EP1716236A2 - Antisense oligonucleotides for treating unwanted pigmentation of the skin and hair - Google Patents

Abstract

The invention relates to an oligonucleotide or a physiologically compatible salt thereof, that is able to hybridise with an mRNA or a gene sequence encoding at least one structure contributing to the pigmentation of the skin and/or hair, said structures contributing to (I) the actual melanin synthesis (melanosome structures) and/or to (II) the expression of said melanosome structures and/or to (III) the transfer of the melanosomes (into the keratinocytes).

Description

 Beiersdorf Aktiengesellschaft Hamburg

description

Antisense oligonucleotides for the treatment of undesirable pigmentation of the skin and hair

The invention relates to compositions containing antisense oligonucleotides which are suitable for the treatment and prophylaxis of undesired skin pigmentation (skin tanning), as occurs, for example, as a result of UV radiation. Likewise, the present invention relates to unwanted hair pigmentation. In a preferred embodiment, the present invention relates to cosmetic and dermatological preparations for the prophylaxis and treatment of undesirable pigmentation, for example local hyper- and deficient pigmentations (liver spots, freckles, age spots, melasma, post-inflammatory hyperpigmentation), but also purely the cosmetic lightening of larger, individual skin types adequately pigmented skin areas.

Melanocytes are responsible for the pigmentation of the skin. These are found in the lowest layer of the epidermis, the stratum basale, next to the basal cells as - depending on the skin type either isolated or more or less frequently occurring - pigment-forming cells. As characteristic cell organelles, melanocytes contain melanosomes in which the melanin is formed. When stimulated by UV radiation, among other things, melanin is increasingly formed. This is ultimately transported via the living layers of the epidermis (keratinocytes) into the horny layer (corneocytes) and causes a more or less pronounced brown to brown-black skin color. Melanin is formed as the final stage of an oxidative process, in which tyrosine with the help of the enzyme tyrosinase via several intermediate stages to the brown to brown-black eumelanins (DHICA and DHI melanin) or under loading portion of sulfur-containing compounds is converted to reddish pheomelanin. DHICA and DHI melanin are produced via the common intermediate stages dopaquinone and dopachrome. The latter is implemented, partly with the participation of further enzymes, either in indole-5,6-quinone carboxylic acid or in indole-5,6-quinone, from which the two eumelanins mentioned arise. The formation of phaeomelanin occurs among other things via the intermediates dopaquinone and cysteinyldopa. The expression of the melanin-synthesizing enzymes is controlled by a specific transcription factor (microphthalmia-associated transcription factor, MITF). In addition to the described enzymatic processes of melanin synthesis, other proteins are also important for melanogenesis in the melanosomes. The so-called p-protein appears to play an important role here, although the exact function is still unclear.

In addition to the previously described process of melanin synthesis in the melanocytes, the transfer of the melanosomes, their whereabouts in the epidermis and their breakdown and breakdown of the melanin is also of crucial importance in the pigmentation of the skin. It could be shown that the PAR-2 receptor is important for the transport of the melanosomes from the melanocytes into the keratinocytes (M. Seiberg et al., 2000, J. Cell. Sei., 113: 3093-101). The size and shape of the melanosomes also influence their light-scattering properties and thus the color appearance of the skin. For example, large black spheroidal, predominant melanosomes are found in black Africans, whereas in Caucasians, smaller melanosomes are found in groups.

Basically, one can differentiate between skin pigmentation structures that: • the actual melanin synthesis process in the melanosomes (Tyrosianse, TRP-1, TRP-2, p-protein) • the transfer / distribution of the melanosomes to the neighboring cells , in particular keratinocytes (PAR-2) and • on the expression of the above Structures (especially via the MITF transcription factor) are involved.

Problems with hyperpigmentation of the skin have various causes or are side effects of many biological processes, e.g. UV radiation (e.g. freckles, ephelidβs), genetic disposition, incorrect pigmentation of the skin during wound healing or scarring (post-inflammatory hyperpigmentation) or skin aging (eg Lntigines seniles).

Active substances and preparations are known which counteract skin pigmentation. Preparations based on hydroquinone are essentially in practical use, but some of them only show their effect after several weeks of use, the excessive use of which is also of concern for toxicological reasons. By Albert Kligman et al. a so-called triformula was developed, which is a combination of 0.1% tretinoin, 5.0% hydroquinone, 0.1% dexamethasone (A. Kligman, 1975, Arch. Dermatol., 111: 40-48). However, this formulation is also very controversial because of possible irreversible changes in the skin's pigmentation system. The use of mercury compounds is also common, which is also highly toxicologically problematic. Skin peeling methods (chemical and mechanical "peelings") are also used, but these often result in inflammatory reactions and, because of the postinflammatory hyperpigmentation that occurs afterwards, can even lead to stronger instead of reduced pigmentation.

In addition to skin health and skin care, hair care is an extremely intensively researched area in cosmetics. Hair is the thread-like, almost universal (attached to the palms of the hands, soles of the feet, extensible sides of the toes, end fingers) of the skin; distinguished as long hair (the head, beard, armpit, pubic hair = Capilli, Barba, Hirci or Pubes; in men also chest hair), short, bristle hair (Supercilia, Cilia, Vibrissae, Tragi) and wool hair (Lanugo , Velvet hair). The structure of all of these hairs is roughly similar: the central hair mark (from epithelial cells with eosinophilic horny substance = trichohyalin granules), surrounded by the hair cortex (from horny cells; contains pigments) and the cuticle (cuticle pili; coreless epidermal layer) ) and layers of the epithelial and connective tissue hair sheath.

The hair is divided into the hair shaft protruding from the skin and the oblique hair root reaching into the subcutis, the layers of which correspond approximately to those of the epidermis. The thickened lower end of the root, the hair bulb, sits on a vascular connective tissue cone, the hair papilla, protruding into it (both as a hair floor). The onion is in the initial (= anagen) phase, the cyclically repeated hair formation layered onion-like as a result of the constant new formation of cells by their papillae Layer (matrix), later closed, bulbous, completely horny (piston hair) and is finally, in the end (= telogen) phase, displaced by a new hair - starting from a newly formed hair papilla - towards the follicle opening.

Melanin is responsible for the personal hair color. Melanin is formed in the melanocytes, cells that occur in the hair bulb in association with the keratinocytes of the hair market. As characteristic cell organelles, melanocytes contain melanosomes, in which the melanin is formed. This is transferred via the long dendrites of the melanocytes into the keratinocytes of the precortical matrix and creates the more or less pronounced blonde to brown-black hair color. The processes of melanin synthesis and the distribution of melanin in the hair are carried out analogously to the processes described above.

Eumelanin is the black-brown pigment. It is mainly about the depth of color of the hair. In brown and black hair it occurs in clearly recognizable granules.

Phaeomelanin is the red pigment. It is responsible for light blonde, blonde and red hair. The structure of this melanin is much finer and smaller. The different hair colors result from the different proportions of the melanin types: • Blond hair contains little eumelanin and a lot of phaeomelanin. • Dark hair contains a lot of eumelanin and little phaeomelanin. • Red hair also has little eumelanin and a lot of phaeomelanin. • All shades of hair in between result from different mixing ratios of the two melanin types.

The pigment formation process can only take place if sufficient tyrosinase is available. This enzyme is produced less frequently with age. This gradually leads to gray hair. The reason: with little tyrosinase, less and less tyrosine is formed. The production of melanin also decreases. The missing melanin is replaced by the storage of air bubbles. The hair appears gray.

This process is usually insidious. It begins at the temples and then extends to the entire hair on the head. Then it hits the beard and eyebrows. Finally, all of the body's hair is gray. Medically, gray hair is called canities. There are several ways of graying. Premature graying, from the age of 20, is also called Canities praecox.

The symptomatic canity, or symptomatic graying of the hair, can have various causes. These include: • Pernicious anemia (vitamin B deficiency anemia), • Severe endocrinological disorders, e.g. B. in thyroid diseases. • acute, febrile illnesses, • drug side effects, • cosmetics, • metals.

The coloring of hair, especially of living human hair, using natural dyes, as has been known for the dye henna since ancient times, and which has been pushed into the background for years in favor of synthetic dyes, has been the subject of a new one for some years interest. A disadvantage is the red color created by henna.

With increasing age, the melanin production that causes the hair color decreases: the hair becomes gray or white. It is a cosmetic wish of some consumers to reverse this process or to let it run more slowly. For this purpose, the cosmetic industry uses lead acetate in some countries, which is toxic and is therefore prohibited in the European Cosmetics Regulation. This lead acetate is preferably applied to the hair as a solution and remains there for a long time without being washed off.

For dyeing keratin fibers, e.g. B. hair, wool or fur, generally either direct dyes or oxidation dyes, which are formed by oxidative coupling of one or more developer components with one another or with one or more coupler components, are used. Coupler and developer components are also referred to as oxidation dye precursors.

Primary aromatic amines with a further free or substituted hydroxy or amino group in the para or ortho position, diaminopyridine derivatives, heterocyclic hydrazones, 4-aminopyrazolone derivatives and 2,4,5,6-tetraaminopyrimidine and its derivatives are usually used as developer components used. Specific representatives are, for example, p-phenylenediamine, p-toluenediamine, 2,4,5,6-tetraaminopyrimidine, p-aminophenol, NN-bis - ^ - hydroxyethy-p-phenylenediamine, 2- (2,5-diaminophenyl) ethanol, 2- (2,5-diaminophenoxy) ethanol _I 1- phenyl -3-carboxyamido-4-aminopyrazolone-5, 4-amino-3-methylphenol, 2-aminomethyl-4-aminophenol, 2-hydroxy-5 methyl -4-aminophenol, 2-hydroxy-4,5,6-triaminopyrimidine ₁ 2 _l 4-dihydroxy-5,6-diaminopyri- midin and 2.5 _I 6-triamino-4-hydroxypyrimidine. M-Phenylenediamine derivatives, naphthols, resorcinol and resorcinol derivatives, pyrazolones and m-aminophenols are generally used as coupler components. Suitable coupler substances are in particular α-naphthol, 1,5-, 2,7- and 1,7-dihydroxynaphthalene, 10 5-amino-2-methylphenol, m-aminophenol, resorcinol, resorcinol monomethyl ether, m-phenylenediamine, 2, 4-diaminophenoxyethanol, 1-phenyl-S-methyl-pyrazolon-S, 2,4-di-chloro-3-aminophenol, 1,3-bis (2,4-diaminophenoxy) propane, 2-chlororesorcinol, 4- Chlororesorcinol, 2-chloro-6-methyl-3-aminophenol, 2-methylresorcinol and 5-methylresorcinol. With regard to further customary dye components, reference is expressly made to the "Dermatology" series, edited by Ch. Culnan, H. Maibach, publisher Marcel Dekker Inc., New York, Basel, 1986, vol. 7, Ch. Zviak, The Science of Hair Care, chap. 7, pages 248-250 (direct dyes), and chap. 8, pages 264-267 (oxidation dyes), as well as the "European inventory of cosmetic raw materials", 1996, published by the European

'• / ( ^■ see Commission, available in diskette form from the Federal Association of German Industry

20 companies and retailers for pharmaceuticals, health products and body care products eV, Mannheim. With oxidation dyes it is possible to achieve intensive dyeings with good fastness properties, but the development of the color generally takes place under the influence of oxidizing agents such as. B. H ₂ O _> which in some cases can damage the fiber. Furthermore, some oxidation dye precursors or certain mixtures of oxidation dye precursors can sometimes have a sensitizing effect on people with sensitive skin. Direct dyes are applied under gentler conditions, but their disadvantage is that the dyeings often have inadequate fastness properties.

