Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
  • A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/16—Emollients or protectives, e.g. against radiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/007—Preparations for dry skin

Definitions

• a compatible solute or solute mixture for use in the prevention or treatment of diseases with barrier defects in epithelial tissues for use in the prevention or treatment of diseases with barrier defects in epithelial tissues
• the present invention relates to a compatible solute or solute mixture and to a composition comprising at least one solute or a solute mixture for use in the prevention or treatment of barrier defects of epithelial tissues associated with at least one bio-based noxious agent, in particular diseases comprising at least one barrier defect in at least one cell layer of at least an epithelial tissue, wherein at least one solute is selected from compounds of the formula I, the formula II, the physiologically acceptable salts of the formula I and formula II, the stereoisomeric forms of the compounds of the formula I, formula II and the physiologically acceptable salts of the stereoisomeric forms or a mixture of at least two of the aforementioned compounds.
• the at least one compatible solute, solute mixture and / or composition are provided in the form of a cosmetic, medical device, drug, an adjunct to any of the foregoing or as part of an in vitro diagnostic product (IVD).
• Compatible solutes also called osmolytes, are low molecular weight organic compounds. They are used as protective substances in cosmetic compositions as well as in medical products and pharmaceuticals.
• Animated factors are e.g. Insects, parasites and pests, pets and plants, which can cause adverse effects on human health through effects on the human body.
• Inanimate factors are components or compounds from the environment or from nature. Frequently inanimate factors are e.g. Secretions of the living factors, such as feces, toxins or components of the living factors, such as pollen, needles, secretions, etc. These can also, if you come into contact with the human organism, lead to a human health impairment.
• the above-mentioned animated and inanimate factors can be summarized as bio-based noxae.
• bio-based pollutants The burden of human and animal organisms on bio-based pollutants is omnipresent. On the way to work, at work, during leisure time and on vacation, the environment, space, air and water are enriched with a multitude of different bio-based pollutants.
• the use of ventilation systems that direct the outside air into the interior or through air conditioning systems, will facilitate the circulation and distribution of bio-based pollutants promoted. Due to seasonal differences, the exposure to bio-based pollutants varies depending on the season, temperature, wind and / or humidity.
• Bio-based pollutants can trigger different diseases with typical symptoms. Frequently, reactions occur on, under and / or in the skin. A reaction of the skin or general skin change is also called efflorescence. Efflorescences are primarily visible and / or palpable primitives of skin and / or subcutaneous disease, and include primary efflorescences (or primary lesions), i. Efflorescences, which have arisen without any intermediate stage from the healthy skin, and secondary efflorescences (or secondary lesions), that is, efflorescences that have arisen from primary lesions.
• the resulting diseases show symptoms such as e.g. Nausea, diarrhea, fever, edema, redness, etc.
• Diseases include superficial infections, internal inflammation, pneumonia, asthma, bronchial diseases, subcutaneous diseases, diseases of the gastrointestinal mucosa, etc.
• epithelial tissue the diseases triggered by bio-based noxae have at least partially damaged the epithelial tissue.
• the most common cause is a disturbed, defective or destroyed barrier function (selective permeability barrier) of the affected epithelial tissue.
• Epithelium is the tissue that lines the inner and outer surfaces of the body and functions as a barrier to foreign substances, such as skin. bio-based pollutants, fulfilled. Therefore, epithelial cells or epithelial tissue act as a barrier against mechanical injury, invading noxious agents, fluid loss and evaporation.
• epithelial tissue Characteristic of individual epithelial cells and epithelial tissue is their polarity.
• the epithelium (synonymous epithelial tissue) consists of polar cells that have a basal (synonymous basolateral) side and an apical (lumen) side. On the basal side they are in contact with the basement membrane and laterally via cell contacts with other cells.
• Epithelial tissue has no blood vessels, but the detection of cytokeratins is characteristic of the different epithelial tissues.
• the barrier achieved by the epithelial cells, particularly the selective permeability barrier, and cohesion are strengthened by the intercellular junctions.
• the so-called epithelial terminal block complex is formed by a unit (complex) of zonula occludens, zonula adhaerens and desmosomes and occurs in most single-layered epithelia.
• the epithelial terminal block complex ensures a selective permeability barrier in the space between the body cells (synonym intercellular space), which prevents an uncontrolled paracellular mass transfer between the body cells. This controls or prevents the penetration of bio-based pollutants. If the barrier described above, in particular the selective permeability barrier, has gaps or if the penetrating noxae are so small that they can nevertheless pass through the barrier, health impairments are the result in the sense of the invention.
