Composition for the topical treatment of the stratum corneum

Abstract

The present invention relates to a composition for the treatment of the human stratum corneum comprising at least one organic acid having at least two functional groups, wherein at least one functional group is a carboxylic acid, and a water-soluble inorganic polyvalent salt, as well as to the use of said composition.

Description

[0001] 226139PWO Dr. Wolff

[0002] Composition for the topical treatment of stratum corneum

[0003] The present invention relates to a composition for the treatment of the human stratum corneum (horny layer of the skin) comprising at least one organic acid with at least two functional groups, wherein at least one functional group is a carboxylic acid, and a water-soluble inorganic polyvalent salt, and its use.

[0004] The term stratum corneum (horny layer) refers to the outermost layer of human skin epithelial tissue, which is composed of several layers of closely connected epithelial cells. Epithelial tissue is one of the four basic tissue types – the other three being muscle, nerve, and connective tissue. Epithelial tissue has several characteristic properties: for example, epithelia do not contain blood vessels. The cells of the epithelial tissue are separated from the connective tissue by the basement membrane, through which they are supplied with nutrients.

[0005] Epithelial tissue covers internal and external body surfaces. The skin, as the largest human organ, is the most significant example of such epithelial tissue. Although the skin performs numerous functions—including thermoregulation, immune defense, and sensory perception—its primary function is as a barrier and protective layer. This barrier prevents the body from drying out and simultaneously protects against the penetration of external substances, including UV radiation, microorganisms, and foreign chemicals.

[0006] The effective barrier function of the skin is primarily provided by the stratum corneum, the outermost layer of the epidermis. While the epidermis as a whole forms the outer protective layer, it is specifically the stratum corneum that defines the skin's mechanical, chemical, and physical resistance. This layer consists of anucleate, flattened, and brick-like corneocytes, whose individual cells are connected via corneodesmosomes involving cadherins and calcium ions (Ca3-). 2+The corneocytes are connected to each other by transmembrane glycoproteins from the group of adhesion proteins. In these corneocytes, the original cell membrane is replaced by the so-called cornified envelope, an insoluble structure of cross-linked proteins such as loricrin and involucrin, which completely encloses the corneocyte and, together with the highly dense bundles of keratin filaments located inside the cell, gives it considerable mechanical stability. 226139PWO Dr. Wolff

[0007] Furthermore, a lamellar lipid matrix is ​​located between the corneocytes, which additionally contributes to sealing the stratum corneum and plays a significant role in minimizing transepidermal water loss. The combination of high mechanical strength and diffusion resistance forms the basis for the stability and functionality of the skin barrier, with an increase in protein density, and in particular an increase in keratin density in the stratum corneum, correlating positively with the moisture content of the stratum corneum and the integrity of the skin barrier.

[0008] The natural pH of the skin surface typically ranges between 4 and 7. Beneath the stratum corneum lies the remaining epidermis, which consists of various continuously differentiating layers of keratinocytes. The epidermis rests on the mesodermal connective tissue of the dermis (corium), to which it is firmly interlocked via papilla-like projections and ridges. The dermis supplies nutrients to the avascular epidermis and contains the receptors responsible for touch, pain, and temperature sensation.

[0009] To maintain its vital barrier function, the epidermis renews itself through the continuous formation and differentiation of keratinocytes from the basal germ layer approximately every 30 days.

[0010] The outermost layer of the stratum corneum (horny layer) is composed of multiple, brick-like layers of fully differentiated corneocytes (typically 12 to 20 layers) and effectively protects the deeper, more sensitive layers of skin from external influences. A disruption of this barrier function can manifest clinically in symptoms such as irritation, redness, itching, scaling, and fissures.

[0011] Cosmetic and dermatological preparations for skin care have been known for a long time. These are typically oil-in-water (O / W) or water-in-oil (W / O) emulsions based on mixtures of long-chain fatty acids, mono- and diglycerides, ethoxylated fatty acid esters, nonpolar lipids, fatty alcohols, lipophilic thickeners, hydrogenated polyisobutenes, or polar lipids. Many of these formulations are intended to support the skin barrier by delivering lipids to the skin from the outside.

[0012] However, such externally applied lipids have several disadvantages: Their penetration depth into the skin is usually shallow, which can lead to an unpleasantly greasy feeling. Externally applied lipids typically only reach the uppermost layers of the stratum corneum, which consists of 12 to 20 layers. After contact with water or surfactants, the lipids are easily washed away; friction from clothing further removes them. Moreover, with increasing age, the activity of keratinocytes decreases, thus reducing the body's own regeneration and the formation of the natural skin barrier.

[0013] This creates a need for improved pharmaceutical and cosmetic treatment methods, particularly a need for formulations that specifically strengthen the structure and function of the stratum corneum, improve the integrity of the stratum corneum, and simultaneously enhance skin feel and appearance, while exhibiting no or only negligible side effects. There is a particular need for formulations that penetrate the stratum corneum and increase both the cohesion and, especially, the mechanical stability of the corneocytes, support the intercellular lipid matrix, and thus not only improve the barrier function of the epidermis but also compensate for skin impairments caused by pre-existing conditions such as poorly healing wounds, irritations, inflammations, and others.

[0014] Based on this, the object of the present invention was to provide a well-tolerated composition for the treatment of the human stratum corneum, in particular for increasing the protein density in the stratum corneum and for improving or stabilizing hydration and the barrier function dependent thereon. Furthermore, this composition should be suitable for topical application and overcome the disadvantages of compositions known from the prior art.

[0015] In particular, the object of the present invention was to provide an effective and well-tolerated composition that supports epidermal regeneration by improving the structural integrity of the stratum corneum and positively influences wound healing. At the same time, the composition should exhibit good formulation and processing properties.

[0016] This problem was surprisingly solved by the composition according to the invention and its use.

[0017] A first aspect of the invention relates to a composition for the treatment of the human stratum corneum, comprising 226139PWO Dr Wolff

[0018] (A) at least one organic acid with at least two functional groups, wherein at least one functional group is a carboxylic acid, and

[0019] (B) a water-soluble inorganic polyvalent salt, the composition having a pH between 2.0 and 8.0, particularly between pH 3.5 and 5.5, and especially between pH 4.0 and 5.0.

[0020] The composition according to the invention preferably further comprises

[0021] (C) at least one amino acid, an amino acid derivative and / or any mixture thereof.

[0022] In a preferred embodiment, the treatment of the stratum corneum according to the invention with a composition disclosed herein relates to a densification of the keratin-rich protein structures of the corneocytes.

[0023] In a preferred embodiment, the treatment of the stratum corneum according to the invention comprises the stabilization and / or improvement of the moisture content of the stratum corneum.

[0024] Without being bound to any specific theory, it can be assumed that treating the stratum corneum with a composition according to the invention leads to a change in the tertiary and / or quaternary structures of the proteins and peptides, in particular the keratin fibers. According to the invention, this ultimately results in increased diffusion resistance and improved barrier performance against pathogens and chemical foreign substances. Additionally, the structural change leads to a "hydrophobization" of the protein matrix, causing the skin to swell less and become less permeable to water.

[0025] Without being bound to any theory, it is assumed that the organic acid (A) in the composition according to the invention adjusts the isoelectric point of the protein structures of the corneocytes. It is further assumed that the multivalent ions of the salt (B) subsequently contribute to cross-linking of the protein structures, so that a synergistic strengthening effect on the skin barrier is achieved according to the invention.

[0026] Strengthening the skin's chemical barrier can be measured, for example, by reducing the penetration of model substances, particularly Raman-active, skin-compatible organic molecules such as caffeine. Preferably, the treatment according to the invention leads to a reduction in the penetration of model substances, especially caffeine, through and / or into the stratum corneum by at least 10%, preferably at least 20%, more preferably at least 30%, and even more preferably 30-70%, particularly after an application period of two weeks with the composition according to the invention, and especially measured at a penetration depth of 40-60 pm.