30 The object of the present invention is to reduce the independent melanin production of the hair, but without coloring agents and in particular oxidizing agents such. B. H ₂ 0 _{2 to be} instructed. In addition, the agents must have no or only a very low sensitization potential. WO 01/58918 A2 describes oligonucleotides with 7 to 25, in particular 20, nucleic acids which hybridize with a gene which encodes an enzyme which is tyrosinase or TRP-1 and the use of such oligonucleotides.

Mehta et al., The Journal Of Investigative Dermatology 115 (2000) 805, describe the treatment of psoriasis by inhibiting the expression of the intercellular adhesion molecule 1 (ICAM-1), the expression of which is increased in psoriasis plaques, and therefore as an attractive target for treatment of psoriasis is considered, with phosphothioantanthene sequonucleotides. The use of antisense oligonucleotides for the prophylaxis and treatment of undesired pigmentation of the skin and hair, and preparations containing them, has not hitherto been described, apart from the tyrosinase and TRP1 structures described in WO 01/589 18 A1.

In the following, the enzymes and proteins involved in the pigmentation of skin and hair are also collectively referred to as "structures involved in the pigmentation (of skin and hair)". Structures involved in pigmentation are to be understood in particular as those which influence melanogenesis, This includes the MITF transcription factor and in particular the melanocyte-specific M isoforms (MITF-M) and very particularly the p-protein (OCA2): Vf-

MITF (ID O75030) MITF-M1 (ID O75030-9)

MITF-M2 (ID O75030-10) and in particular

P protein (ID Q04671).

The object of the present invention is to provide compositions which enable an effective treatment of and prophylaxis against undesirable pigmentation of the skin and hair, in particular against irregular pigmentation of the skin (“uneven skin tone, age spots, melasma etc.), without the disadvantages of the prior art to show the technology.

It has surprisingly been found that an oligonucleotide or a physiologically acceptable salt thereof which is capable of hybridizing with an mRNA or a gene sequence which one or more is involved in pigmenting the skin and / or the hair coding structures, which structures involved in pigmenting the skin and / or hair

(I) the actual melanin synthesis (melanosome structures) and / or on the

(II) Expression of these melanosome structures and / or are involved in (III) transfer of the melanosomes (into the keratinocytes) which remedies the disadvantages of the prior art.

Such an oligonucleotide can have a length of 15, 16, 17, 18, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 base pairs. This very selective procedure does not interfere with other physiological processes in the skin. There are very clear target proteins whose formation is prevented in a highly selective manner. The only task of these proteins is pigmentation (melanin synthesis) and thus the coloring in skin and hair. No other physical functions are known. It is therefore a) a biological goal that has no overlap with other biological processes in the skin, b) a technique that only selectively switches off pigmentation processes. Above all, this requires an extremely low rate of side effects - this is theoretically zero - an unusually high efficiency and excellent effectiveness. The undesirable side effects of classic skin lighteners (hydroquinone, mercury salts, etc.) do not occur.

The oligonucleotides according to the invention are accordingly antisense oligonucleotides. In addition to the oligonucleotides mentioned, physiologically tolerable salts of such oligonucleotides are also suitable according to the invention. In the following, for the sake of simplicity, the term oligonucleotide is used both for the oligonucleotides themselves and for their salts, unless stated otherwise. The term oligonucleotide also includes modified forms of DNA and RNA. It has further been found that it is preferred if the structures involved in the pigmentation of the skin and / or hair are involved in (I) the actual melanin synthesis (melanosome structures) and / or in the (II) expression of these melanosome structures and / or are involved in the (III) transfer of the melanosomes (into the keratinocytes). This has the advantage of being particularly effective. The pigmentation of skin and hair can be roughly divided into the three processes III. The more you inhibit individual steps, the better the overall result, since the individual effects multiply.

Accordingly, it is preferred if the structure involved in the actual melanin synthesis is the enzyme tyrosinase, TRP1, TRP2 or the p-protein. This will make the Melanin formation, so to speak, "nipped in the bud" because tyrosinase is the pacemaker enzyme for melanin formation. In this context, TRP1, TRP2 and in particular p-protein have a rather supportive function in melanin formation. In contrast, the state of the art is only inhibition of the existing pacemaker enzyme tyrosinase by more or less specific inhibitors (kojic acid etc.) In contrast, the antisense response is highly selective.

It is preferred if the oligonucleotide has a length of 21, 22, 23 or 24 base pairs. It is particularly preferred if the structure involved in the actual melanin synthesis is the enzyme tyrosinase, TRP1 or TRP2 and very particularly the p-protein. It is also very particularly preferred if the structure involved in the expression of the melanin synthesis is the transcriptin factor MITF.

The invention also includes pharmaceutical or cosmetic compositions for topical application, which contain one or more such oligonucleotides.

The enzymes involved in melanin synthesis are the following oxidases / tautomerases tyrosinase p14679 (EC 1.14.18.1)

TRP-1 p17643 (EC 1.14.18.-)

TRP-2 P40126 (EC 5.3.3.12)

Tyrosinase (Tyr, Tyro) is the pacemaker enzyme for melanin synthesis. The enzymes TRP-1 (tyrosinase related peptide 1, Tyrpl, Tyr1) and TRP-2 (tyrosinase related peptide 2, Dct, Tyr2) control to what extent the brown DHICA or, exclusively under the influence of tyrosinase, the black DHI- Melanin is formed. The numbers given are the access numbers (Accession Numbers) of the Swiss-PROT database of the EMBL-EBI (European Bioinformatics Institute Heidelberg). It is also preferred if the structure involved in the expression of the melanin synthesis is the transcriptin factor MITF. This causes an inhibition of the expression of the pacemaker enzyme tyrosinase, which does not take place without the transcription factor MITF, since it controls the expression of the tyrosinase, among other things. In addition, MITF - strictly speaking MITF-M- is a very exclusive transcription factor that only controls genes in the skin that are relevant for pigmentation. This in turn has the advantages that a) the melanin formation is nipped in the bud very early, b) no side effects occur, since there is no interference with other metabolic pathways, as is the case with Inhμ "General transcription factors" such as p53, NFkB or AP1 occur, some of which are also involved in the regulation of pigmentation.

Accordingly, the most preferred structures that influence melanogenesis include the transcription factor MITF and, in particular, the melanocyte-specific M isoforms (MITF-M) and very particularly the p-protein (OCA2):

MITF (ID O75030)

MITF-M 1 (ID O75030-9)

MITF-M2 (ID O75030-10) and in particular P protein (ID Q04671).

The access numbers (Accession Numbers) of the Swiss-PROT database of the EMBL-EBI (European Bioinformatics Institute Heidelberg) are given here.

Furthermore, the structures which influence the pigmentation processes in the skin and which are preferred are those structures which are involved in the transport of the melanosomes into the epidermis. This also includes the peptidases trypsin and trypsin-like enzymes and various serine proteases (including mast cell tryptase beta III (ID Q96RZ7; MMCP-7-like tryptase (ID Q996RZ7)). The following is particularly important as an important structure:

PAR-2 human (ID P55085) This is the access number (Accession Numbers) of the Swiss-PROT database of the EMBL-EBI (European Bioinformatics Institute Heidelberg).

It is therefore particularly preferred if the structure involved in the transfer of the melanosomes is proteinase activated receptor 2 (PAR-2). In the prior art, in which PAR-2 is deactivated by inhibiting skin proteases via classic protease inhibitors, no melanin is transported further and as a result the melanin synthesis comes to a standstill. At the same time, the inhibition of the proteases inhibits their important functions in the skin, which leads to side effects. In contrast, the highly selective switching off of PAR-2, which is not formed at all, does not affect the proteases (desquamation, etc.), which continue to perform their physiological functions. Nevertheless, the melanin transport is suppressed because none or less PAR-2 is present. This leads to skin lightening without side effects.

It is particularly preferred if the oligonucleotide or oligonucleotides can hybridize with one or more of the sequences SequenceName 1 to SequenceName 12, with the region from nucleotide 1381 to downstream, the region from nucleotide 121 to 1380, the translation initiating region (region from nucleotide 121 to 453), the region from nucleotide 120 to upstream and / or the region adjacent to the start sequence (region from nucleotide 121 to 150), the target sequence "Human 075030" MAO-TF "" (NCBI Acc: NM_000248). It is furthermore particularly preferred if the oligonucleotide (s) can hybridize with one or more of the sequences SequenceName 13 to SequenceName 24 and / or with the region from nucleotide 2570 on downstream, the region from nucleotide 53 to 2569, the translation initiating region (region from nucleotide 53 to 169), the region from nucleotide 52 to upstream and / or the region adjacent to the start sequence (region from nucleotide 53 to 85) JHuman 004671 "p protein" "(EMBL ID: HSPPRO AC M99564).

An oligonucleotide is preferred that inhibits the expression of the gene of the structure involved in the pigmentation of skin and / or hair by at least 25%, particularly preferably by at least 50%, very particularly preferably by at least 80% and very particularly preferably by at least 85% inhibit. If necessary, the expression of the target gene is first induced in the cells in a suitable manner to measure the inhibition. Tumor cells are preferably used to determine the effectiveness of the oligoribonucleotides according to the invention. Suitable primary cultures can be used in the same way. The oligoribonucleotides are introduced into the cells and then, if necessary after induction of the expression of the target gene, the expression rate of the target gene in these cells is measured and compared with that found in cells that have not been transfected with the respective oligoribonucleotide.

Those oligonucleotides are preferred which belong to the 3'- or 5'-untranslated region, the open reading frame, the translation-initiating region or the region of the genes or the corresponding regions of the mRNA of the genes of the genes adjacent to the start sequence mentioned enzymes are complementary.

The compositions according to the invention can contain one or preferably more oligonucleotides. These can be oligonucleotides that are linked to the gene Sequences or mRNAs of several different structures that modulate the pigmentation of the skin and / or with different sequence regions of the same gene or the same mRNA of different structures that modulate the pigmentation of the skin can hybridize. In the case of MΠT, oligonucleotides which are directed against one or more of the sequences SequenceName 1 to 12 are preferred, in the case of p-protein oligonucleotides which are directed against one or more of the sequences SequenceName 13 to 24.