• the affected person has various medicines, medical devices and cosmetics at their disposal.
• these preparations contain steroids, antibiotics, antimycotics, analgesics and / or other synthetic agents and adjuvants.
• the aforementioned preparations treat the infection e.g. by attacking the parasites, bacteria, viruses or fungi.
• the restoration of the barriers of the affected epithelial tissue is not promoted by these drugs. Instead, the body's own mechanisms, the immune system and specific expression factors, must restore the barrier.
• the abovementioned substance classes have the disadvantage that they frequently have strong side effects and / or can trigger allergic reactions in humans.
• the regeneration of the above-described epithelial, selective permeability barrier relies on the body's own vitality to restore the barrier function of epithelial tissues.
• it is often decreased and the body may be slow or unable to maintain or restore the barrier of epithelial tissues.
• a compound or a mixture which caused by bio-based noxious efflorescences, eczema, inflammation of the skin, the eye, the oral / nasal mucosa, respiratory diseases, fluid loss, dehydration of (mucous) skin, conjunctiva, cornea and / or prevents or reduces allergic reactions of epithelial tissues. It is also an object of the present invention to provide a compound or mixture for use in the prevention or treatment of the aforementioned health impairments and diseases comprising at least one barrier defect in at least one epithelial tissue. Furthermore, a composition comprising the above-described compound or mixture for use in the prevention or treatment of rashes of human or animal skin and mucosa is to be provided.
• Another object of the present invention is to provide cosmetic formulations and formulation for medical devices and medicaments containing the above-described solute and / or the above-described composition comprising the at least one compound for oral, nasal or topical administration.
• the object of the invention is to provide cosmetic products, medical products and medicaments for the prevention or treatment of barrier defects of epithelial tissues associated with at least one bio-based noxious agent, in particular of diseases comprising at least one barrier defect in at least one cell layer of at least one epithelial tissue.
• an object of the present invention is a compatible solute or solute mixture for use in the prevention or treatment of epithelial tissue barrier defects associated with at least one bio-based noxa, preferably disrupted and diminished selective permeability barrier, in particular diseases comprising at least one barrier defect in at least one cell layer of at least an epithelial tissue containing at least one compound selected from compounds of the formula I, the formula II, the physiologically acceptable salts of the formula I and formula II, the stereoisomeric forms of the compounds of the formula I, formula II and the physiologically tolerable salts of the stereoisomeric forms or a Mixture of at least two of the aforementioned compounds, wherein in formula I
• R1 H or alkyl
• R2 H, COOH, COO-alkyl or CO-NH-R5,
• R3 and R4 are each independently H or OH
• R5 H, alkyl, amino acid residues, dipeptide residues or tripeptide residues
• alkyl an alkyl radical with CrC 4 carbon atoms.
• Alkyl in the meaning of the invention comprises linear, cyclic and branched alkyl radicals comprising methyl (-CH 3), ethyl (-C 2 H 5), propyl (-CH 2 CH 2 CH 3 or -CH (CH 3) 2 ) and butyl (-CH 2 CH 2 CH 2 CH 3, H 3 C (CH) CH 2 CH 3, - CH 2 CH (CH 3) 2 and C (CH 3 ) 3 ).
• Amino acid residues are derived from the corresponding amino acids and their stereoisomeric forms, such as L and D forms, and include the amino acids alanine, ss-alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine , Lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, y-amino butyrate, Ne-acetyllysine, NS-acetyltornithine, Ny-acetyldiaminobutyrate and Na-acetyldiaminobutyrate.
• L-amino acids such as L-cysteine, L-valine, L-arginine, L-asparagine, L-histidine, L-tryptophan, L-phenylalanine and L-lysine.
• Dipeptide residues are composed of two amino acids and include linear and cyclic dipeptide residues, with linear dipeptide residues having one and cyclic dipeptide residues having two peptide bonds.
• Tripeptide residues are composed of three amino acids and comprise linear and cyclic tripeptide residues which have three peptide bonds in the case of a linear structure or four in the case of a cyclic structure.
• a peptide bond is an amide bond (-CO-NH-) between the nitrogen atom of the amine group of a first amino acid and an oxygen atom of the carboxy group of a second amino acid.
• Preferred dipeptide radicals and tripeptide radicals consist of the abovementioned amino acids and more preferably of the above-described particularly preferred amino acids.