[0027] 226139PWO Dr. Wolff

[0028] Organic acid (A)

[0029] The composition according to the invention comprises an organic acid with at least two functional groups, wherein at least one functional group is a carboxylic acid.

[0030] The term "functional group," as used herein, describes a group comprising at least one heteroatom. In general, functional groups of a chemical compound significantly determine its properties and reactivity. The heteroatoms of the functional groups can be chosen independently from O, N, P, or S.

[0031] According to the invention, preferred functional groups can be independently selected from the group comprising -COOH, -(C=O)-, -C(=O)-O-, -OH , -SH, -NR2, wherein R is in turn independently selected from H and Methyl, Ethyl or Propyl, wherein H is preferred.

[0032] Preferably, the organic acid (A) comprises at least two O-functional groups. O-functional groups are functional groups comprising oxygen, in particular functional groups comprising only oxygen as a heteroatom(s). Preferred O-functional groups include -COOH, -(C=O)-, -C(=O)-O-, and -OH. Particularly preferred are all functional groups of the organic acid (A) O-functional groups.

[0033] The organic acid (A) is preferably a carboxylic acid and, in particular, preferably a polyhydric carboxylic acid with pKa values ​​between 1.5 and 10. Particularly preferred is (A) a polyhydric carboxylic acid with pKa values ​​between 2.5 and 6.0. In preferred embodiments, the organic acid (A) can be a dicarboxylic acid.

[0034] The organic acid (A) is preferably selected from the group consisting of malic acid, maleic acid, tartaric acid, fumaric acid, gallic acid, gluconic acid, glycolic acid, mandelic acid, lactic acid, succinic acid, pyruvic acid, L-(+)-ascorbic acid, D-quinic acid, citric acid, glutaric acid, malonic acid and / or mixtures thereof.

[0035] Malic acid is particularly preferred. Other particularly preferred acids are succinic acid, maleic acid, and fumaric acid, as well as mixtures thereof.

[0036] Malic acid (2-hydroxysuccinic acid) according to the invention comprises dextrorotatory D-malic acid and levorotatory L-malic acid, as well as racemates and any mixtures of D- and L-malic acid. 226139PWO Dr. Wolff

[0037] In general, according to the invention, organic acids that occur as enantiomers can be used in their D or L or R or S configuration, as a racemate (1 :1 mixture of the enantiomers) or in any mixtures.

[0038] Preferably, the composition according to the invention comprises 0.001 to 10 wt.%, in particular 0.01 to 5 wt.%, more preferably 0.1 to 2.0 wt.%, more preferably 0.3 to 2.0 wt.% and even more preferably 0.4 to 2.0 wt.%, of organic acid (A).

[0039] Unless otherwise stated, the term "% by weight" herein always refers to the total weight of the composition.

[0040] Water-soluble inorganic polyvalent salt (B)

[0041] The composition according to the invention contains a water-soluble inorganic polyvalent salt.

[0042] The inorganic salt preferably exhibits either slight solubility in water, i.e., a solubility greater than 100 g / l at 20°C, or moderate solubility in water, i.e., between 10 and 100 g / l at 20°C. Slight solubility is preferred. Preferably, the inorganic salt is present in the composition according to the invention completely dissolved.

[0043] The inorganic polyvalent salt is preferably divalent or trivalent. Divalent salts are preferred. The composition according to the invention may additionally comprise inorganic monovalent salts. In other preferred embodiments, the composition does not include any monovalent inorganic salts.

[0044] The inorganic polyvalent salt preferably comprises at least one cation selected from the group consisting of Mg 2+ , Ca 2+ , Sr 2+ , Zn 2+ , Al 3+ , Fe 3+ , La 3+ , or any mixture thereof.

[0045] Preferably, the inorganic polyvalent salt is a calcium salt. In a further preferred embodiment, the composition according to the invention contains both a calcium and a magnesium salt. Magnesium salts, in particular, have a soothing and moisturizing effect. They support the skin barrier, can reduce feelings of tightness, and are used to treat dry and / or sensitive skin. 226139PWO Dr. Wolff

[0046] Calcium is used in skin. Calcium-containing salts play a less dominant role in cosmetic formulations. Calcium generally supports the skin's natural regeneration and helps to stabilize the upper layer of skin, but it is usually only used in small amounts because it can have a drying effect in higher concentrations.

[0047] The anion of the inorganic polyvalent salt is derived from an inorganic acid. Preferred inorganic acids can be selected from the group comprising hydrochloric acid (examples: NaCl, MgCh, CaCh, AlCh), sulfuric acid (example: magnesium sulfate (MgSCU)), carbonic acid (example: lanthanum carbonate (La₂(CC>3)₃)₃), phosphoric acid (examples: zinc phosphate (Zns(PO₄)₂) and calcium phosphate (Ca₃(PO₄)₂)), boric acid (example: sodium borate (Na₂B₄O₆)), phosphorous acid (example: calcium phosphonate CaHPCh), and phosphinic acid (example: calcium hypophosphite (Ca(H₂PO₄)₂)). According to the invention, phosphinic acid may be particularly preferred.

[0048] Phosphinic acid, also known as hypophosphorous acid, is one of the acids of phosphorus and has the molecular formula H3PO2. Its salts are called phosphinates or hypophosphites. According to the invention, divalent salts of phosphinic acid are used. The additional use of monovalent salts is not excluded.

[0049] According to the invention, calcium hypophosphite (Ca^PCh ) is particularly preferred as a water-soluble inorganic polyvalent salt (B).

[0050] According to the invention, compositions containing NaCl and / or magnesium sulfate (MgCl₂>4), particularly MgCh₂ and / or CaCh₂, are also preferred. Magnesium chloride is highly water-soluble and supports the skin barrier. It has a moisturizing effect and is perceived by many as soothing, especially for dry or irritated skin. Furthermore, magnesium plays a role in various enzymatic processes in the skin. Calcium chloride, on the other hand, is found much less frequently in cosmetic formulations. Calcium chloride is a mineral that is fundamentally important for the skin. It stimulates cell regeneration and contributes in particular to the stabilization and regeneration of the epidermis. Due to its strong hygroscopicity, it can draw moisture from the skin if the concentration or the overall formulation is not optimally balanced.In the compositions according to the invention, this problem is solved by a coordinated overall formulation. According to the invention, the combination of calcium chloride and magnesium chloride, in particular, in combination with an organic acid (A) as defined herein, has a positive effect on the epithelial tissue.

[0051] The composition according to the invention contains, in preferred embodiments, 0.001 to 30.0 wt.%, in particular 0.01 to 10 wt.%, preferably 0.1 to 2.0 wt.%, particularly preferably 0.3 to 1.0 wt.% of water-soluble inorganic polyvalent salt.

[0052] The composition according to the invention contains, in preferred embodiments, 0.001 to 30.0 wt.%, in particular 0.01 to 10 wt.%, preferably 0.1 to 2.5 wt.% calcium hypophosphite.

[0053] In a further preferred embodiment, the composition according to the invention comprises a calcium salt and a magnesium salt, wherein the calcium cations and the magnesium cations are present in a weight ratio of 1:2 to 1:4.5, preferably in a weight ratio of 1:3.0 to 1:3.5. These ratios are within the range of those found in seawater.

[0054] Preferably, the calcium salt is present in an amount of 0.1 to 2.5 wt.%, particularly preferably in an amount of 0.8 to 1.5 wt.%, and the magnesium salt in an amount of 0.3 to 8 wt.%, preferably in an amount of 3.0 to 4.5 wt.%.

[0055] In other preferred embodiments, the composition according to the invention does not include any salts of phosphinic acid, in particular no calcium salts of phosphinic acid and especially preferably no calcium hypophosphite.

[0056] It may also be preferred that the composition according to the invention does not include a zinc salt and / or a compound with free thiol groups. In particular, the composition preferably does not include dithiothreitol, cysteine, N-acyl-cysteine, especially N-acetylcastone, and / or 2-mercaptoethanol.