Compositions which each contain at least one oligonucleotide which is directed against MITF and the p-protein are very particularly preferred. Particularly suitable are those oligonucleotides at 27 to 47 ° C, preferably at 27 to 37 ^β C and most preferably at 32 ^β C, at a pH value of 4 to 9, preferably 5 to 8 and at physiological osmolarity, salt - and hybridize electrolyte concentration specifically with the genes or gene segments mentioned or their mRNAs. Based on 20 bases, the invention preferably has a maximum of 0 to 8, particularly preferably 0 to 4 and very particularly preferably 0 to 2, very exceptionally particularly preferably no mismatches. This has the advantage of being particularly effective because it increases with the degree of agreement with the target sequence. It is also preferable if the oligonucleotide according to the invention is homologous to a section of the gene of the structure involved in the pigmentation of skin and / or hair, the sense strand of which is on the 5 'side by two adenosine residues and on the 3' side by two thymidine residues or by flanking a thymidine and a cytosine residue, particularly preferred if it carries two deoxythymidine residues at the 3 'end. It has surprisingly been found that the antisense oligonucleotides contained in the compositions according to the invention, after application to the skin, hybridize with the genes or mRNAs which code for structures which influence the pigmentation processes in the skin, and thus, through intervention, expression modulate the structures involved in the pigmentation of the skin, ie directly and specifically inhibit the transcription and / or translation of these enzymes, in particular also of alternative splice forms, thus preventing skin pigmentation without side effects and in this way effective treatment and prophylaxis of Enabling pigmentation disorders without showing the disadvantages of the prior art. The oligonucleotides according to the invention can be in the form of oligoribo- or oligodeoxyribonucleotides. However, they are preferably oligonucleotides which are chemically modified at the level of the sugar residues, the nucleobases, the phosphate groups and / or the skeleton located between them, for example to increase the stability of the oligonucleotides in the cosmetic or dermatological preparation and / or in the skin increase, for example compared to nucleolytic degradation, in order to improve the penetration of the antisense oligonucleotides into the skin and the cell, in order to influence the effectiveness of the antisense oligonucleotides favorably and / or to improve the affinity for the sequence sections to be hybridized.

Preferred are oligonucleotides in which one or more phosphate groups are replaced by phosphorothioate, methylphosphonate and / or phosphoramidate groups, e.g. N3 '→ P5'-phosphoramidate groups are exchanged. Oligonucleotides in which phosphate groups are replaced by phosphorothioate groups are particularly preferred. One or more of the phosphate groups of the oligonucleotide can be modified. In the case of a partial modification, terminal groups are preferably modified, but oligonucleotides in which all phosphate groups have been modified are particularly preferred. This applies mutatis mutandis to the modifications described below.

Preferred sugar modifications include the replacement of one or more ribose or deoxyribose residues of the oligonucleotide with morpholine rings (morpholine oligonucleotides) or with amino acids (peptide oligonucleotides). All R ^' h bose or deoxyribose residues of the oligonucleotide are preferably replaced by amino acid residues and in particular morpholine residues.

Morpholine oligonucleotides in which the morpholine residues are linked to one another via sulfonyl or preferably phosphoryl groups are particularly preferred, as can be seen in formula 1 or 2: Formula 1 Formula 2

B represents a modified or unmodified purine or pyrimidine base, preferably adenine, cytosine, guanine, or uracil,

X stands for O or S, preferably O, Y stands for O or N-CH3, preferably O,

Z stands for alkyl, O-alkyl, S-alkyl, NH2, NH (alkyl), NH (O-alkyl), N (alkyl) 2, N (alkyl) (O-alkyl), preferably N (alkyl) 2, where alkyl is linear or branched alkyl groups having 1 to 6, preferably 1 to 3 and particularly preferably 1 or 2 carbon atoms.

Formulas 1 and 2 each represent only a section of an oligonucleotide chain.

Morpholine oligonucleotides in which the morpholine residues are connected to one another via phosphoryl groups are very particularly preferred, as shown in formula 2, in which X is O, Y is O and Z is N (CH3) 2.

Furthermore, the ribose or deoxyribose residues can be modified by fluorine, alkyl or O-alkyl residues. Exemplary modifications are 2'-fluoro-, 2'-alkyl, 2'-O-alkyl, 2'-O-methoxyethyl modifications, 5'-palmftate derivatives and 2'-O-methylribonucleotides.

Unless otherwise stated, alkyl here preferably represents linear, branched or cyclic alkyl groups having 1 to 30, preferably 1 to 20, particularly preferably 1 to 10 and very particularly preferably 1 to 6 carbon atoms. Branched and cyclic radicals naturally have at least 3 carbon atoms, cyclic Residues with at least 5 and in particular at least 6 carbon atoms are preferred.

Oligonucleotides containing α-nucleosides can also be used. This makes the oligonucleotides more stable and therefore more effective. Suitable base modifications are e.g. in US 6,187,578 and WO 99/53101, to which express reference is hereby made. A modification of one or more pyrimidines in position 5 with I, Br, Cl, NH3 and N3 has proven to be advantageous.

The synthesis of modified and unmodified oligonucleotides and other suitable modification options are described in the literature. In addition, the production of modified and unmodified oligonucleotides is now also offered by numerous companies as a service, e.g. morpholine oligonucleotides by Gene Tools, One Summerton Way, Philomath, OR 97370, USA; Phosphothioate oligonucleotides e.g. from Biomol GmbH, Waidmannstrasse 35, 22769 Hamburg. It is preferred if the oligonucleotide according to the invention is integrated one or more times into an expression vector.

To increase stability and / or penetration, the oligonucleotides can also be used in encapsulated form, for example encapsulated in liposomes. They can also be stabilized by adding cyclodextrins. The invention also encompasses a pharmaceutical or cosmetic composition containing one or more of the oligonucleotides described or a physiologically tolerable salt thereof and a corresponding composition for topical use.

It is preferred if such a composition contains several oligonucleotides which inhibit the expression of several different structures involved in the pigmentation of skin and / or hair.

The compositions according to the invention preferably contain 0.00001 to 10% by weight, particularly preferably 0.0003 to 3% by weight and very particularly preferably 0.01 to 1.0 of the oligonucleotide (s) according to the invention, based on the total weight of the Composition. When using oligonucleotides which are integrated in vectors, the above quantity relates to the mass of the oligonucleotides integrated in the vector, the mass of the vector itself is not taken into account. It is also preferred if such a composition contains several oligonucleotides which contain different sequence regions of one and the same gene on the actual melanin synthesis (melanosome structures; Tyrosianse, TRP-1, TRP-2, p-protein) and / or on the expression of these melanosome structures (MITF) and or the structure (PAR-2) involved in the transfer of the melanosomes (into the keratinocytes).

Compositions of oligonucleotides which are directed against the expression of MITF and / or the p-protein are very particularly preferred.

Compositions according to the invention can also preferably contain 1 to 5 different oligonucleotides, preferably exclusively contain those oligonucleotides that inhibit the expression of one or more structures involved in the pigmentation of skin and skin.

Such compositions are preferably in the form of a solution, cream, ointment, lotion, hydrodispersion, lipodispersion, emulsion, Pickering emulsion, a gel, a solid stick or as an aerosol. The invention also encompasses the use of a described oligonucleotide or a physiologically tolerable salt thereof or a described preparation for producing a cosmetic or therapeutic composition for topical application.

The oligonucleotides and compositions are suitable for the treatment and prophylaxis of undesirable pigmentation of the skin and hair, in particular the symptoms described above. They are suitable for the cosmetic and therapeutic treatment of undesired pigmentation, which are caused by endogenous and exogenous factors, in particular UV radiation, dryness, roughness and flaccidity of the skin, wrinkling, the reduced regreasing by sebum glands, and an increased susceptibility to mechanical Stress (cracking), for the treatment of photodermatoses, the symptoms of senile xerosis, photoaging and a breakdown of the connective tissue of the skin, which are associated with undesirable pigmentation of the skin or hair. The compositions according to the invention can prevent incorrect pigmentation and permanently remove (incorrect) pigmentation present and without the risk of side effects. For example, the method described in WO02 / 053773 can be used to determine the effectiveness of the oligonucleotides according to the invention. The oligonucleotides according to the invention are particularly suitable for the prevention and treatment of undesired pigmentation of the skin, such as occurs in the form of chronically sun-damaged skin (age spots, "uneven skin tone"), but also in the case of freckles and melasma. In an equally preferred form, they are suitable oligonucleotides of the invention to prevent and treat also of sonnenexposit ^'i- onsbedingter skin tanning as well as for lightening the pigmentation of the hair. to oligonucleotides of the invention is suitable for lightening a reasonable per se to the skin type pigmentation.

On account of their prophylactic effect, the oligonucleotides and compositions according to the invention are also outstandingly suitable for skin care and for the production of a cosmetic or therapeutic composition for topical application and for skin care or treatment of undesired pigmentation of the skin or hair and for the treatment of changes or damage with regard to the pigmentation on the skin or hair caused by UV radiation in the skin, dryness, roughness and flaccidity of the skin, wrinkling, the reduced regreasing due to sebum glands, and an increased susceptibility to mechanical stress (cracking) Treatment of photodermatoses, the symptoms of senile xerosis, photoaging and a breakdown of the connective tissue of the skin, which are associated with undesirable pigmentation of the skin or hair. Such compositions can preferably be in the form of a solution, cream, ointment, lotion, hydrodispersion, lipodispersion, emulsion, Pickering emulsion, a gel, a solid stick or as an aerosol.

Compositions for topical use are preferred according to the invention. The compositions can be in all galenical forms which are usually used for topical application, for example as a solution, cream, ointment, lotion, shampoo, that is to say emulsion of the water-in-oil (W / O) type or of the type oil-in-water (O / W), multiple emulsion, for example of the type water-in-oil-in-water (W / O / W), or oil-in-water-in-oil (O / W / O ), Hydrodispersion or lipodispersion, Pickering emulsion, gel, solid stick or aerosol. The cosmetic or medical treatment of the indications mentioned is generally carried out by applying the compositions according to the invention to the skin, preferably to the affected skin areas, once or several times. The compositions according to the invention are suitable for cosmetic and therapeutic, ie in particular dermatological, use.

The omission of a single component affects the unique properties of the overall composition. Therefore, all of the specified components of the preparations according to the invention are absolutely necessary in order to carry out the invention.

To increase stability and / or penetration, the oligoribonucleotides can also be used in encapsulated form, for example encapsulated in liposomes. They can also be stabilized by adding cyclodextrins.

Cyclodextrins are also known as cycloamyloses and cycloglucans. The cyclodextrins are cyclic oligosaccharides consisting of α-1, 4 linked glucose units. As a rule, six to eight glucose building blocks (α-, β- or γ-cyclodextrin) are linked together. Cyclodextrins are obtained when Bacillus maceraπs acts on starch. They have a hydrophobic interior and a hydrophilic exterior. According to the invention, both the cyclodextrins themselves, in particular α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, and derivatives thereof are suitable.

According to the invention, the cyclodextrin (s) in cosmetic and dermatological compositions are preferably in a concentration of 0.0005 to 20.0% by weight, in particular 0.01 to 10% by weight and particularly preferably in a concentration of 0.1 to 5.0% by weight used.

According to the invention, it is advantageous to use native, polar and / or nonpolar substituted cyclodextrins. These preferably but not exclusively include methyl-, in particular random-methyl-β-cyclodextrin, ethyl and hydroxypropyl-cyclodextrins, for example hydroxypropyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin. The particularly preferred cyclodextrin species according to the invention are γ-cyclodextrin and hydroxypropyl-β-cyclodextrin. Polar cyclodextrins are also particularly preferred according to the invention.

Liposomes can be prepared in a manner known per se using natural ones

Phospholipids, e.g. Manufacture phosphatidylcholine from eggs, soybeans, etc., or synthetic phospholipids (see G. Betageri (editor), “Liposome Drug Delivery

Systems ", Lancaster Techonomic Publishing Company 1993; Gregoriadis (Editor), "Liposome Technology", CRC Press). Preferred methods and materials for the production of liposomes are described in WO 99/24018.