• Physiological salts of the compound of formula I and the compound of formula II include alkali, alkaline earth or ammonium salts, such as Na, K, Mg or Ca salts, as well as salts derived from organic bases, e.g. aliphatic or aromatic amines, such as triethylamine or tris (2-hydroxyethyl) amine.
• Preferred physiologically acceptable salts of the compounds of the formula I and of the formula II are obtained by reaction with inorganic acids, such as hydrochloric acid, sulfuric acid and phosphoric acid, or with organic carboxylic or sulfonic acids, such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p toluenesulfonic.
• inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid
• organic carboxylic or sulfonic acids such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p toluenesulfonic.
• the present invention is the use of the compounds of the formula I and of the formula II, the physiologically tolerable salts of the formula I and formula II, the stereoisomeric forms of the compounds of the formula I, formula II and the physiologically tolerated salts of the stereoisomeric forms or a A mixture, as well as the preferred embodiments described herein, for the manufacture of a cosmetic product, medical device, in vitro diagnostic product (IVD), drug and / or an adjunct or ingredient to one of said products for the prevention or treatment of barrier defects associated with at least one bio-based noxious agent of epithelial tissues, in particular of diseases, comprising at least one barrier defect in at least one cell layer of at least one epithelial tissue.
• IVD in vitro diagnostic product
• Preferred compounds of formula I and formula II are compounds wherein R 1 is hydrogen or methyl (CH 3), R 2 is hydrogen or COOH, R 3 and R 4 are each independently hydrogen or OH and n is equal to 2.
• Particularly preferred compounds according to the abovementioned definitions are 1, 4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid (ectoine) and 1, 4,5,6-tetrahydro-5-hydroxy-2-methyl-4-pyrimidinecarboxylic acid (Hydroxyectoine) and the physiologically acceptable salts and stereoisomeric forms of the aforementioned compounds.
• compounds of formula I and of formula II wherein R1 is hydrogen or methyl (CH3 ), R2 is a hydrogen atom or a COOH, R3 and R4 are each independently a hydrogen atom or an OH and n is 3 or 4.
• Particularly preferred compounds according to the abovementioned definitions are (S) -4,5,6,7-tetrahydro-2-methyl-1 H- [1,3] -diazepine-4-carboxylic acid (homoectin) with n equal to 3 and 3, 4,5,6,7,8-hexahydro-2-methyl-1, 3-diazocine-4-carboxylic acid (HHMDCA) with n equal to 4, and the physiologically acceptable salts and stereoisomeric forms of the aforementioned compounds.
• homoectin homoectin
• HHMDCA 4,5,6,7,8-hexahydro-2-methyl-1, 3-diazocine-4-carboxylic acid
• the above-described compounds may exist as optical isomers, diastereomers, racemates, zwitterions, cations or as a mixture of at least two of the aforementioned forms.
• Isomers include (R, R), (R, S), (S, S) and (S, R) configurations of the aforementioned compounds.
• isomers, diastereomers, racemates, zwitterions, cations and mixtures of the abovementioned compounds are likewise provided by the invention.
• Derivatizations may be made with hydroxy, sulfonic acid, carboxylic acid derivatives such as amides, esters, etc., carbonyl, ethers, alkoxy and dydroxyl groups.
• a possible derivative, but not limited to, is (S, S) -alpha-amino-beta-hydroxyectoine.
• Solut is to be understood synonymously for “compatible solute” and “mixture synonymous for” solute mixture.
• Solut mixture always refers to a mixture of at least two solutes of the formula I and / or formula II.
• Estoin “ Hydroxyectoin”
• Homoectoin always includes all stereoisomeric forms of the respective compound. Specific isomers are characterized as such.
• the at least one biobased noxious agent is selected from animal noxae, vegetable noxae, noxae of insects and pests, microbial noxae, environmental noxae, food boxes, in each case components and / or compounds of the aforementioned Noxen and / or combinations of at least two of the bio-based Noxen.
• Biobased pollutants within the meaning of the invention are exclusively of natural origin, originating from nature and of biogenic origin. This also includes wind and weather related temperatures and humidity levels in the environment.
• bio-based Noxen are preferably biobased Noxen, which come into contact with the human or animal organism, at least on the outer epithelial tissue.
