucose, propylthiouracil and other thiols such as thioredoxin, glutathione, cysteine, cystine, cystamine and their glycosyl, N-acetyl, methyl, Ethyl, propyl, amyl, butyl and lauryl, palmitoyl, oleyl, γ-linoleyl, cholesteryl and glyceryl esters and their salts, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and their derivatives such as esters, ethers, peptides, lipids , Nucleotides, nucleosides and salts as well as sulfoximine compounds such as buthionine sulfoximine, Homocysteine sulfoximine, buthionine sulfone, penta-, hexa-, heptathionine sulfoximine. Furthermore, metal chelators such as α-hydroxy fatty acids, palmitic acid, phytic acid, lactoferin, α-hydroxy acids such as citric acid, lactic acid, malic acid, humic acid, bile acid, bile extracts, bilirubin, biliverdin, EDTA, EGTA and their derivatives, unsaturated fatty acids and their derivatives such as γ -Linolenic acid, linoleic acid, oleic acid, folic acid and its derivatives, alanine diacetic acid, flavonoids, polyphenols, catechins, vitamin C and derivatives such as ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbylacetate, tocopherols and their derivatives such as vitamin E acetate and coniferic acid and benzoic acid benzoate, the benzoin ruthenate, of benzoin and benzoic acid benzoate their derivatives, ferulic acid and their derivatives, butylhydroxy toluene, butylhdroxyanisole, nordihydroguajakarzarzäure, nordihydroguajaretic acid, trihydroxybutyrophenone, uric acid and their derivatives, mannose and their derivatives, zinc, zinc oxides and zinc salts, selenium and selenium salts, salts and their salts, selenium and its salts, stilbene and its salts as well as mixtures of ge named compounds can be used as antioxidants.

The antioxidant content, based on the total composition, is preferably 0.001 to 30% by weight, more preferably 0.05 to 20% by weight and in particular 1 to 10% by weight.

In addition to deoxynoj irimycin and / or its derivatives and, where appropriate, antioxidants, one or more medicaments such as antibiotics, steroidal and non-steroidal agents and anti-inflammatory substances can be added to the topical compositions according to the invention to enhance the action.

The topical compositions according to the invention can also contain substances which absorb UV radiation in the UVB range, the total amount of the filter substances preferably 0.1 to 30% by weight, more preferably 0.5 to 10% by weight and in particular 1.0 to 6.0 wt .-%, based on the total weight of the composition. UVB filters according to the invention are, for example, 3-benzylidene camphor derivatives such as 3- (4-methylbenzylidene) camphor, or 3-benzylidene camphor, aminobenzoic acid derivatives such as 4- (dimethylamino) benzoic acid (2-ethylhexyl) ester or 4- (dimethylamino) benzoic acid amyl ester, esters of cinnamic acid such as 4-methoxycinnamic acid (2-ethylhexyl) ester or 4-methoxycinnamic acid isopentyl ester, esters of salicylic acid such as salicylic acid (2-ethyl-hexyl) ester, salicylic acid (4-isopropylbenzyl) ester or salicylic acid homomethyl ester, derivatives of benzophenone such as 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxy-4'-methylbenzophenone or 2, 2 ' -Dihydroxy-4-methoxybenzophenone, esters of benzalmalonic acid such as 4-methoxybenzalmalonic acid di (2-ethylhexyl) ester, 2,4,6-trianilino- (p-carbo-2'-ethyl-1 '-hexyloxy) -1,3 , 5-triazine; Salts of 2-phenylbenzimidazole-5-sulfonic acid such as its sodium, potassium or triethanolammonium salt, sulfonic acid derivatives of benzophenone such as 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid and their salts, sulfonic acid derivatives of 3-benzylidene camphor such as 4- (2- Oxo-3-bornylidene-methyl) benzenesulfonic acid, 2-methyl-5- (2-oxo-3-bornylidene-methyl) sulfonic acid and its salts and 1,4-di (2-oxo-10-sulfo-3-bornylidene-methyl) -benzene and its Salts and benzene-1,4-di (2-oxo-3-bornylidenemethyl-10-sulfonic acid.

It can also be advantageous to use UVA filters. These 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 are usually used in the same quantities as the UVB filters.

Topical compositions according to the invention preferably also contain inorganic pigments based on metal oxides and / or other metal compounds which are sparingly soluble or insoluble in water, in particular oxides of titanium (Ti0 ₂ ), zinc (ZnO), iron (for example Fe ₂ 0 ₃ ), zirconium (Zr0 ₂ ), Silicon (Si0 ₂ ), manganese (eg MnO), aluminum (A1 ₂ 0 ₃ ), cerium (eg Ce ₂ 0 ₃ ), mixed oxides of the corresponding metals and mixtures of the oxides. It is preferably a pigment based on TiO ₂ .

The inorganic pigments are particularly preferably in hydrophobic form, ie they are water-repellent on the surface treated. This surface treatment can consist in that the pigments are provided with a thin hydrophobic layer by known methods. Such methods are described for example in DE-OS 33 14 742.

Particularly when inorganic micropigments are to be incorporated into the preparations according to the invention, the topical compositions according to the invention preferably contain anionic, nonionic and / or amphoteric surfactants and mixtures thereof.

The following examples are intended to illustrate the present invention without restricting it. The numerical values in the examples mean percentages by weight, based on the total weight of the respective preparations.

PIT: emulsions

O / W creams

O / W creams

W / O emulsions,

hydrodispersions

Gel Cream

W / O cream-gel

W / O / W Cream

Claims

claims

1. Use of a topical composition containing deoxynojirimycin and / or its derivatives for the prevention or treatment of degenerative skin conditions.

2. Use according to claim 1, characterized in that the content of deoxynojirimycin and / or its derivatives, based on the total composition, is 0.001 to 10% by weight.

3. Use according to claim 2, characterized in that the content of deoxynojirimycin and / or its derivatives, based on the total composition, is 0.01 to 1 wt .-%.

4. Use according to one of the claims 1 to 3, characterized in that miglitol is used.

5. Use according to one of claims 1 to 4, characterized in that the topical composition is a solution, an emulsion, a hydrodispersion, a lipo dispersion or a gel.

6. Use according to claim 5, characterized in that the topical composition is an emulsion.

7. Use according to claim 6, characterized in that the emulsion is a water-in-oil (W / 0-), oil-in-water (0 / W), water-in-oil-in-water. (W / O / W) - or oil-in-water-in-oil

(O / W / O-) emulsion.

8. Use according to one of claims 1 to 7, characterized in that the composition additionally contains antioxidants.

9. Use according to claim 8, characterized in that the content of antioxidants, based on the total Settlement, 0.001 to 30 wt .-% is.

10. Use according to claim 9, characterized in that the composition additionally contains light protection filters.

11. Use according to one of claims 1 to 10, characterized in that the skin irritation is caused by ultraviolet light.

12. Use according to one of claims 1 to 10, characterized in that the skin irritation is caused by dry skin.

13. Use according to one of claims 1 to 12, characterized in that the skin irritation is a skin inflammation.

14. Use according to one of claims 1 to 13, characterized in that the skin irritation is an atopic eczema.

15. Use according to claim 14, characterized in that the skin irritation is neurodermatitis.