The compositions according to the invention are also suitable for the treatment of those caused by UV rays, e.g. the ultraviolet part of the sun's radiation, caused skin damage. UVB rays (290 to 320 nm) cause, for example, erythema, sunburn or even more or less severe burns. UVA rays (320 nm to 400 nm) can cause irritation to light-sensitive skin and lead to damage to the elastic and collagen fibers of the connective tissue, which leaves the skin prematurely old. They are also the cause of numerous phototoxic and photo-allergic reactions. The oligoribonucleotides according to the invention are also suitable for the treatment of e.g. structural damage caused by UV rays and functional disorders in the epidermis and dermis of the skin, such as for example visible vascular dilatations such as telangiectasias and cuperosis, skin sagging and the formation of wrinkles, local hyper-, hypo- and incorrect pigmentations, such as e.g. B. age spots, and increased susceptibility to mechanical stress, such as Cracked skin.

Further areas of application for the compositions according to the invention are the treatment and prevention of age and / or UV-induced collagen degeneration and the breakdown of elastin and glycosaminoglycans; degenerative symptoms of the skin, such as loss of elasticity and loss of the epidermal and dermal cell layers, the components of the connective tissue, the reticles and capillary vessels) and / or the appendages of the skin; from environmental, for example caused by ultraviolet radiation, smoking, smog, reactive oxygen species, free radicals and the like, negative changes in the skin and the appendages of the skin; deficient, sensitive or hypoactive skin conditions or deficient, sensitive or hypoactive conditions of skin appendages; the reduction in skin thickness; from sagging and / or skin fatigue; changes in transepidermal water loss and normal skin moisture; change in the energy metabolism of healthy skin; deviations from normal cell-cell communication in the skin, which can manifest itself, for example, through the formation of wrinkles; changes in normal fibroblast and keratinocyte proliferation; changes in normal fibroblast and keratinocyte differentiation; of polymorphic light dermatosis, vitiligo; of wound healing disorders; from disorders of normal collagen, Hyaluronic acid, elastin and glycosaminoglycan homeostasis; the increased activation of proteolytic enzymes in the skin, such as B. of metalloproteinases.

Cosmetic skin care primarily means that the natural function of the skin acts as a barrier against environmental influences (e.g. dirt, chemicals, microorganisms) and against the loss of the body's own substances (e.g. water, natural fats, Electrolytes) is strengthened or restored. If this function is disturbed, there may be an increased absorption of toxic or allergenic substances or an infestation of microorganisms and, as a result, toxic or allergic skin reactions. The aim of skin care is also to compensate for the loss of fat and water in the skin caused by daily washing. This is especially important when the natural regeneration ability is insufficient. In addition, skin care products are intended to protect against environmental influences, especially sun and wind.

For cosmetic use, the compositions according to the invention therefore preferably contain those components which are suitable for the purposes mentioned. Such substances are known per se to the person skilled in the art. For example, one or more antisense oligoribonucleotides can be incorporated into conventional cosmetic and dermatological preparations, which can be in various forms.

According to a particularly preferred embodiment, the compositions according to the invention for cosmetic use are in the form of an emulsion, e.g. in the form of a cream, a lotion, a cosmetic milk. In addition to the oligoribonucleotides mentioned, these contain other components such as Fats, oils, waxes and / or other fat bodies, as well as water and one or more emulsifiers, as are usually used for such a type of formulation.

Emulsions generally contain a lipid or oil phase, an aqueous phase and preferably also one or more emulsifiers. Compositions which also contain one or more hydrocolloids are particularly preferred.

The compositions according to the invention preferably contain 0.001 to 35% by weight, particularly preferably 2 to 15% by weight of emulsifier, 0.001 to 45% by weight, particularly preferably 10 to 25% by weight of lipid and 10 to 95% by weight , particularly preferably 60 to 90 wt .-% water. The lipid phase of the cosmetic or dermatological emulsions according to the invention can advantageously be selected from the following group of substances: (1) mineral oils, mineral waxes; (2) oils, such as triglycerides of capric or caprylic acid, and also natural oils, such as castor oil; (3) fats, waxes and other natural and synthetic fat bodies, preferably esters of fatty acids with alcohols with a low C number, for example with isopropanol, propylene glycol or glycerol, or esters of fatty alcohols with alkanoic acids with a low C number or with fatty acids; (4) alkyl benzoates; (5) silicone oils such as dimethylpolysiloxanes, diethylpolysiloxanes, diphenylpolysiloxanes and mixed forms thereof.

Unless stated otherwise, the term “low C number” here means preferably 1 to 5, particularly preferably 1 to 3 and very particularly preferably 3 carbon atoms.

The oil phase of the emulsions of the present invention is advantageously selected from the group of the esters from saturated and / or unsaturated, branched and / or unbranched alkane carboxylic acids with a chain length of 3 to 30 carbon atoms and saturated and / or unsaturated, branched and / or unbranched alcohols a chain length of 3 to 30 carbon atoms, from the group of esters of aromatic carboxylic acids and saturated and / or unsaturated, branched and / or unbranched alcohols of a chain length of 3 to 30 carbon atoms. Such ester oils can then advantageously be selected from the group of isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl stearate, isononylisononanoate, 2-ethyl-2-ethylhexyl, ethyl-2-ethylhexyl Hexyldecyl stearate, 2-octyldodecyl palmitate, oleyl oleate, olerlerucate, erucyl oleate, erucylerucate as well as synthetic, semi-synthetic and natural mixtures of such esters, e.g. Jojoba oil.

Furthermore, the oil phase can advantageously be chosen from the group of branched and unbranched hydrocarbons and waxes, the silicone oils, the dialkyl ethers, the group of saturated or unsaturated, branched or unbranched alcohols, and also the fatty acid triglycerides, especially the triglycerol esters of saturated and / or unsaturated, branched and / or unbranched alkane carboxylic acids with a chain length of 8 to 24, in particular 12 - 18 carbon atoms. The fatty acid triglycerides can, for example, advantageously be selected from the group of synthetic, semisynthetic and natural oils, for example olive oil, sunflower oil, soybean oil, peanut oil, rapeseed oil, almond oil, palm oil, coconut oil, palm kernel oil and the like. Any mixtures of such oil and wax components can also be used advantageously for the purposes of the present invention. It may also be advantageous to use waxes, for example cetyl palmitate, as the sole lipid component of the oil phase. The oil phase is advantageously selected from the group 2-ethylhexyl isostearate, octyldodecanol, isotridecyl isononanoate, isoeicosane, 2-ethylhexyl cocoate, C ₂ -i ₅ -alkyl benzoate, caprylic capric acid triglyceride, dicaprylyl ether.

Mixtures of C ₂ -i ₅ alkyl benzoate and 2-ethylhexyl isostate, mixtures of C ₁₂ - 5 alkyl benzoate and isotridecyl isononanoate, and mixtures of C _2- i ₅ alkyl benzoate, 2-ethyl hexyl isostearate and isotridecyl isononanoate are particularly advantageous.

Of the hydrocarbons, paraffin oil, squalane and squalene can be used advantageously for the purposes of the present invention.

The oil phase can also advantageously contain cyclic or linear silicone oils or consist entirely of such oils, although it is preferred to use an additional content of other oil phase components in addition to the silicone oil or the silicone oils. Such silicones or silicone oils can be present as monomers, which are generally characterized by structural elements, as follows:

R ₂ - O— S - O— R ₃ R ₄

Linear silicones with a plurality of siloxy units which can advantageously be used according to the invention are generally characterized by structural elements as follows:

wherein the silicon atoms can be substituted with the same or different alkyl radicals and / or aryl radicals, which are generally represented here by the radicals R ₁ - R ₄ (to say that the number of different radicals is not necessary) is limited to up to 4), m can assume values from 2 to 200,000. Unless otherwise stated, aryl is preferably phenyl herein.

Cyclic silicones to be used advantageously according to the invention are generally characterized by structural elements as follows

where the silicon atoms can be substituted with the same or different alkyl radicals and / or aryl radicals, which are generally represented here by the radicals R 1 - R ₄ (to say that the number of different radicals is not necessarily limited to up to 4), n can take values from 3/2 to 20. Broken values for n take into account that there may be odd numbers of siloxyl groups in the cycle.

Cyclomethicone (e.g. decamethylcyclopentasiloxane) is advantageously used as the silicone oil to be used according to the invention. However, other silicone oils can also be used advantageously for the purposes of the present invention, for example undecamethylcyclotrisiloxane, polydimethylsiloxane, poly (methylphenylsiloxane), cetyldimethicone, behenoxydimethicone.

Mixtures of cyclomethicone and isotridecyl isononanoate and those of cyclomethicone and 2-ethylhexyl isostearate are also advantageous.

It is also advantageous to choose silicone oils of similar constitution to the above designated Neten compounds derivatized ^'itenketten whose organic Se, for example polyethoxylated and / or polypropoxylated. These include, for example, polysiloxane-polyalkyl-polyether copolymers such as the cetyl-dimethicone copolyol, the (cetyl-dimethicone copolyol (and) polyglyceryl-isostearate (and) hexyl laurate).

Mixtures of cyclomethicone and isotridecyl isononanoate, of cyclomethicone and 2-ethylhexyl isostearate are also particularly advantageous. The aqueous phase of the preparations according to the invention optionally advantageously contains alcohols, diols or polyols of low C number, and also their ethers, preferably ethanol, isopropanol, propylene glycol, glycerin, 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 can advantageously be selected from the group consisting of silicon dioxide, aluminum silicates.

Preparations according to the invention in the form of emulsions preferably contain one or more emulsifiers. These emulsifiers can advantageously be selected from the group of nonionic, anionic, cationic or amphoteric emulsifiers.

The nonionic emulsifiers include (1) partial fatty acid esters and fatty acid esters of polyhydric alcohols and their ethoxylated derivatives (eg glyceryl monostearates, sorbitan stearates, glyceryl stearyl citrates, sucrose stearates); (2) ethoxylated fatty alcohols and fatty acids; (3) ethoxylated fatty amines, fatty acid amides, fatty acid alkamides; (4) alkylphenol polyglycol ether (e.g. Triton X).

The anionic emulsifiers include soaps (e.g. sodium stearate); Fatty alcohol sulfates; Mono-, di- and trialkylphosphonic acid esters and their ethoxylates. The cationic emulsifiers include quaternary ammonium compounds with a long-chain aliphatic radical, e.g. Distearyldimonium Chloride.

The amphoteric emulsifiers include alkylamininoalkane carboxylic acids, betaines, sulfobetaines, imidazoline derivatives.

There are also naturally occurring emulsifiers, which include beeswax, wool wax, lecithin and sterols.