[0057] composition

[0058] The composition according to the invention has a pH value between 2.0 and 8.0.

[0059] The pH value of the composition according to the invention is preferably in the range between 3 and 7, particularly preferably in the range between 4 and 6, and most preferably in the pH range between 4.0 and 5.0. As already described, the pH value of the composition can also be adjusted by pH regulators. 226139PWO Dr. Wolff

[0060] The composition preferably comprises at least one water-soluble calcium salt.

[0061] The formula primarily contains glycerin. Among other things, glycerin helps to retain moisture in the skin and can thus help prevent dry and chapped skin. Glycerin is suitable for all skin types.

[0062] The composition preferably has a viscosity between 100 and 150,000 mPsec (determined 0-4 days after production).

[0063] All viscosity data are based on a measurement according to DIN 53019-1 :2008-09 with a Haake RheoStressl type rheometer (ThermoFisher Scientific) at 20 °C and a shear rate of 10 / s in plate-plate geometry (rotating body PP60 Ti).

[0064] The pH value can be adjusted using pH regulators. pH regulators are substances that can maintain a specific pH range, preferably between pH 5.5 and 8.0.

[0065] Examples of pH regulators include acetic acid, acetates, lactic acid, lactates, malic acid, malates, fumaric acid, citric acid, citrates, tartaric acid, tartrates, orthophosphates, di-, tri- and polyphosphates, hydrochloric acid, chlorides, sulfuric acid, sulfates, hydroxides, oxides, adipic acid, adipates, gluconic acid, gluconates, phosphoric acid, calcium carbonate, or a hydrate thereof. A preferred example of a pH regulator that can be added when a lower pH is desired is phosphoric acid (H3PO4).

[0066] According to the invention, embodiments which contain neither DMG nor a salt of phosphinic acid and in particular no calcium hypophosphite are also preferred.

[0067] Amino acid / amino acid derivative (C)

[0068] The composition according to the invention may preferably comprise at least one amino acid, an amino acid derivative and / or any mixtures thereof.

[0069] The composition according to the invention can comprise any amino acid. Preferred amino acids are arginine, asparagine, valine, serine, cysteine, tryptophan, glutamine, histidine, methionine, lysine, proline, leucine and / or glycine. 226139PWO Dr. Wolff

[0070] Arginine plays an important role in cell division and DNA synthesis. Arginine supports skin hydration and has a regenerative effect on damaged skin cells.

[0071] Asparagine is involved in collagen formation and strengthens the skin surface by improving stability, elasticity and firmness.

[0072] Valine has a moisturizing effect and an antioxidant effect.

[0073] Serine has moisturizing, skin-soothing, and anti-inflammatory properties, supports cell regeneration, and has an antioxidant effect. By improving skin hydration, serine helps increase skin elasticity, resulting in firmer skin.

[0074] Tryptophan strengthens the skin's natural moisture barrier and ensures a radiant complexion. Tryptophan regulates the skin's oil production and reduces age spots and redness.

[0075] Glutamine promotes the formation of skin cells and prevents or slows down the breakdown of tissue structures and skin aging.

[0076] Histidine has a soothing effect on the skin and antioxidant properties.

[0077] Methionine has a protective effect on the skin due to its antioxidant properties.

[0078] Lysine is involved in collagen synthesis and strengthens the skin's surface by improving its stability, elasticity, and firmness. Lysine also plays a crucial role in repairing skin damage.

[0079] Proline, leucine, and glycine reduce fine lines and wrinkles. Proline, like glycine, is involved in collagen production. Glycine is involved in the formation of elastin and collagen. It not only ensures the skin's elasticity and firmness but also prevents tissue breakdown. Together, proline, leucine, and glycine reduce the appearance of crow's feet.

[0080] Amino acid derivatives within the meaning of the present invention are chemical compounds derived from amino acids. Amino acid derivatives are formed when the amino acid structure is modified by chemical reactions, such as by modifying the functional groups of the amino acids (amino group or carboxylic acid group) or by introducing additional substituents. Example 226139PWO Dr. Wolff

[0081] Modifications include hydroxylation, carboxylation, phosphorylation, methylation and / or acetylation.

[0082] Preferred amino acid derivatives include amino acids with one or more modifications, which are independently selected from the group consisting of hydroxylation, carboxylation, phosphorylation, methylation and acetylation.

[0083] Amino acid derivatives that play a role in pharmaceuticals and / or cosmetics are known to those skilled in the art and include neurotransmitters (e.g., dopamine (derived from tyrosine), serotonin (derived from tryptophan), GABA (gamma-aminobutyric acid (derived from glutamate)), hormones (e.g., thyroxine (derived from tyrosine), adrenaline (derived from tyrosine)), alkaloids (e.g., histamine (derived from histidine)), fatty acid derivatives (e.g., sphingosine (derived from serine)), ceramides (lipid compounds made from sphingolipid-like amino acid derivatives), sodium PCA (salt of pyrrolidone carboxylic acid (derived from glutamic acid)), glutathione (tripeptide made from glutamic acid, cysteine, and glycine), amino acid-based surfactants (e.g., sodium cocoyl glutamate), and / or dimethylglycine or a dimethylglycinate.

[0084] The composition according to the invention preferably comprises 0.0001 to 10 wt.%, in particular preferably 0.01 to 5 wt.%, an amino acid, an amino acid derivative and / or any mixtures thereof.

[0085] The composition according to the invention preferably comprises the amino acid derivative (C) dimethylglycine or a dimethylglycinate.

[0086] Dimethylglycine (N,N-dimethylglycine) occurs in plants, animals, and humans, although it is produced in humans only in very small amounts. It is formed as an intermediate in the multi-step biosynthesis of glycine from choline through the transamination of betaine by betaine homocysteine ​​methylase.

[0087] N,N-Dimethylglycine, also (dimethylamino)acetic acid (DMG), is represented by the following chemical formula 1: 226139PWO Dr. Wolff

[0088] According to the invention, not only dimethylglycine but also its salts, solvates, and hydrates are used. These are preferably pharmaceutically or cosmetically acceptable salts of dimethylglycine. The salt is particularly preferably a water-soluble salt with a solubility in water of at least 10 g / l at 20°C.

[0089] In a preferred presentation form, the salt of dimethylglycine is an alkali, alkaline earth or ammonium salt of dimethylglycine.

[0090] Examples include sodium, potassium, calcium, magnesium, and ammonium salts. In the ammonium salts, the ammonium cation bears one to four alkyl groups, each with one to four carbon atoms independent of one another. The sodium and potassium salts of dimethylglycine are preferred, especially the sodium salt of dimethylglycine, namely sodium dimethylglycinate (sodium N,N-dimethylglycinate).

[0091] In an alternative preferred embodiment, the salt of dimethylglycine can be the salt of an inorganic acid containing dimethylglycine.

[0092] Examples of salts of dimethylglycine with an inorganic acid are the hydrochloride, hydrobromide, hydroiodide, hydrogen sulfate, sulfate, hydrogen sulfite, sulfite, hydrogen carbonate, carbonate, monophosphate, diphosphate, and triphosphate of dimethylglycine, as well as mixtures thereof. The hydrochloride of dimethylglycine, namely dimethylglycine hydrochloride (N,N-dimethylglycine hydrochloride), is particularly preferred.

[0093] According to the invention, preferably the dimethylglycine and / or salt of dimethylglycine is selected from the group consisting of dimethylglycine, sodium dimethylglycinate and dimethylglycine hydrochloride.

[0094] According to the invention, preferably the dimethylglycine and / or salt of dimethylglycine is selected from the group consisting of dimethylglycine, sodium dimethylglycinate and dimethylglycine hydrochloride.

[0095] The composition according to the invention preferably comprises 0.0001 to 10 wt.%, more preferably 0.01 to 5 wt.%, even more preferably 0.1 to 2.0 wt.% dimethylglycine or a dimethylglycinate or any mixtures thereof.