O / W emulsifiers can, for example, advantageously be selected from the group of the polyethoxylated or polypropoxylated or polyethoxylated and polypropoxylated products, for example the fatty alcohol ethoxylates, the ethoxylated wool wax alcohols, the polyethylene glycol ethers of the general formula RO - (- CH ₂ -CH ₂ - O-) n-R ', the fatty acid ethoxyate of the general formula R-COO - (- CH2-CH ₂ -O-) _n -H, the etherified fatty acid ethoxyate of the general formula R-COO - (- CH2-CH2 -O) _n -R ', the esterified fatty acid ethoxylate of the general formula R-COO - (- CH2-CH ₂ -O-) _n -C (O) -R', the polyethylene glycol glycerin fatty acid ester, the ethoxylated sorbitan ester, the Cholesterol ethoxylates, the ethoxy triglycerides, the alkyl ether carboxylic acids of the general formula RO - (- CH ₂ -CH ₂ - O-) _n -CH ₂ -COOH, the polyoxyethylene sorbitol fatty acid esters, the alkyl ether sulfates of the general formula RO - (- CH ₂ -CH ₂ -O-) _n -SO ₃ -H, the fatty alcohol propoxylate of the general formula RO - (- CH ₂ -CH (CH ₃ ) -O-) _n -H, the polypropylene glycol ether of the general formula RO - (- CH ₂ -CH (CH ₃ ) -O -) _n -R ', the propoxylated wool wax alcohols, the etherified fatty acid propoxylates, R-COO - (- CH ₂ -CH (CH ₃ ) -O-) _n -R', the esterified fatty acid propoxylates of the general formula R- COO - (- CH ₂ -CH (CH ₃ ) -O-) _n -C (O) -R ', the fatty acid propoxylates of the general formula R-COO - (- CH ₂ -CH (CH ₃ ) -O-) _n -H, the polypropylene glycol glycerol fatty acid ester, the propoxylated sorbitan esters, the cholesterol propoxylates, the propoxylated triglycerides, the alkyl ether carboxylic acids of the general formula RO- (-CH ₂ -CH (CH ₃ ) O-) _n -CH ₂ -COOH, the alkyl ether sulfates or the acids on which these sulfates are based of the general formula RO - (- CH ₂ -CH (CH ₃ ) -O-) _n -SO ₃ -H, the fatty alcohol ethoxylates / propoxylate θ of the general formula ROX _n -Y _m -H, the polypropylene glycol ether of the general formula RO- Xn-Y _m -R ', the etherified fatty acid propoxylates of the general formula R-COO-Xn-Y _m -R', the fatty acid ethoxylates / propoxylates of the general formula R-COO-X _n -Y _m -H.

In all cases, the variables n and m each independently represent an integer from 1 to 40, preferably 5 to 30.

According to the invention, the polyethoxylated or polypropoxylated or polyethoxylated and polypropoxylated O / W emulsifiers selected are particularly advantageously selected from the group of substances with HLB values of 11-18, very particularly advantageously with HLB values of 14.5-15.5 if the O / V emulsifiers have saturated radicals R and R '. If the O / W emulsifiers have unsaturated radicals R and / or R ', or if isoalkyl derivatives are present, the preferred HLB value of such emulsifiers can also be lower or higher.

It is advantageous to choose the fatty alcohol ethoxylates from the group of the ethoxylated stearyl alcohols, cetyl alcohols, cetylstearyl alcohols (cetearyl alcohols). The following are particularly preferred:

Polyethylene glycol (13) stearyl ether (steareth-13), polyethylene glycol (14) stearyl ether (steareth-14), polyethylene glycol (15) stearyl ether (steareth-15), polyethylene glycol (16) stearyl ether (steareth-16), polyethylene glycol ( 17) stearyl ether (Steareth-17), polyethylene glycol (18) stearyl ether (Steareth-18), polyethylene glycol (19) stearyl ether (Steareth-19), polyethylene glycol (20) stearyl ether (Steareth-20), Polyethylene glycol (12) isostearyl ether (isosteareth-12), polyethylene glycol (13) isostearyl ether (isosteareth-13), polyethylene glycol (14) isostearyl ether (isosteareth-14), polyethylene glycol (15) isostearyl ether (isosteareth-15), polyethylene glycol ( 16) isostearyl ether (isosteareth-16), polyethylene glycol (17) isostearyl ether (isosteareth-17), polyethylene glycol (18) isostearyl ether (isosteareth-18), polyethylene glycol (19) isostearyl ether (isosteareth-19-), polyethylene glycol (20) isostearyl ether (isosteareth-20),

Polyethylene glycol (13) cetyl ether (ceteth-13), polyethylene glycol (14) cetyl ether (ceteth-14), polyethylene glycol (15) cetyl ether (ceteth-15), polyethylene glycol (16) cetyl ether (ceteth-16), polyethylene glycol (17) cetyl ether ( Ceteth-17), polyethylene glycol (18) cetyl ether (ceteth-18), polyethylene glycol (19) cetyl ether (ceteth-19), polyethylene glycol (20) cetyl ether (ceteth-20),

Polyethylene glycol (13) isocetyl ether (isoceteth-13), polyethylene glycol (14) isocetyl ether (isoceteth-14), polyethylene glycol (15) isocetyl ether (isoceteth-15), polyethylene glycol (16) - isocetyl ether (isoceteth-16), polyethylene glycol (17) ) isocetyl ether (isoceteth-17), polyethylene glycol (18) isocetyl ether (isoceteth-18), polyethylene glycol (19) isocetyl ether (isoceteth-19), polyethylene glycol (20) isocetyl ether (isoceteth-20),

Polyethylene glycol (12) oleyl ether (oleth-12), polyethylene glycol (13) oleyl ether (oleth-13), polyethylene glycol (14) oleyl ether (oleth-14), polyethylene glycol (15) oleyl ether (oleth-15),

Polyethylene glycol (12) lauryl ether (Laureth-12), polyethylene glycol (12) isolauryl ether (Isolaueth-12).

Polyethylene glycol (13) cetylstearyl ether (ceteareth- 13), polyethylene glycol (14) cetylstearyl ether (ceteareth- 14), polyethylene glycol (15) cetylstearylether (ceteareth-15), polyethylene glycol (16) cetylstearylether (ceteareth-16), polyethylene glycol 17) cetylstearyl ether (Ceteareth-17), polyethylene glycol (18) cetylstearylether (Ceteareth-18), polyethylene glycol- (19Jcetylstearylether (Ceteareth-19), polyethylene glycol (20) cetylstearylether (Ceteareth-20),

It is also advantageous to choose the fatty acid ethoxylates from the following group:

Polyethylene glycol (20) stearate, polyethylene glycol (21) stearate, polyethylene glycol (22) stearate, polyethylene glycol (23) stearate, polyethylene glycol (24) stearate, polyethylene glycol (25) stearate, Polyethylene glycol (12) isostearate, polyethylene glycol (13) isostearate, polyethylene glycol (14) isostearate, polyethylene glycol (15) isostearate, polyethylene glycol (16) isostearate, polyethylene glycol (17) isostearate, polyethylene glycol (18) isostearate, polyethylene glycol (19) isostearate , Polyethylene glycol (20) isostearate, polyethylene glycol (21) isostearate, polyethylene glycol (22) isostearate, polyethylene glycol (23) isostearate, polyethylene glycol (24) isostearate, polyethylene glycol (25) isostearate,

Polyethylene glycol (12) oleate, Polyethylene glycol (13) oleate, Polyethylene glycol (14) oleate, Polyethylene glycol (15) oleate, Polyethylene glycol (16) oleate, Polyethylene glycol (17) oleate, Polyethylene glycol (18) oleate, Polyethylene glycol (19) oleate, polyethylene glycol (20) oleate, sodium laureth-11-carboxylate can advantageously be used as the ethoxylated alkyl ether carboxylic acid or its salt.

Sodium laureth 1-4 sulfate can advantageously be used as alkyl ether sulfate.

Polyethylene glycol (30) cholesteryl ether can advantageously be used as the ethoxylated cholesterol derivative. Polyethylene glycol (25) soyasterol has also proven itself.

Polyethylene glycol (60) evening primrose glycerides can advantageously be used as ethoxylated triglycerides (evening primrose = evening primrose)

It is also advantageous to use the polyethylene glycol glycerol fatty acid esters from the group polyethylene glycol (20) glyceryl laurate, polyethylene glycol (21) glyceryl laurate, polyethylene glycol (22) glyceryl laurate, polyethylene glycol (23) glyceryl laurate, polyethylene glycol (6) glyceryl capthalate, caprinate ) glyceryl oleate, polyethylene glycol

(20) glyceryl isostearate, polyethylene glycol (18) glyceryl oleate / cocoat to choose.

It is also favorable to choose the sorbitan esters from the group consisting of polyethylene glycol (20) sorbitan monolaurate, polyethylene glycol (20) sorbitan monostearate, polyethylene glycol (20) sorbitan monoisostearate, polyethylene glycol (20) sorbitan monopalmitate, polyethylene glycol (20) sorb ^' rtan monooleate.

Advantageous W / O emulsifiers that can be used are: fatty alcohols with 8 to 30 carbon atoms, monoglycerol esters of saturated and / or unsaturated, branched and / or unbranched alkane carboxylic acids with a chain length of 8 to 24, in particular 12 to 18 carbon atoms, and diglycerol esters saturated and / or unsaturated, branched and / or unbranched alkane carboxylic acids with a chain length of 8 to 24, in particular 12-18, carbon atoms, monoglycerol ethers of saturated and / or unsaturated, branched ter and / or unbranched alcohols with a chain length of 8 to 24, in particular 12 - 18 C-atoms, diglycerol ethers of saturated and / or unsaturated, branched and / or unbranched alcohols with a chain length of 8 to 24, in particular 12 - 18 C-atoms, propylene glycol esters saturated and / or unsaturated, branched and / or unbranched alkane carboxylic acids with a chain length of 8 to 24, in particular 12-18 C atoms, and sorbitan esters of saturated and / or unsaturated, branched and / or unbranched alkane carboxylic acids with a chain length of 8 to 24, in particular 12 - 18 carbon atoms.

Particularly advantageous W / O emulsifiers are glyceryl Glycerylmonoi- sostearat, glyceryl monomyristate monoisostearate, glyceryl, diglyceryl monostearate, Diglyceryl-, propylene glycol, propylene glycol monoisostearate glycol, propylene colmonocaprylat, propylene glycol monolaurate, sorbitan, Sorbitanmo-, sorbitan, Sorbitanmonoisooleat, sucrose, Cetylalko- hol, Stearyl alcohol, arachidyl alcohol, behenyl alcohol, isobehenyl alcohol, selachyl alcohol, chimyl alcohol, polyethylene glycol (2) stearyl ether (steareth-2), glyceryl monolaurate, glyceryl monocaprinate, glyceryl monocaprylate.

Preparations according to the invention in the form of emulsions preferably also contain one or more hydrocolloids. These hydrocolloids can advantageously be selected from the group consisting of gums, polysaccharides, cellulose derivatives, layered silicates, polyacrylates and / or other polymers. Preparations according to the invention which are present as hydrogels contain one or more hydrocolloids. These hydrocolloids can advantageously be selected from the aforementioned group.

Gums include plant or tree sap that harden in the air and form resins or extracts from aquatic plants. Gum arabic, locust bean gum, tragacanth, karaya, guar gum, pectin, gellan gum, carrageenan, agar, algine, chondrus, xanthan gum can advantageously be selected from this group for the purposes of the present invention.

The use of derivatized gums such as hydroxypropyl guar (Jaguar® HP 8) is also advantageous. The polysaccharides and derivatives include, for example, hyaluronic acid, chitin and chitosan, chondroitin sulfates, starch and starch derivatives. The cellulose derivatives include, for example, methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose.

Layered silicates contain naturally occurring and synthetic clays such as Montmorillonite, bentonite, hectorite, laponite, magnesium aluminum silicates such as Veegum®. These can be used as such or in a modified form such as e.g. Stearylalkonium hektorite.

Furthermore, silica gels can also advantageously be used.

The polyacrylates include e.g. Carbopol types from Goodrich (Carbopol 980, 981, 1382, 5984, 2984, EDT 2001 or Pemulen TR2). Among the polymers are e.g. Polyacrylamides (Seppigel 305), polyvinyl alcohols, PVP, PVP / VA copolymers, polyglycols.

According to a further preferred embodiment, the oligoribonucleotides used according to the invention are inserted into aqueous systems or surfactant preparations for cleaning the skin and hair. In addition to the components mentioned, the cosmetic preparations according to the invention preferably also contain auxiliaries as are usually used in such preparations, e.g. Preservatives, bactericides, deodorizing substances, antiperspirants, insect repellents, vitamins, anti-foaming agents, dyes, pigments with a coloring effect, thickening agents, softening substances, moisturizing and / or moisturizing substances (moisturizers), or other common components of a cosmetic Formulation such as polyols, polymers, foam stabilizers, electrolytes, organic solvents or silicone derivatives, antioxidants and in particular UV absorbers.

Moisturizers are substances or mixtures of substances that give cosmetic or dermatological preparations the property of reducing the release of moisture from the horny layer (also known as trans-epidermal water loss (TEWL)) and / or hydrating the skin after application or distribution on the skin surface To influence the horny layer positively. Advantageous moisturizers for the purposes of the present invention are, for example, glycerol, lactic acid, pyrrolidone carboxylic acid and urea. It is also particularly advantageous to use polymeric moisturizers from the group of water-soluble and / or water-swellable and / or water-gellable polysaccharides. Hyaluronic acid, for example, is particularly advantageous and / or a fucose-rich polysaccharide, which is filed in the Chemical Abstracts under the registration number 178463-23-5 and z. B. is available under the name Fucogel 1000 from the company SOLABI A SA.

When used as a particularly preferred moisturizer, glycerin is preferably used in an amount of 0.05-30% by weight, particularly preferably 1-10%.

The cosmetic compositions can advantageously also contain one or more of the following natural active ingredients or a derivative thereof: alpha-lipoic acid, phytoene, D-biotin, coenzyme Q10, alpha glucosylrutin, carnitine, camosin, natural and / or synthetic isoflavonoids, creatine, hops or hop-malt extract, taurine. It has been shown that active ingredients that positively influence aging skin, which reduce the formation of wrinkles or existing wrinkles, such as bioquinones and especially ubiquinone Q10, soy, creatinine, creatine, liponamide, or promote the restructuring of connective tissue, such as isoflavone, in the Formulations according to the invention can be used very well. It was also shown that the formulations are particularly suitable for combination with active ingredients to support skin functions in dry skin, in particular dry skin such as serinol and osmolytes, for example taurine. The incorporation of active ingredients to alleviate or positively influence irritant skin conditions proved to be similar, be it with sensitive ones. Skin in general or in the case of skin irritated by noxious substances (UV light, chemicals), as advantageous. Active substances such as sericosides, various extracts of licorice, licochalcone, in particular licochalcone A, silymarin, silyphos, dex panthenol, inhibitors of prostaglandin metabolism (especially cyclooxygenase) and leukotriene metabolism (especially 5-lipoxygenase, but also of the 5-lipoxygenase inhibitor protein (FLAP). The incorporation of modulators of the pigmentation also proved to be advantageous. Active substances that reduce the pigmentation of the skin and thus lead to a cosmetically desired lightening of the skin and / or reduce the appearance of age spots and / or brighten existing age spots (tyrosine sulfate, dioic acid (8-hexadecene-1,16- dicarboxylic acid), lipoic acid and liponamide, various extracts of licorice, kojic acid, hydroquinone, arbutin, fruit acids, in particular alpha-hydroxy acids (AHAs), bearberry (Uvae ursi), ursolic acid, ascorbic acid, green tea extracts). According to a particularly preferred embodiment, the compositions according to the invention contain one or more UV absorbers. Preferred UV absorbers are those which absorb in the range of UVB and / or U VA rays.

Numerous compounds are known for protection against UVB radiation, which are derivatives of 3-benzylidene camphor, 4-aminobenzoic acid, cinnamic acid, salicylic acid, benzophenone and also 2-phenylbenzimidazole. Filters with an absorption maximum in the range of 308 nm are preferred, since this is where the maximum erythema effectiveness of sunlight lies.

Advantageous UV-A filter substances for the purposes of the present invention are dibenzoyl methane derivatives, in particular 4- (tert-butyl) -4'-methoxydibenzoylmethane (CAS No. 70356-09-1), which is available from Givaudan under the Parsol brand ^® 1789 and is sold by Merck under the trade name Eusolex® 9020.

The preparations according to the invention advantageously contain substances that absorb UV radiation in the UV-A and / or UV-B range, the total amount of filter substances, for. B. 0.1 wt .-% to 30 wt .-%, preferably 0.5 to 20 wt .-%, in particular 1.0 to 15.0 wt .-%, based on the total weight of the preparations to cosmetic To provide preparations that protect the hair or skin from the entire range of ultraviolet radiation. They can also serve as a sunscreen for the hair or skin. Further advantageous UV-A filter substances are the phenylene-1,4-bis (2-benzimidazyl) -3,3'-5,5'-tetrasulfonic acid

and their salts, especially the corresponding sodium, potassium or triethanolammonium salts, in particular the phenylene-1-4 -benzimidazy -S.S'-S.δ'-tetrasulfonic acid-bis-sodium salt

with the INCI name bisimidazylate, which is available, for example, from Haarmann & Reimer under the trade name Neo Heliopan AP.

Also advantageous are the 1,4-di (2-oxo-10-sulfo-3-bomylidenemethyl) benzene and its salts (especially the corresponding 10-sulfato compounds, especially the corresponding sodium, potassium or triethanolammonium salt) , which is also called benzene-1,4-di (2-oxo-3-bornylidenemethyl-10-sulfonic acid) and is characterized by the following structure:

Advantageous UV filter substances in the sense of the present invention are also so-called broadband filters, i.e. Filter substances that absorb both UV-A and UV-B radiation.

Advantageous broadband filters or UV-B filter substances are, for example, bis-resorcinyltriazine derivatives with the following structure:

where R ¹ , R ² and R ^{3 are} independently selected from the group of branched and unbranched alkyl groups having 1 to 10 carbon atoms or represent a single hydrogen atom. Particularly preferred are the 2,4-bis - {[4- (2-ethylhexyloxy) -2-hydroxy] phenyl} -6- (4-methoxyphenyl) -1,3,5-triazine (INCI: Aniso triazine ), which is available under the trade name Tinosorb® S from CIBA-Chemikalien GmbH and the ^4,4, 4 "- (1,3,5-triazine-2,4,6-triyltriimino) -tris-benzoic acid tris (2-ethylhexyl ester), synonymous: 2,4,6-tris [anilino- (p-carbo-2'-ethyl-1'-hexyloxy)] - 1,3,5-triazine (INCI: octyl triazone) , which is sold by BASF Aktiengesellschaft under the trade name UVINUL® T 150.

Also other UV filter substances, which the structural motif

are advantageous UV filter substances for the purposes of the present invention, for example the s-triazine derivatives described in European patent application EP 570 838 A1, the chemical structure of which is given by the generic formula

is reproduced, wherein R represents a branched or unbranched C ₁ -C ₈ alkyl radical, a C ₅ -C ₂ cycloalkyl radical, optionally substituted with one or more C ₁ -C 4 alkyl groups,

X represents an oxygen atom or an NH group,

Ri is a branched or unbranched C ₁ -C ₈ alkyl radical, a C ₅ -Ci ₂ cycloalkyl radical, optionally substituted with one or more C ₁ -C ₄ alkyl groups, or a hydrogen atom, an alkali metal atom, an ammonium group or a group of formula

means in which A represents a branched or unbranched C ₁ -C ₈ alkyl radical, a C ₅ -Ci ₂ cycloalkyl or aryl radical, optionally substituted by one or more C ₁ -C ₄ alkyl groups, R _{3 is} a hydrogen atom or represents a methyl group, n represents a number from 1 to 10, R _{2 is} a branched or unbranched -C ₈ alkyl radical, a C ₅ -C ₂ cycloalkyl radical, optionally substituted with one or more C1-C4 alkyl groups, when X represents the NH group, and a branched or unbranched -CC ₈ -alkyl radical, a C ₅ -C ₂ -cycloalkyl radical, optionally substituted with one or more CC ₄ - alkyl groups, or a hydrogen atom, an alkali metal atom, an ammonium group or a group of the formula

means in which A represents a branched or unbranched C 1 -C ₈ alkyl radical, a C ₅ -C ₂ cycloalkyl or aryl radical, optionally substituted with one or more C1-C4 alkyl groups, R3 represents a hydrogen atom or a methyl group , n represents a number from 1 to 10 when X represents an oxygen atom.

A particularly advantageous UV filter substance in the sense of the present invention is also an asymmetrically substituted s-triazine, the chemical structure of which is represented by the formula

is reproduced, which is also referred to below as dioctylbutylamidotriazon (INCI: Dictylbutamidotriazone) and is available under the trade name UVA SORB HEB from Sigma 3V.

The European patent application EP 775 698 also advantageously uses. 3is-resorcinyltriazine derivatives described, their chemical structure by the generic formula

is reproduced, wherein Ri, R ₂ and A represent a wide variety of organic radicals.

For the purposes of the present invention, 2,4-bis - {[4- (3-sulfonato) - 2-hydroxypropyloxy) -2-hydroxy] phenyl} -6- (4-methoxyphenyl) -1, 3,5-triazine sodium salt, the 2,4-bis - {[4- (3- (2-propyloxy) -2-hydroxypropyloxy) -2-hydroxy] phenyl} -6- (4-methoxyphenyl ) -1, 3,5-triazine, the 2,4-bis - {[4- (2-θthylhexyloxy) -2-hydroxy] phenyl} -6- [4- (2-methoxyethyl carboxyl ) -phenylamino] -1,3,5-triazine, the 2,4-bis - {[4- (3- (2-propyloxy) -2-hydroxy- propyloxy) -2-hydroxy] phenyl} -6- [4- (2-ethylcarboxyl) phenylamino] -1, 3,5-triazine, the 2,4-bis - {[4- (2-ethyl -hexyloxy) -2-hydroxy] -phθnyl} -6- (1-methyl-pyrrol-2-yl) -1, 3,5-triazine, the 2,4-bis - {[4-tris (trimethylsiloxysilylpropyloxy ) -2-hydroxy] phenyl} -6- (4-methoxyphenyl) -1,3,5-triazine, the 2,4-bis - {[4- (2 "-methylpropenyloxy) -2-hydroxy] phenyi } -6- (4-methoxyphe- nyl) -1,3,5-triazine and 2,4-bis - {[4- (1M ', 1', 3 ', 5', ^{5, 5,} - Heρtamethylsiloxy-2 '' - methyl-propyloxy) -2-hydroxy] phenyl-6- (4-methoxyphenyl) -1,3,5-triazine.

An advantageous broadband filter for the purposes of the present invention is 2,2'-methylene-bis- (6- (2H-benzotriazol-2-yl) -4- (1, 1, 3,3-tetramethylbutyl) -phenol) [INCI : Bisoctyltriazole], which is characterized by the chemical structural formula

is identified and is available under the trade name Tinosorb® M from CIBA Chemical GmbH.