[0096] In other preferred embodiments, the invention comprises 226139PWO Dr Wolff

[0097] The composition contains no amino acid derivatives and especially no DMG.

[0098] Further components of the composition according to the invention

[0099] The composition according to the invention may further comprise at least one additional active ingredient and / or additive.

[0100] Antibacterial substances are preferred, among others. Zinc is a preferred substance according to the invention with antibacterial properties. The composition according to the invention may preferably include zinc in an amount of 0.01–30.0 wt.%, preferably 0.1–5.0 wt.%, in each case based on the total weight of the composition.

[0101] Preferably, the active ingredient is selected from the group consisting of biotin, menthol, taurine, ectoin, ubiquinone-10, echinacea, panthenol, nicotinamide, tocopherol, tocopherol acetate, urea and salt of pyrrolidone carboxylic acid and any mixtures thereof.

[0102] Biotin, also known as vitamin B7 or vitamin H, is a water-soluble vitamin from the B complex. According to the invention, biotin can strengthen the skin. In the composition according to the invention, biotin can be present in an amount of 0.001–10.0 wt.%, preferably 0.005–1.0 wt.%, based on the total weight of the composition.

[0103] Menthol is a monocyclic monoterpene alcohol and can be added to the composition according to the invention as a blood circulation-stimulating agent. In addition, menthol can provide a refreshing sensory stimulation of the skin.

[0104] According to the invention, taurine or 2-aminoethanesulfonic acid also acts as an antioxidant, further stabilizing the skin.

[0105] Ectoine is a cyclic amino acid and exists in aqueous solution as a mesomeric-stabilized zwitterion. According to the invention, ectoine has a moisturizing effect and stabilizes the natural structure of the skin. Furthermore, ectoine has been shown to protect against UV radiation and may be helpful in the treatment of inflammatory diseases.

[0106] Ubiquinone-10 (Q10 or Coenzyme Q10) is a quinone derivative. Q10, which belongs to the ubiquinone pool, is considered an antioxidant and, according to the invention, has a stabilizing effect on the skin. 226139PWO Dr. Wolff

[0107] According to the invention, echinacea has a soothing effect on the skin and relieves itching and tightness. Furthermore, echinacea can stimulate blood circulation in the skin.

[0108] Panthenol (also known as dexpanthenol) plays a role in wound healing of the skin, particularly the epidermis. After being absorbed through the skin, it is converted into pantothenic acid, which plays a crucial role in cell regeneration. Panthenol also increases the skin's moisture retention capacity, thus nourishing it and improving its elasticity. Furthermore, anti-inflammatory and itch-relieving effects have been described.

[0109] Nicotinamide (also known as niacinamide and nicotinamide) is the amide of nicotinic acid and is also called vitamin B3. In addition to other properties, such as reducing oxidative stress, niacinamide has a skin-protective effect according to the invention.

[0110] Tocopherol, also known as vitamin E, is a fat-soluble substance with skin-strengthening antioxidant properties.

[0111] Tocopherol acetate exhibits antioxidant properties and, according to the invention, has a stabilizing effect on the skin.

[0112] Urea attracts water and binds it in the skin. This helps to moisturize the skin and improve its hydration. This property is particularly beneficial for dry skin. The skin becomes more resistant to external influences such as cold, wind, or dry air. In higher concentrations (typically 5-10%), urea also has a keratolytic effect, meaning it gently removes dead skin cells from the skin's surface. This can help to smooth the skin and improve the appearance of rough or flaky skin. Due to its moisturizing and exfoliating properties, urea can also be used in anti-aging products. It helps to soften fine lines and wrinkles by improving skin texture. Urea also has anti-inflammatory properties and can help soothe irritated skin.Therefore, it is frequently used in products for sensitive skin or for skin diseases such as eczema or psoriasis.

[0113] Pyrrolidone carboxylic acid and its salts play an important role in skincare. The sodium salt of pyrrolidone carboxylic acid occurs naturally in human skin and protects it by maintaining a certain level of hydration in the outermost layer of the skin. 226139PWO Dr. Wolff

[0114] To maintain the epidermis from dehydration. By stimulating the epidermal differentiation process, it can enhance the protective function of the skin barrier. According to the invention, the sodium and zinc salts of pyrrolidone carboxylic acid are particularly preferred.

[0115] In a preferred embodiment of the invention, the composition according to the invention contains at least one further active ingredient selected from menthol, biotin, niacinamide, panthenol, ectoin, ubiquinone-10, taurine, pantolactone, echinacea, tocopherol, tocopherol acetate, urea, salt of pyrrolidone carboxylic acid and any mixtures thereof, each in a proportion of 0.001 wt.% to 10.0 wt.%, more preferably 0.005 wt.% to 7.50 wt.%, even more preferably 0.01 wt.% to 5.0 wt.%, in particular 0.1 wt.% to 3.0 wt.%, based on the total weight of the composition.

[0116] In one embodiment, the composition comprises a surfactant. The surfactant can be an anionic, non-ionic, cationic, or zwitterionic surfactant. Preferably, the surfactant is an anionic or non-ionic surfactant, in particular a mild (i.e., especially skin-friendly) anionic or non-ionic surfactant. According to the invention, non-ionic surfactants are used especially because of their very good emulsifying properties and their excellent skin-care properties. Anionic surfactants are preferred because they exhibit particularly high cleaning performance. The preferred surfactants of the present invention are described, among other places, in the book "Surfactants and Interfacial Phenomenology" by Milton Rosen and Joy Kunjappu, John Wiley & Sons, Ine. Verlag, 2012, 4th edition.

[0117] In a preferred embodiment, the surfactant is an anionic surfactant selected from alkyl sulfonates, alkyl sulfates, alkyl ether sulfates, alkyl phosphates, alkyl sarcosinates, alkyl taurates, amino acid surfactants, and mixtures thereof. Particularly preferred is a surfactant selected from alkyl sulfates, alkyl sarcosinates, alkyl taurates, alkyl glutamate (such as sodium cocoyl glutamate / disodium cocoyl glutamate), alkyl glycinate, alkyl alaninate (such as sodium cocoyl alaninate), and mixtures thereof. Also preferred, due to their cleaning performance, are fatty alcohol polyglycerol ether sulfates, monoglyceride sulfates, mono- and / or dialkyl sulfosuccinates, fatty acid isethionates, and o-olefin sulfonates.

[0118] In one embodiment, the surfactant is a nonionic surfactant (also referred to as a nonionic emulsifier). Non-limiting examples include glycerol fatty acid esters, polyoxyethylene ethers of one or more fatty alcohols, alkoxylated fatty acid alkyl esters, 226139PWO Dr. Wolff

[0119] Polyglycerol ethers of fatty alcohols, polyglycerol esters of fatty acids, polyethylene glycol and / or polypropylene glycol ethers, fatty acid amides, alkylphenol polyglycol ethers, amine oxides and alkyl polyglucosides.

[0120] In one embodiment, the surfactant is selected from the group consisting of glycerol fatty acid esters, polyoxyethylene ethers of one or more fatty alcohols, polyglycerol ethers of fatty alcohols, polyglycerol esters of fatty acids and mixtures thereof.

[0121] In one embodiment, the surfactant comprises a cationic surfactant, such as a quaternary surfactant. Quaternary surfactants contain at least one nitrogen atom covalently bonded to four alkyl or aryl groups. This results in a positive charge, independent of pH. Advantageous examples include alkyl betaine, alkylamidopropyl betaine, and alkylamidopropyl hydroxysulfaine.The cationic surfactants used according to the invention can preferably be selected from the group of quaternary ammonium compounds, in particular benzyltrialkylammonium chlorides or bromides, such as benzyldimethylstearylammonium chloride, furthermore alkyltrialkylammonium salts, for example cetyltrimethylammonium chloride or bromide, alkyldimethylhydroxyethylammonium chlorides or bromides, dialkyldimethylammonium chlorides or bromides, alkylamidethyltrimethylammonium ether sulfates, alkylpyridinium salts, for example laurylpyrimidinium or cetylpyrimidinium chloride, hmdazoline derivatives and compounds with cationic character such as amine oxides, for example alkyldimethylamine oxides or alkylaminoethyldimethylamine oxides. The following are particularly advantageous:

[0122] to use cetyltrimethylammonium salts.