An advantageous broadband filter in the sense of the present invention is also the 2- (2H-benzotriazole ^ -ylH-methyl-β-p-methyl-S-II.SSS-tetramethyl-1-KtrimethylsilylJoxyjdisiloxanyl] propyl] phenol (CAS no .: 155633-54-8) with the INCI name Drometrizole Trisiloxane, which is characterized by the chemical structural formula

is marked. The UV-B filters can be oil-soluble or water-soluble. Advantageous oil-soluble UV-B filter substances are e.g. E.g .: 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; 2,4,6-trianilino- (p-carbo-2'-ethyl-1'-hexyloxy) - 1,3,5-triazine; Esters of benzalmalonic acid, preferably 4-methoxybenzalmalonic acid di (2-ethylhexyl) ester; Esters of cinnamic acid, preferably 4-methoxycinnamic acid (2-ethylhexyl) ester, 4-methoxycinnamic acid isopentyl ester; Derivatives of benzophenone, preferably 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxy-4-methylbenzophenone, 2,2 ^, -dihydroxy-4-methoxybenzophenone and UV filters bound to polymers.

Advantageous water-soluble UV-B filter substances are e.g. B. salts of 2-phenylbenzimidazole-5-sulfonic acid, such as its sodium, potassium or triethanolammonium salt, and the sulfonic acid itself; Sulfonic acid derivatives of 3-benzylidene camphor, such as. B. 4- (2-oxo-3-bornylidene methyl) benzenesulfonic acid, 2-methyl-5- (2-oxo-3-bornylidene methyl) sulfonic acid and salts thereof.

A further light protection filter substance to be used advantageously according to the invention is ethylhexyl-2-cyano-3,3-diphenylacrylate (octocrylene), which is available from BASF under the name Uvinul ^® N 539 and is distinguished by the following structure:

It can also be of considerable advantage to use polymer-bound or polymeric UV filter substances in preparations according to the present invention, in particular those as described in WO-A-92/20690. Benzoxazole derivatives such as, in particular, 2,4-bis- [5-1 (dimethylpropyl) benzoxazol-2-yl- (4-phenyl) -imino] -6- (2-ethylhexyl) imino-1 are also particularly advantageous according to the invention , 3,5-triazine with the CAS No. 288254-16-0, which for example is sold under the The name Uvasorb® K2A is available, as well as hydroxy benzophenones such as, in particular, the 2- (4'-diethylamino-2'-hydoxybenzoyl) benzoic acid hexamate or aminobenzophenone, which is available under the Uvinul A Plus.

It may also be advantageous, if appropriate, to incorporate further UV-A and / or UV-B filters into cosmetic or dermatological preparations, for example certain salicylic acid derivatives such as 4-isopropylbenzyl salicylate, 2-ethylhexyl salicylate (= octyl salicylate), homomenthyl salicylate.

The list of the UV filters mentioned, which can be used in the sense of the present invention, should of course not be limiting. Furthermore, the compositions according to the invention can contain antioxidants to protect the cosmetic preparation itself or to protect the constituents of the cosmetic preparations from harmful oxidation processes.

The antioxidants are advantageously selected from the group consisting of amino acids (eg glycine, histidine, tyrosine, tryptophan) and their derivatives, imidazoles (eg urocanic acid) and their derivatives, peptides such as D, L-camosin, D-camosin, L- Camosin and its derivatives (e.g. Anserin), carotenoids, carotenes (e.g. α-carotene, ß-carotene, lycopene) and their derivatives, retinol, aurothioglucose, propylthiouracil and other thiols (e.g. thioredoxin, glutathione, cysteine, cystine, cystamine and their glycosyl -, N-acetyl, methyl, ethyl, propyl, amyl, butyl and lauryl, palmitoyl, oleyl, γ-linoleyl, cholesteryl and glyceryl esters) and their salts, dilauryl thiodipropionate, Distearyl thiodipropionate, thiodipropionic acid and their derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts) as well as sulfoximine compounds (e.g. buthioninsulfoximines, homocystinsulfoximines, buthioninsulfones, penta-, hexa-, heptathioninsulfoximines) in very low tolerable dosages (for example, very low tolerable doses) pmol up to μmol / kg), also (metal) chelators (eg α-hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin), α-hydroxy acids (eg 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 (e.g. γ-linolenic acid, linoleic acid, oleic acid), folic acid and their derivatives, alanine diacetic acid, flavonoids, polyphenols, catechins, vitamin C and derivatives (e.g. ascorbyl palmitate, Mg -Ascorbyl phosphate, ascorbyl acetate), tocopherols and derivatives (eg vitamin E acetate), and konferyl benzoate of benzoin, rutinic acid and its derivatives, ferulic acid and its derivatives, butylated hydroxytoluene, butylated hydroxyanisole, nordihydroguajak resinic acid, nordihydrophyroxyne, trihydroxybenzate, trihydric acid, trihydric acid, trihydric acid, trihydric acid, trihydroxy acid, de- derivatives, mannose and their derivatives, zinc and its derivatives (e.g. ZnO, ZnSO ₄ ) selenium and its derivatives (e.g. selenomethionine), stilbenes and their derivatives (e.g. stilbene oxide, trans-stilbene oxide) and the derivatives suitable according to the invention (salts, esters, ethers , Sugars, nucleotides, nucleosides, peptides and lipids) of these active ingredients. The amount of the antioxidants (one or more compounds) in the preparations is preferably 0.001 to 30% by weight, particularly preferably 0.05 to 20% by weight, in particular 1 to 10% by weight, based on the total weight of the preparation ,

Cosmetic and therapeutic preparations according to the invention advantageously also contain inorganic pigments based on metal oxides and / or other metal compounds which are sparingly soluble or insoluble in water, in particular the oxides of titanium (TiO ₂ ), zinc (ZnO), iron (eg Fe O ₃ ), Zirconium (ZrO ₂ ), silicon (SiO), manganese (e.g. MnO), aluminum (AI ₂ O ₃ ), cerium (e.g. Ce ₂ O ₃ ), mixed oxides of the corresponding metals and mixtures of such oxides. Pigments based on TiO _{2 are} particularly preferred. For the purposes of the present invention, it is particularly advantageous, although not essential, if the inorganic pigments are present in hydrophobic form, ie that they have been treated to be water-repellent on the surface. This surface treatment can consist in that the pigments are provided with a thin hydrophobic layer by methods known per se. Such a method consists, for example, in that the hydrophobic surface layer is produced after a direction according to n TiO ₂ + m (RO) ₃ Si-R '-> n TiO ₂ (surface), n and m being stoichiometric to be used at will Parameters, R and R 'the desired organic residues. For example, hydrophobized pigments shown in analogy to DE-OS 33 14 742 are advantageous.

Advantageous TiO ₂ pigments are available, for example, under the trade names MT 100 T from TAYCA, M 160 from Kemira and T 805 from Degussa.

Preparations according to the invention, especially if crystalline or microcrystalline solids, for example inorganic micropigments, are to be incorporated into the preparations according to the invention, also anionic, nonionic and / or amphoteric re surfactants included. Surfactants are amphiphilic substances that can dissolve organic, non-polar substances in water.

The hydrophilic parts of a surfactant molecule are mostly polar functional groups, for example -COO ^" , -OSO ₃ ^2" , -SO ₃ ^' , while the hydrophobic parts generally represent non-polar hydrocarbon radicals. Surfactants are generally classified according to the type and charge of the hydrophilic part of the molecule. Four groups can be distinguished here, namely anionic surfactants, cationic surfactants, amphoteric surfactants and nonionic surfactants.

Anionic surfactants generally have carboxylate, sulfate or sulfonate groups as functional groups. In an aqueous solution they form negatively charged organic ions in an acidic or neutral environment. Cationic surfactants are characterized almost exclusively by the presence of a quaternary ammonium group. In aqueous solution they form positively charged organic ions in an acidic or neutral environment. Amphoteric surfactants contain both anionic and cationic groups and accordingly behave like anionic or cationic surfactants in aqueous solution depending on the pH. They have a positive charge in a strongly acidic environment and a negative charge in an alkaline environment. In the neutral pH range, however, they are zwitterionic, as the following example should illustrate: pH = 2 RNH ₂ ⁺ CH ₂ CH ₂ COOH X (X ^" = any anion, eg Cl ^" )

pH = 7 RNH ₂ ⁺ CH ₂ CH ₂ COO-

pH = 12 RNHCH ₂ CH ₂ COO ^" B ⁺ (B ⁺ = any cation, e.g. Na ⁺ )

Polyether chains are typical of non-ionic surfactants. Non-ionic surfactants do not form ions in an aqueous medium.

Anionic surfactants to be used advantageously are: Acylamino acids (and their salts), such as (1) acylglutamates, for example sodium acylglutamate, di-TEA-palmitoylaspartate and sodium caprylic / capric glutamate; (2) acyl peptides, for example palmitoyl-hydrolyzed milk protein, sodium cocoyl-hydrolyzed soy protein and sodium / potassium cocoyl-hydrolyzed collagen; (3) sarcosinates, for example myristoyl sarcosin, TEA-lauroyl sarcosinate, sodium lauroyl sarcosinate and sodium cocoyl sarcosinate; (4) taurates, for example sodium lauroyl taurate and sodium methyl cocoyl taurate; (5) acyl lactylates such as lauroyl lactylate and caproyl lactylate; (6) Alanines;

Carboxylic acids and derivatives such as lauric acid, aluminum stearate, magnesium alkanolate and zinc undecylenate; Ester carboxylic acids, for example calcium stearoyl lactylate, laureth-6 citrate and sodium PEG-4 lauramide carboxylate; Ether carboxylic acids, for example sodium laureth-13 carboxylate and sodium PEG-6 cocamide carboxylate;

Carboxylic acids, ester carboxylic acids and ether carboxylic acids preferably contain 1 to 50 and in particular 2 to 30 carbon atoms. Phosphoric acid esters and salts, such as, for example, DEA-oleth-10-phosphate and dilureth-4-phosphate;

Sulfonic acids and salts, such as (1) acyl isethionates, for example sodium / ammonium cocoyl isethionate; (2) alkylarylsulfonates; (3) alkyl sulfonates, for example sodium coconut monoglyceride sulfate, sodium C ₁₂ -ι olefin sulfonate, sodium lauryl sulfoacetate and magnesium PEG-3 cocamide sulfate; (4) sulfosuccinates, for example dioctyisodium sulfosuccinate, disodium laureth sulfosuccinate, disodium lauryl sulfosuccinate and disodium undecyleneamido MEA sulfosuccinate;

Schwefelsäureester such as (1) alkyl ether sulfate, for example sodium, ammonium, magnesium, MIPA, TIPA Lau rethsulfat sulfate, sodium and sodium C ₁₂ - ₁₃ Parethsu I- fat; (2) alkyl sulfates, e.g. sodium, ammonium and TEA lauryl sulfate.

Cationic surfactants to be used advantageously are alkylamines, alkylimidazoles, ethoxylated amines and quaternary surfactants and esterquats.

Quaternary surfactants contain at least one N atom that is covalently linked to 4 alkyl or aryl groups. Regardless of the pH value, this leads to a positive charge. Alkyl betaine, alkyl amidopropyl betaine and alkyl amidopropyl hydroxysulfain are advantageous. The cationic surfactants used according to the invention can furthermore preferably be selected from the group of quaternary ammonium compounds, in particular Benzyltrialkylammonium chlorides or bromides, such as Benzyldimethylstea- rylammoniumchlorid, also alkyltrialkylammonium, for example cetyltrimethylammonium ammonium chloride or bromide, alkyldimethylhydroxyethylammonium chlorides or bromides, dialkyldimethylammonium chlorides or bromides, Alkylamidethyltrimethylammonium- ether sulfates, alkylpyridinium salts, for example, lauryl or Cθtylpyrimidiniumchlorid, imidazoline derivatives and compounds with cationic character such as amine oxides, for example alkyldimethylamine oxides or alkylaminoethyldimethylamine oxides. Cetyltrimethylammonium salts are particularly advantageous.

Amphoteric surfactants to be used advantageously are (1) acyl- / dialkylethylenediamine, for example sodium acylamphoacetate, disodium acylamphodipropionate, disodium alkyl amphodiacetate, sodium acylamphohydroxypropylsulfonate, disodium acylamphodiacetate and sodium acylamphopropionate; (2) N-alkyl amino acids, for example aminopropyl alkyl glutamide, alkyl aminopropionic acid, sodium alkyl imidodipropionate and lauroamphocarboxyglycinate. Nonionic surfactants to be used advantageously are (1) alcohols; (2) alkanolamides such as Cocamide MEA / DEA / MIPA; (3) amine oxides such as cocoamidopropylamine oxide; (4) esters formed by esterification of carboxylic acids with ethylene oxide, glycerin, sorbitan or other alcohols; (5) ethers, for example ethoxylated / propoxylated alcohols, ethoxylated / propoxylated esters, ethoxylated /, propoxylated glycerol esters, ethoxylated / propoxylated cholesterols, ethoxylated / propoxylated triglyceride esters, ethoxylated propoxylated lanolin, ethoxylated / propoxylated polysiloxanes, such as propoxylated POEglycosides and propoxylated POEglycos and ethoxylated Lauryl glucoside, decyl glycoside and cocoglycoside; (6) sucrose esters, ethers; (7) polyglycerol esters, diglycerol esters, monoglycerol esters; (8) Methyl gluosester, ester of hydroxy acids. It is also advantageous to use a combination of anionic and / or amphoteric surfactants with one or more nonionic surfactants.

The surface-active substance can be present in the preparations according to the invention in a concentration between 1 and 95% by weight, based on the total weight of the preparations. Preparations for medical use do not differ in their composition from cosmetic products and can also contain the substances mentioned above. They differ from them primarily in that they have to go through a special approval process. The invention is explained in more detail below on the basis of exemplary embodiments. In the examples, all figures relate to% by weight, unless stated otherwise. In all of these it is possible in individual cases that the above-mentioned concentration values are slightly exceeded or fallen short of and that preparations according to the invention are nevertheless obtained. In view of the wide-ranging variety of suitable components of such preparations, this is not unexpected for the person skilled in the art, so that he knows that the present invention will not be left behind in the event of such exceeding or falling short.

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.

Example 1: Preparation of PIT Emulsions By mixing the components listed in the table, phase inversion temperature emulsions (PIT emulsions) of the composition likewise given were prepared. SsDNA was used as the oligoribonucleotide.

Table 1: PIT emulsions

Analog PIT formulations were obtained by using MITF (SequenceNameComp 2) or p-protein (SequenceNameComp 14) antisense oligonucleotides or 0.1% by weight of a mixture of equal parts of Anti-SequenceNameComp 5, Anti-SequenceNameComp 15 and Anti-SequenceNameComp 18 received. The expression anti-MITF-ssDNA (SequenceNameComp 1) or anti-MITF-ssDNA (SequenceNameComp 3) denotes MITF antisense oligonucleotides which hybridize with the sequence SequenceName 1 or SequenceName 3. The other terms used in this and the other examples for the oligonucleotides used are to be understood analogously.

Example 2: Production of creams based on oil-in-water emulsions

By mixing the components shown in the table, creams of the composition likewise given were prepared.

Table 2: O / W creams

Table 2: O / W creams (continued)

Example 3: Preparation of water-in-oil emulsions By mixing the components shown in the table, water-in-oil emulsions of the composition likewise given were prepared.

Table 3: W / O emulsions

Table 3: W / O emulsions (continued)

Analog emulsions were obtained using p-protein (SequenceNameComp 13 and 14) or 0.1% by weight of a mixture of equal parts of SequenceNameComp 2, 5 and 7 and SequenceNameComp 13 and 14. Example 4: Preparation of hydrodispersions By mixing the components listed in the table, hydrodispersions of the composition likewise given were prepared. Table 4: Hydrodispersions

Analog emulsions were obtained using p-protein (SequenceNameComp 13 and 15) or 0.1% by weight of a mixture of equal parts of SequenceNameComp 1, 2 and 5 and SequenceNameComp 13 and 15.

Example 5: Preparation of a gel cream By mixing the components specified in the table, a gel cream of the composition likewise given was prepared. The pH of the gel cream was then adjusted to 6.0.

Table 5: Gel cream

Analog gel creams were prepared using MITF (SequenceNameComp 2, 3 and 5) or pProtein (SequenceNameComp 13, 16 and 17) antisense oligonucleotides or 0.1% by weight of a mixture of equal parts of SequenceNameCo p 13 , 16 and 17 and SequenceNameComp 2, 3 and 5.

Example 6: Preparation of a cream based on a water-in-oil emulsion. By mixing the components given in the table, a cream of the composition likewise given was prepared on the basis of a water-in-oil dispersion.

Table 6: W / O cream

Analog creams were made using MITF (SequenceNameComp 1, 2, 5 and 7 or p-protein (SequenceNameComp 14, 15 and 19) antisense oligonucleotides or 0.1% by weight of a mixture of equal parts of these antisense oligonucleotides.

Example 7: Preparation of a cream based on a water-in-oil-in-water emulsion

By mixing the components specified in the table, a cream of the composition likewise specified was prepared on the basis of a water-in-oil-in-water dispersion.

Table 7: W / O W cream

Analog creams were obtained by using the MITF antisense oligonucleotides (SequenceNameComp 1 and 5) or 0.1% by weight of a mixture of equal parts of SequenceNameComp 13 and 21 and SequenceNameComp 1 and 5.

Claims

claims

1. oligonucleotide or a physiologically acceptable salt thereof, which is able to hybridize with an mRNA or a gene sequence which encode one or more structures involved in the pigmentation of the skin and / or the hair, these in the pigmentation of the skin and / or the structures involved in (I) the actual melanin synthesis (melanosome structures) and / or in the (II) expression of these melanosome structures and / or in (III) transfer of the melanosomes (into the keratinocytes).

2. Oligonucleotide according to claim 1, characterized in that the expression in the structure involved in the melanin synthesis is the transcriptin factor MITF.

3. Oligonucleotide according to one of the preceding claims, characterized in that it can hybridize with one or more of the sequences SequenceName 1 to SequenceName 12.

4. Oligonucleotide according to one of the preceding claims, characterized in that it has the region of nucleotide 1381 downstream, the region of nucleotide 121 to 1380, the region of nucleotide 121 to 453, also referred to as the translation initiating region, the region of nucleotide 120 upstream, the region adjacent to nucleotide 121 to 150 and / or the start sequence can hybridize in each case based on the target sequence "Human 075030" MAO-TF "" (NCBI Acc: NM_000248).

5. Oligonucleotide according to claim 1, characterized in that the p protein is involved in the expression of the structure involved in melanin synthesis.

6. Oligonucleotide according to claim 5, characterized in that it can hybridize with one or more of the sequences SequenceName 13 to SequenceName 24.

7. oligonucleotide according to claim 5 or 6, characterized in that it with the region of nucleotide 2570 downstream, the region of nucleotide 53 to 2569, the region of nucleotide 53 to 169, also referred to as the translation initiating region, the region of nucleotide 52 upstream, the region adjacent to nucleotide 53 to 85 and / or the start sequence can hybridize in each case based on the target sequence “Human 004671”; “p protein” (EMBL ID: HSPPRO AC M99564).

8. Oligonucleotide according to one of the preceding claims, characterized in that it inhibits the expression of the gene of the structure involved in the pigmentation of skin and / or hair by at least 25%.

9. Oligonucleotide according to one of the preceding claims, characterized in that it inhibits the expression of the gene of the structure involved in the pigmentation of skin and / or hair by at least 50%.

10. Oligonucleotide according to one of the preceding claims, characterized in that it deviates from the target sequence based on a length of 20 base pairs in a maximum of 0 to 2 base pairs.

11. Oligonucleotide according to one of the preceding claims, characterized in that it is homologous to a portion of the gene of the structure involved in the pigmentation of skin and / or hair, the sense strand on the 5 'side by two adenosine residues and on the 3' side is flanked by two thymidine residues or by one thymidine and one cytosine residue.

12. Oligonucleotide according to one of the preceding claims, characterized in that it carries two deoxythymidine residues at the 3 'end.

13. Oligonucleotide according to one of the preceding claims, characterized in that it is integrated one or more times in an expression vector.

14. Oligonucleotide according to one of the preceding claims, characterized in that one or more phosphate groups are replaced by phosphorothioate, methylphosphonate and / or phosphoramidate groups.

15. Oligonucleotide according to one of the preceding claims, characterized in that one or more ribose or deoxyribose residues are replaced by amino acid residues or morpholine residues.

16. Oligonucleotide according to one of the preceding claims, characterized in that one or more ribose or deoxyribose residues are modified by fluorine, alkyl or O-alkyl residues.

17. Oligonucleotide according to one of the preceding claims, characterized in that it contains one or more alpha nucleosides.

18. A pharmaceutical or cosmetic composition containing one or more oligonucleotides according to one of the preceding claims or a physiologically tolerable salt thereof.

19. The composition of claim 20 for topical use.

20. The composition according to claim 20 or 21, characterized in that it contains several oligonucleotides which inhibit the expression of several different structures involved in the pigmentation of skin and / or hair.

21. The composition according to claim 20 or 21, characterized in that it contains several oligonucleotides, the different sequence regions of the same gene one on the actual melanin synthesis (melanosome structures; Tyrosianse) and / or on the expression of these melanosome structures (MITF) unαVoder structure (PAR-2) involved in the transfer of the melanosomes (into the keratinocytes).

22. Composition according to one of the preceding claims, characterized in that it contains 0.00001 to 10 wt .-% oligonucleotide.

23. Composition according to one of the preceding claims, characterized in that it contains 1 to 5 different oligonucleotides.

24. Composition according to one of the preceding claims, characterized in that it contains only those oligonucleotides that inhibit the expression of one or more structures involved in the pigmentation of skin and skin.

25. Composition according to one of the preceding claims, characterized in that it is in the form of a solution, cream, ointment, lotion, hydrodispersion, Lipodispersion, emulsion, Pickering emulsion, a gel, a solid stick or as an aerosol.

26. Use of an oligonucleotide or a physiologically acceptable salt thereof or a preparation according to one of the preceding claims for the production of a cosmetic or therapeutic composition for topical application.

27. Use of an oligoribonucleotide or a physiologically acceptable salt thereof according to one of the preceding claims for the production of a cosmetic or therapeutic agent for skin care or treatment of undesirable pigmentation of the skin or hair.

28. Use according to any one of claims 29 to 30 for the treatment of changes or damage to the pigmentation on skin or hair, which are caused by UV radiation in the skin, dryness, roughness and flaccidity of the skin, wrinkling, the reduced regreasing due to Sebaceous glands, and an increased susceptibility to mechanical stress (cracking), for the treatment of photodermatosis, the symptoms of senile xerosis, photoaging and a breakdown of the connective tissue of the skin, which are associated with undesirable pigmentation of the skin or hair.