[0123] In a preferred embodiment, the composition according to the invention is an oil-in-water (O / W) emulsion in which the surfactant components described above (also referred to as emulsifier components) have an HLB value of 8-40, preferably 8-22, and particularly preferably 8-18. In another preferred embodiment, the composition according to the invention is a water-in-oil (W / O) emulsion in which the surfactant components described above (also referred to as emulsifier components) have an HLB value of 3-8, preferably 4-5. The calculation method for the combined HLB value is known and can be referred to as the Griffin or Davies method (Ullmann's Encyclopedia of Industrial Chemistry, Part 9, Emulsion, 2005; Surfactant Application Encyclopedia, Liu Cheng, Beijing Industry Press, 1997).

[0124] Additives may be selected from the group consisting of emollients, 226139PWO Dr. Wolff

[0125] Preservatives, stabilizers, perfumes, antioxidants, rheology modifiers, thickeners, conditioning agents, dyes, pearlescent agents, brighteners, solvents, sunscreens and combinations thereof.

[0126] Preferred additives are those commonly used in emulsions for skin treatment. The at least one additive may be present in a proportion of 0.01 wt.% to 12.0 wt.%, more preferably from 0.25 wt.% to 10.0 wt.%, and particularly from 1.0 wt.% to 7.0 wt.%.

[0127] Emollients, also called re-fatting agents or superfatting agents, are lipophilic substances that can prevent a disruptive effect on the epidermal barrier function. Examples of emollients include lanolin, squalane, liquid paraffin, vegetable oils, silicones, and cetyl palmitate.

[0128] Preservatives are substances used for preservation by killing microorganisms that degrade the composition and / or inhibiting their growth. Preferably, the preservatives can be selected from the group consisting of benzoic acid, benzoic acid derivatives, sorbic acid, sorbic acid derivatives, salicylic acid, salicylic acid derivatives, phenoxyethanol, parabens, and combinations thereof. In a preferred embodiment, sodium benzoate and / or potassium sorbate are used as preservatives in the composition according to the invention. Sodium benzoate releases benzoic acid and potassium sorbate releases sorbic acid in a slightly acidic environment. Both acids are attributed with antimicrobial properties.

[0129] Stabilizers can protect light-sensitive components from radiation and are preferably UV absorbers such as benzophenone derivatives.

[0130] The addition of fragrances can give the composition a pleasant scent. Examples include perfumes, which are well-known to experts.

[0131] An antioxidant is a chemical compound that slows down or completely prevents the oxidation of other components in the composition according to the invention. Examples of suitable antioxidants include citric acid, ascorbic acid, and butylhydroxyanisole.

[0132] Rheology modifiers and thickening agents can help to improve the application properties of the composition according to the invention. (See 226139PWO Dr. Wolff)

[0133] The addition of sodium chloride (table salt) can be considered as a rheology modifier and thickening agent. The addition of sodium chloride allows the flowability of the composition according to the invention to be influenced within certain limits and adjusted to the required level. Naturally occurring gelling agents, preferably selected from agar, xanthan gum, cellulose and / or cellulose derivatives, or alginic acid, can also be used as thickeners.

[0134] For the purposes of this application, "skincare products" should be understood to mean substances that care for the skin. Hydrolyzed wheat protein, shea butter, urea, and allantoin have a skin-care effect.

[0135] Hydrolyzed wheat protein primarily has moisturizing properties.

[0136] Shea butter has an intensive nourishing effect and provides the skin with essential fatty acids. Shea butter is particularly suitable for dry and rough skin areas and leaves a pleasant feeling on the skin.

[0137] Urea has a moisturizing effect and helps to smooth rough skin.

[0138] Allantoin promotes skin regeneration. It supports the formation of new skin cells and aids the healing of minor injuries or cracks.

[0139] Dyes are optionally used to give the composition according to the invention a characteristic color, so that it can be easily distinguished from other products.

[0140] A solvent or solvent mixture commonly used by those skilled in the art in this field can be employed. Preferred solvents are ethanol or butylene glycol, in particular 1,4-butylene glycol, propylene glycol, and isopropyl alcohol. Ethanol is preferred. These solvents may preferably be present in the composition according to the invention in an amount of 0.1 to 70% by weight. They are most preferably present in an amount of 0.1 to less than 5.0% by weight. Furthermore, solvents aid in the penetration of the active ingredients and thus enhance their efficacy.

[0141] Suitable sunscreens include UVA filters and / or UVB filters and / or inorganic pigments. 226139PWO Dr. Wolff

[0142] Advantageously, emulsions according to the invention can contain substances that absorb UV radiation in the UVB range, wherein the total amount of the filter substances is, for example, 0.1 wt.% to 30 wt.%, preferably 0.5 to 10 wt.%, in particular 1 to 6 wt.%, based on the total weight of the emulsion.

[0143] UVB filters can be oil-soluble or water-soluble. Examples of oil-soluble substances include: 3-benzylidene camphor and its derivatives, e.g., 3-(4-methylbenzylidene)camphor; 4-aminobenzoic acid derivatives, preferably 4-(dimethylamino)benzoic acid (2-ethylhexyl) ester, 4-(dimethylamino)benzoic acid amyl ester; esters of cinnamic acid, preferably 4-methoxycinnamic acid (2-ethylhexyl) ester, 4-methoxycinnamic acid isopentyl ester; esters of salicylic acid, preferably salicylic acid (2-ethylhexyl) ester, salicylic acid. (4-isopropylbenzyl) esters, salicylic acid homomethyl esters, derivatives of benzophenone, preferably 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxy-4'-methylbenzophenone, 2,2'-dihydroxy-4-methylbenzophenone, esters of benzalmalonic acid, preferably 4-methoxybenzalmalonic acid di(2-ethylhexyl) esters, 2,4,6-trianilino-(p-carbo-2'-ethyl-r-hexyloxy)-l,3,5-triazine.

[0144] Advantageous water-soluble substances include: 2-phenylbenzimidazole-5-sulfonic acid and its salts, e.g., sodium, potassium, or triethanolammonium salts; sulfonic acid derivatives of benzophenones, preferably 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid and its salts; sulfonic acid derivatives of 3-benzylidene camphor, such as 4-(oxo-3-bornylidenemethyl)benzenesulfonic acid, 2-methyl-5-(2-oxo-3-bornylidenemethyl)sulfonic acid, and their salts.

[0145] The emulsions according to the invention can also contain UVA filters. Such filter substances are preferably derivatives of dibenzoylmethane, in particular 1-(4'-tert-butylphenyl)-3-(4'-methoxyphenyl)propane-1,3-dione and 1-phenyl-3-(4-isopropylphenyl)propane-1,3-dione. Emulsions containing combinations of the aforementioned filters are also the subject of the invention. The same amounts of UVA filter substances can be used as those specified for UVB filter substances.

[0146] The emulsions according to the invention can also contain inorganic pigments commonly used in cosmetics to protect the skin from UV radiation. These are oxides of titanium, zinc, iron, zirconium, silicon, manganese, aluminum, cerium, and mixtures thereof. Pigments 226139PWO Dr. Wolff based on titanium dioxide are particularly preferred. The amounts specified for the above combinations can be used.

[0147] Application of the composition

[0148] The composition according to the invention is particularly suitable for the treatment of the human stratum corneum, the outer layer of the epithelial tissue.

[0149] The composition according to the invention can be used for medical and / or cosmetic purposes.

[0150] Accordingly, the invention preferably comprises the composition according to the invention in a method for treating and / or preventing damage to the stratum corneum.

[0151] The cosmetic, non-medical use of the composition according to the invention is also preferred.

[0152] The stratum corneum is the outermost layer of the epidermis. It consists of dead squamous epithelial cells (corneocytes) that lack a nucleus or other cell organelles. It is primarily composed of keratin, a protein that forms an effective outer barrier of the skin. Among other things, keratin prevents water evaporation. The thickness of the stratum corneum varies in different parts of the body and depends mainly on the mechanical stress placed on the skin. It can range from 12 to 200 cell layers, depending on the region.

[0153] Epithelial tissue itself is one of the four basic tissue types, which also include muscle, nerve, and connective tissue. Epithelia are cell groups that cover and line surfaces and perform a wide variety of functions.

[0154] A basic distinction can be made based on the location and function of the tissue. For example, a distinction is made between glandular epithelium as part of the glandular tissue and surface epithelium, which is further subdivided based on different cell arrangements into: simple epithelium, pseudostratified epithelium, stratified epithelium, and transitional epithelium (urothelium).

[0155] The treatment of keratinized multilayered 226139PWO Dr. Wolff is particularly preferred.

[0156] Epidermal epithelium. Although stratified epithelium can be keratinized or non-keratinized, the present invention relates to the treatment of stratified squamous epithelium. Squamous epithelium is an epithelium whose outermost cell layer consists of flat, interconnected cells.

[0157] Particularly preferred is the treatment of the stratum corneum of the epidermis, i.e., the epithelial tissue of the skin, which histologically consists of stratified squamous epithelium. Accordingly, the treatment, care, and / or prevention of skin damage represent preferred embodiments.

[0158] The composition according to the invention is applied topically. “Topical” describes an external, usually local, application.

[0159] The compositions according to the invention are preferably skin care products (i.e., treatments such as treatments, lotions, shower gels, day or night creams, face creams, facial fluids, face masks, skin protectant creams, cleansers, sunscreens, deodorizing compositions, shaving creams, aftershave balms, and / or toners) and not (purely) styling products. In other words, the topical compositions of the invention focus on the medical / pharmaceutical or cosmetic treatment of the skin.

[0160] The present invention further relates to the use of the composition according to the invention for treating the stratum corneum of the skin. Accordingly, the stratum corneum of the body skin, including the upper and lower body, as well as including the hands, arms, legs and feet, and / or the facial skin, including the neck and nape, is particularly preferred according to the invention. The skin preferably excludes the scalp, i.e., the skin beneath the hair.

[0161] In a preferred embodiment, the treatment of the stratum corneum of the skin relates to purely optical-aesthetic improvement, such as creating a smoother and simply more beautiful skin appearance. However, according to the invention, further cosmetic / medical effects are particularly preferably achieved, such as improved protective function and strengthened barrier properties. In addition, wound healing is improved.

[0162] In other words, the use according to the invention leads to a densification of the keratin-rich protein structures of the stratum corneum, in particular to an increased 226139PWO Dr Wolff

[0163] Protein density of corneocytes. This structural improvement results in increased cohesion of the stratum corneum and improved homeostasis, particularly of the moisture content of the (entire) epidermis, and correlates with increased integrity of the stratum corneum, improved appearance, and improved protection against infections (microbial diseases).

[0164] Strengthening the skin's chemical barrier can be measured, for example, by reducing the penetration of model substances. Raman-active organic molecules, preferably those that are skin-compatible, such as caffeine or octocrylene, can be used as model substances. According to the invention, caffeine is preferred as a model substance. The treatment according to the invention preferably leads to a reduction in the penetration of model substances, particularly caffeine, through and / or into the stratum corneum by at least 10%, preferably at least 20%, more preferably at least 30%, and even more preferably 30-70%. In preferred embodiments, a reduction in penetration of at least 50% is achieved.The reduction in penetration is achieved particularly after an application period of two weeks with the composition according to the invention and can preferably be determined by measuring the penetration after two weeks of treatment compared to the penetration before treatment. During the two-week period, the treatment is preferably administered at least once daily, more preferably at least twice daily, and particularly twice daily. The penetration of the model substance is preferably measured at a penetration depth of 40–60 pm and can be performed using Raman spectroscopy, for example, using a confocal Raman system (e.g., highly sensitive confocal Raman system gen2-SCA®, RiverD International BV, Rotterdam, The Netherlands). The penetration depth of the model substance is preferably measured on the forearm. A detailed description of an exemplary measurement can be found below in the examples.

[0165] In medical applications, the invention encompasses both the therapeutic and prophylactic treatment of skin diseases. The treatment preferably addresses conditions that are directly or indirectly associated with an impairment of the stratum corneum and its barrier function. These diseases preferably include microbial skin infections, skin inflammations, rough skin, dry skin, skin irritations, itching, pruritus, allergies, psoriasis, psoriatic arthritis, eczema, scleroderma, atopic dermatitis, contact dermatitis, systemic lupus erythematosus, acne, and increased susceptibility to contact allergies due to a weakened stratum corneum barrier. 226139PWO Dr. Wolff

[0166] Another aspect of the invention relates to the composition according to the invention for use in the treatment and / or prevention of psoriasis, eczema, atopic dermatitis, neurodermatitis, skin lesions and / or atrophy. These diseases are also regularly associated with impairment of the stratum corneum and, in particular, with disturbed homeostasis of the stratum corneum barrier, so that stabilization and densification of the keratin-rich protein structures of the stratum corneum can at least contribute to alleviating the associated symptoms.

[0167] In another aspect, the use of the disclosed compositions according to the invention includes the treatment and / or prevention of wounds and / or scars and / or lichen sclerosus, which are regularly associated with an impairment of the barrier function of the stratum corneum.

[0168] The non-therapeutic (i.e., purely cosmetic) treatment of the stratum corneum includes, for example, the use of the composition in the treatment of cosmetic skin indications, in particular selected from rough skin, dry skin, sensitive skin, skin irritations, itching and pruritus, whereby strengthening and / or maintaining the integrity of the stratum corneum also contributes to the prevention of skin infections and the reduction of susceptibility to contact allergies.

[0169] The emulsions according to the invention are particularly effective in improving the barrier functions and barrier integrity of the stratum corneum, in promoting wound healing, in the treatment and / or prophylaxis of inflammatory skin conditions, in the treatment and / or prophylaxis of disorders associated with insufficient regeneration of the epidermis, as well as in improving the appearance of the skin, increasing the moisture content of the skin, promoting natural skin protection and / or revitalizing the skin.

[0170] Another aspect of the present invention relates to a composition for treating the human stratum corneum comprising

[0171] (A) 0.01 to 5 wt% malic acid,

[0172] (B) 0.01 to 4 wt% calcium hypophosphite,

[0173] (C) 0.01 to 5 wt% dimethylglycine and / or a salt thereof, wherein the composition has a pH between 4.0 and 6.0.

[0174] This composition is preferably a skin care product, specifically designed for topical application by Dr. Wolff (226139PWO).

[0175] 226139PWO Dr. Wolff

[0176] Brief description of the characters

[0177] Fig. 1: Diagram showing the division of the forearms of study participants into areas AD for the application of different formulations. Areas C1 and C2 are control areas where only the model substance was applied without prior treatment.

[0178] Fig. 2: Percentage change in the penetration of the model substance caffeine between DO and D14 in skin areas treated twice daily for 14 days with the specified formulations. Caffeine penetration was determined at a penetration depth of 40–60 pm using confocal Raman spectroscopy. The average change for 23 study participants is shown.

[0179] Fig. 3: Change in itching and tightness in the face after application of the specified formulations over a period of 28 days. Shown is the average change in parameters for a total of 49 subjects randomly assigned to the two treatment groups (comparison formulation 1 and formulation 2).

[0180] Examples

[0181] In the following example compositions, the quantities given correspond to the weight percentage of the finished composition.

[0182] Unless otherwise specified, the pH value of the exemplary compositions is between 2.0 and 8.0 and can be adjusted to ranges preferred according to the invention of 3.0 to 7, in particular between 4 and 6, and most preferably between 4.0 and 5.0.

[0183] Within the pH range according to the invention, the compositions reduce the ability of the stratum corneum to absorb moisture and generally increase its diffusion resistance to various substances, including water. This prevents, for example, excessive drying of the skin. At the same time, the skin barrier against the penetration of foreign substances is strengthened. Furthermore, the treatment according to the invention contributes to improving the appearance and feel of the skin. With a desirable, even, soft, and elastic appearance of the treated skin areas, excessive swelling in humid or wet environments, such as during housework, bathing, or showering, is thus avoided, for example. 226139PWO Dr. Wolff

[0184] Example 1: Skin care creams

[0185] 226139PWO Dr. Wolff

[0186] Example 2: Skin care cream

[0187] 226139PWO Dr. Wolff

[0188] Example 3: Skin care cream

[0189] 226139PWO Dr. Wolff

[0190] Example 4: Skin care cream

[0191] 226139PWO Dr. Wolff

[0192] Example 5: Skin care cream

[0193] 226139PWO Dr. Wolff

[0194] Example 6: Skin care creams

[0195] Skin care creams 6A-6J are supplied as O / W emulsions with pH = 4.5 ± 0.2.

[0196] 226139PWO Dr. Wolff

[0197] 226139PWO Dr. Wolff

[0198] Example 7: Skin care creams

[0199] Skin care creams 7A-7J are supplied as W / O emulsions with pH = 4.5 ± 0.2.

[0200] 226139PWO Dr. Wolff

[0201] 226139PWO Dr. Wolff

[0202] study

[0203] In a clinical study, the improvement of the skin's barrier properties through the use of formulations according to the invention was tested in comparison to comparator formulations. The following skin care creams were used, wherein formulations 1 and 2 correspond to examples 6J and 6E mentioned above, respectively:

[0204] In 23 study participants, the formulations were randomly applied to the AD areas of the forearms shown in Fig. 1 and applied twice daily for 2 weeks.

[0205] The barrier function of the skin was characterized by the penetration of a model substance (226139PWO Dr. Wolff) by determining the substance concentration at a penetration depth of 40–60 pm using confocal Raman spectroscopy. Caffeine, a 5% solution in water / propylene glycol at pH 6–7, was used as the model substance. A defined amount of the solution was applied to the test areas by a technician using a standardized method. Before measurement with the Raman spectroscope (highly sensitive confocal Raman system gen2-SCA®, RiverD International BV, Rotterdam, The Netherlands), the solution was left on the test areas for two hours to dry. At D14, the formulations were applied at least one hour before the model substance was applied.

[0206] The improvement in the skin's barrier properties is shown by comparing the penetration profiles at DO vs. D14, i.e., before treatment (DO) vs. after 2 weeks of treatment (D14). Figure 2 shows the percentage change in caffeine penetration between DO and D14.

[0207] Result:

[0208] By using the formulations according to the invention, the skin penetration of the model substance can be significantly reduced (see Fig. 2). This indicates an increased integrity of the skin barrier, which, according to the invention, is achieved through improved cohesion of the stratum corneum.

[0209] 226139PWO Dr. Wolff

[0210] Study 2

[0211] In a further clinical study, the skin compatibility and cosmetic efficacy of a formulation according to the invention, which was applied to the face, were evaluated.

[0212] 49 subjects with dry to very dry skin were randomly assigned to two groups. One group applied formulation 2 from study 1 at least once daily for 28 days, while the other group applied comparator formulation 1 from study 1 for the same period (see table in study 1 for formulations).

[0213] Facial skin was examined and assessed by a dermatologist before (DO) application of the product and after (D29) application. In addition, the subjects rated itching and tightness as subjective parameters. Figure 3 shows the average change in itching and tightness from DO to D29.

[0214] Result:

[0215] After 28 days of using the formulation according to the invention, both itching and the feeling of tightness improved more than after using the comparison formulation (see Fig. 3).

[0216] 226139PWO Dr. Wolff

[0217] The following items summarize the invention:

[0218] 1. Composition for the treatment of the human stratum corneum, encompassing

[0219] (A) at least one organic acid with at least two functional groups, wherein at least one functional group is a carboxylic acid, and

[0220] (B) a water-soluble inorganic polyvalent salt having a pH between 2.0 and 8.0.

[0221] 2. Composition according to Item 1, wherein the treatment includes the compaction of the protein structure, in particular the compaction of the keratin structure of the stratum corneum.

[0222] 3. Composition according to one of the preceding items, wherein the treatment includes stabilizing and / or improving the moisture content of the stratum corneum.

[0223] 4. Composition according to one of the preceding items, wherein the treatment leads to a reduction in the penetration of model substances, in particular caffeine, through and / or into the stratum corneum by at least 10%, preferably at least 20%, more preferably at least 30%, and even more preferably 30-70%, particularly after an application period of the composition of 2 weeks, particularly measured at a penetration depth of 40-60 pm.

[0224] 5. Composition according to one of the preceding items, comprising at least one amino acid, one amino acid derivative (C) and / or mixtures thereof.

[0225] 6. Composition according to one of items 1-4, which does not contain an amino acid or an amino acid derivative (C).

[0226] 7. Composition according to one of the preceding items, wherein the inorganic polyvalent salt contains at least one cation selected from the group consisting of Mg 2+ , Ca 2+ , Sr2+ , Zn 2+ , Al 3+ , Fe 3+ , La 3+ , or any mixture thereof.

[0227] 8. Composition according to one of the preceding items, containing at least one water-soluble calcium and / or magnesium salt, preferably a water-soluble calcium salt. 226139PWO Dr. Wolff

[0228] 9. Composition according to one of the preceding items, wherein the salt (B) is the calcium salt of phosphinic acid, i.e. calcium hypophosphite.

[0229] 10. Composition according to any of the preceding items, wherein the composition contains 0.001 to 30.0 wt.%, in particular 0.01 to 10 wt.%, preferably 0.1 to 2.0 wt.%, particularly preferably 0.3 to 1.0 wt.% calcium hypophosphite.

[0230] 11. Composition according to one of items 1-8, wherein the composition does not contain calcium hypophosphite, in particular does not contain any salt of phosphinic acid.

[0231] 12. Composition according to one of the preceding items, wherein the functional groups are selected from -COOH, -(C=O)-, -C(=O)-O-, -OH, -SH, -NR2, wherein R is independently selected from H and Methyl, Ethyl or Propyl, with H being preferred.

[0232] 13. Composition according to one of the preceding items, wherein the organic acid (A) comprises at least two O-functional groups, in particular wherein all functional groups of the organic acid (A) are O-functional groups, wherein O-functional groups are preferably selected from -COOH, -(C=O)-, -C(=O)-O- and -OH.

[0233] 14. Composition according to one of the preceding items, wherein the organic acid (A) is a polyhydric carboxylic acid with pKa values ​​between 1.5 and 10, preferably between 2.5 and 6.0.

[0234] 15. Composition according to one of the preceding items, wherein the pH value is in the range between 3 and 7, preferably in the range between 3.5 and 5.5, particularly in the pH range between 4.0 and 5.0.

[0235] 16. Composition according to one of the preceding items, wherein the organic acid (A) is selected from the group consisting of malic acid, maleic acid, tartaric acid, fumaric acid, gallic acid, gluconic acid, glycolic acid, mandelic acid, lactic acid, succinic acid, pyruvic acid, L-(+)-ascorbic acid, D-quinic acid, citric acid, glutaric acid, malonic acid and / or mixtures thereof.

[0236] 17. Composition according to one of the preceding items, where 226139PWO Dr. Wolff

[0237] Composition containing 0.001 to 10 wt.%, in particular 0.01 to 5 wt.%, more preferably 0.1 to 2.0 wt.%, more preferably 0.3 to 2.0 wt.% and even more preferably 0.4 to 2.0 wt.%, of organic acid (A).

[0238] 18. Composition according to one of the preceding items, wherein the organic acid (A) is a dicarboxylic acid.

[0239] 19. Composition according to one of items 1-5 and 7-18, which contains the amino acid derivative (C) dimethylglycine or a dimethylglycinate.

[0240] 20. Composition according to Item 19, which contains 0.0001 to 10 wt.%, preferably 0.01 to 5 wt.% dimethylglycine or a dimethylglycinate.

[0241] 21. Composition according to one of items 1-18, wherein the composition does not contain dimethylglycine or a salt of dimethylglycine.

[0242] 22. Composition according to one of the preceding items, wherein the

[0243] The composition also contains glycerin.

[0244] 23. Composition according to one of the preceding items, wherein the

[0245] The composition has a viscosity between 100 and 150,000 mP sec.

[0246] 24. Composition according to one of the preceding items, which contains antibacterial substances.

[0247] 25. Composition according to one of the preceding items, wherein the composition is designed for topical application.

[0248] 26. Composition according to one of the preceding items, which further comprises one or more active ingredients from the group consisting of biotin, menthol, taurine, ectoin, ubiquinone-10, echinacea, panthenol, nicotinamide, tocopherol, tocopherol acetate, urea and salt of pyrrolidone carboxylic acid.

[0249] 27. Composition for the treatment of the human stratum corneum, comprising

[0250] (A) 0.01 to 5 wt% malic acid,

[0251] (B) 0.01 to 4 wt% calcium hypophosphite, and

[0252] (C) 0.01 to 5 wt% dimethylglycine and / or a salt thereof, 226139PWO Dr Wolff wherein the composition has a pH between 4.0 and 6.0.

[0253] 28. Composition according to Item 27, wherein the treatment includes the compaction of the protein structure, in particular the compaction of the keratin structure of the stratum corneum.

[0254] 29. Composition according to item 27 or 28, wherein the treatment includes stabilizing and / or improving the moisture content of the stratum corneum.

[0255] 30. Composition according to one of items 27-29, wherein the treatment leads to a reduction in the penetration of model substances, in particular caffeine, through and / or into the stratum corneum by at least 10%, preferably at least 20%, more preferably at least 30%, and even more preferably 30-70%, in particular after an application period of the composition of 2 weeks, in particular measured at a penetration depth of 40-60 pm.

[0256] 31. Composition according to any of the preceding items for use in the treatment and / or prevention of damage to the human stratum corneum.

[0257] 32. Composition according to any of the preceding items for use in the treatment and / or prevention of psoriasis, eczema, atopic dermatitis, neurodermatitis, xerosis cutis (dry skin), pruritus (itching), skin lesions and / or atrophy.

[0258] 33. Composition according to one of the preceding items for use in the treatment and / or prevention of wounds and scars and / or lichen sclerosus.

[0259] 34. Cosmetic use of a composition according to one of items 1-30.

[0260] 35. Cosmetic use according to Item 34 for rough skin, dry skin, sensitive skin, skin irritations, itching and pruritus.

Claims

226139PWO Dr. Wolff Claims 1. Composition for the treatment of the human stratum corneum, encompassing (A) at least one organic acid with at least two functional groups, wherein at least one functional group is a carboxylic acid, and (B) a water-soluble inorganic polyvalent salt having a pH between 2.0 and 8.

0.

2. Composition according to claim 1, wherein the treatment comprises the densification of the protein structure, in particular the densification of the keratin structure of the stratum corneum, and preferably improves or stabilizes the moisture content of the stratum corneum.

3. Composition according to claim 1 or 2, wherein the treatment leads to a reduction in the penetration of model substances, in particular caffeine, through and / or into the stratum corneum by at least 10%, preferably at least 20%, more preferably at least 30%, and even more preferably 30-70%, particularly after an application period of the composition of 2 weeks.

4. Composition according to any of the preceding claims, comprising at least one amino acid, an amino acid derivative (C) and / or mixtures thereof.

5. Composition according to any one of the preceding claims, wherein the inorganic polyvalent salt contains at least one cation selected from the group consisting of Mg 2+ , Ca 2+ , Sr 2+ , Zn 2+ , Al 3+ , Fe 3+ , La 3+ , or any mixture thereof.

6. Composition according to one of the preceding claims, comprising at least one water-soluble calcium and / or magnesium salt, preferably a water-soluble calcium salt.

7. Composition according to any one of the preceding claims, wherein the salt (B) is the calcium salt of phosphinic acid, i.e., calcium hypophosphite, wherein the composition preferably comprises 0.001 to 30.0 wt.%, in particular 0.01 to 10 wt.%, more preferably 0.1 to 2.0 wt.%, particularly 43 226139PWO Dr. Wolff prefers to contain 0.3 to 1.0 wt.% calcium hypophosphite.

8. Composition according to any one of the preceding claims, wherein the organic acid (A) is a polyhydric carboxylic acid with pKa values ​​between 1.5 and 10, preferably between 2.5 and 6.0, preferably a dicarboxylic acid, and / or wherein the organic acid (A) is selected from the group consisting of malic acid, maleic acid, tartaric acid, fumaric acid, gallic acid, gluconic acid, glycolic acid, mandelic acid, lactic acid, succinic acid, pyruvic acid, L-(+)- ascorbic acid, D-quinic acid, citric acid, glutaric acid, malonic acid and / or mixtures thereof.

9. Composition according to any one of the preceding claims, wherein the pH value is in the range between 3 and 7, preferably in the range between 4 and 6, particularly in the pH range between 4.0 and 5.0, and wherein the composition contains 0.001 to 10 wt.%, particularly 0.01 to 5 wt.%, more preferably 0.1 to 2.0 wt.%, more preferably 0.3 to 2.0 wt.% and even more preferably 0.4 to 2.0 wt.%, of organic acid (A).

10. Composition according to any one of the preceding claims, wherein the amino acid derivative (C) dimethylglycine or a dimethylglycinate, preferably Contains 0.0001 to 10 wt.%, particularly preferably 0.01 to 5 wt.% dimethylglycine or a dimethylglycinate.

11. Composition according to any of the preceding claims, wherein the composition is designed for topical application, wherein the composition preferably has a viscosity between 100 and 150,000 mP sec.

12. Composition according to one of the preceding claims, which further comprises one or more active ingredients from the group consisting of biotin, menthol, taurine, ectoin, ubiquinone-10, echinacea, panthenol, nicotinamide, tocopherol, tocopherol acetate, urea and salt of pyrrolidone carboxylic acid, and / or glycerol, and / or antibacterial substances.

13. Composition for the treatment of human epithelial tissue comprising 44 226139PWO Dr. Wolff (A) 0.01 to 5 wt% malic acid, (B) 0.01 to 4 wt% calcium hypophosphite, and (C) 0.01 to 5 wt% dimethylglycine and / or a salt thereof, wherein the composition has a pH between 4.0 and 6.

0.

14. Composition according to claim 13, wherein the treatment comprises the densification of the protein structure, in particular the densification of the keratin structure of the stratum corneum, and preferably improves or stabilizes the moisture content of the stratum corneum.

15. Composition according to claim 13 or 14, wherein the treatment leads to a reduction in the penetration of model substances, in particular caffeine, through and / or into the stratum corneum by at least 10%, preferably at least 20%, more preferably at least 30%, and even more preferably 30-70%, particularly after an application period of the composition of 2 weeks.

16. Composition according to any one of claims 1 to 15 for use in the treatment and / or prevention of damage to the human stratum corneum, preferably comprising the treatment and / or prevention of psoriasis, eczema, atopic dermatitis, neurodermatitis, xerosis cutis (dry skin), pruritus (itching), skin lesions and / or atrophy, and / or for use in the treatment and / or prevention of wounds and scars and / or lichen sclerosus.

17. Cosmetic use of a composition according to any one of claims 1-15, preferably for rough skin, dry skin, sensitive skin, skin irritations, itching and pruritus. 45

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