• bio-based NOXES are peptide-based. If bio-based noxae work exclusively through external contact with the outer epithelial tissue, these are contact noxae. Other noxae also act, or only after ingestion, via the outer epithelial tissue and / or via the mucous membrane (mouth, nose, eyes, gastrointestinal tract).
• Biobased animated pollens plants, insects, pests, bacteria, viruses, fungi, yeasts each reproducible
• bio-based inanimate pollutants include animal, microbial and plant secretions including toxins, compounds, feces, secretions, excretions, food components and physical noxae such as wind, temperature, humidity and sun (photodynamic light exposure).
• Bio-based noxae also include bio-based haptens, which can only act in combination with a protein as a noxa in the human organism.
• the protein may be a further bio-based Noxe according to the invention or an endogenous protein of the affected human. Preference is given to bio-based Noxen, in particular bio-based devisnoxen, peptide-based.
• the at least one Noxe or a combination of at least two bio-based Noxen is selected from at least one of the groups
• animal noxae comprising domestic animals, cats, dogs, pigs, rodents, farm animals, pigs, goats, secretions of the aforementioned animals, animal epithelia and / or animal hair,
• herbal noxae comprising flower pollen, fruit organs, juices, secretions, poisons, resins, fragrances, flavors, toxins, stinging hairs, hooks, needles, thorns, components and / or compounds of plant noxae,
• noxious insects and pests including mites, house dust mites, insect excretions, pests and / or parasites, bee resins, bee venom, wasp poisons, spider venom, pest bites, mosquito, brake and ant stings or bites, components such as sting , Poisonous, re-hooking, and / or compounds of insects or pests, d) microbial noxae comprising microorganisms, fungi, yeasts, Malassezia species, bacteria, Staphylococcus aureus, mold spores, molds, bacterial toxins, delta-toxin, antibiotics, viruses, mycotoxins, components and / or compounds of the microorganisms,
• foodstuffs comprising nuts, peanuts, hazelnuts, wine, cow's milk, wheat, soya, chicken eggs, egg whites, fish, shellfish, crustaceans, molluscs, raw vegetables, raw fruits, food ingredients and / or compounds, and / or
• the respective noxae may themselves have a negative influence on the barrier function of epithelial tissues (Table 2), in particular on the selective permeability barrier, or have a negative to damaging effect on epithelial tissues only by a combination of at least two of the aforementioned noxae.
• primary damage to the barrier function eg mechanical lesions due to environmental noxae, such as high temperatures, strong cold and / or wind
• barrier defects eg infections caused by infectious noxae of microorganisms and allergies caused by non-infectious noxious agents
• pets such as cats, dogs, pigs, rodents, etc .
• Farm animals such as cats, dogs, pigs, rodents, etc .
• Marine animals jellyfish, sea urchins, stingrays, cone snails and squirrels; Sponges (siliceous needles), sea anemones; Cnidarians such as jellyfish, disc jellyfish, jellyfish and crab jellyfish as well as sea vespers and their respective poisons (tentacle / tentacle contact), nettle capsules, thorns, jellyfish, light jellyfish and compass jellyfish; Algae and theirs
• Herbal fragrances and flavorings, toxins, stinging nettles and other irritating plants for example noxa arnica, mugwort, chamomile and yarrow), resins, stinging hair, hooks, needles,
• Herbal substances eg Peruvian Balsam (Balsamum peruvianum), Baummoss (Evernia furfuracea), eucalyptus, etc .; Wool wax alcohols, lanolin, arnica, chamomile, bee resin, marigold
• Stone fruit (apple, pear), pome fruit (plum, cherry, peach), hazelnut, Brazil nut, walnut, almond, celery, carrot, kiwi, spices such as anise, curry; Grass pollen are common causes of allergies to: cereal flour, peanut, soy (bean, flour, milk);
• Herb pollen are common causes of allergies to: celery, carrots, fennel, garlic; Chamomile, parsley; Sunflower seeds; Spices such as cumin, curry, paprika, anise, pepper, nutmeg, cinnamon, ginger, coriander c) mites, dust mites and mite secretions; Ant, spider, worms,
• Pest bites Insects, lice, etc. Pest bites, pest fluids, ant poison, spider pests, bee / wasp toxins (allergens: glycoproteins, phospholipase A1 and A2,
• Hyaluronidase melithin, apamine, MCD peptide 401, antigen 5), spider, mosquito, brake and ant-sting and / or bites, bee resin; Pest and insect components, e.g. Sting, poisonous hair, re-hooking d) microorganisms, fungi, yeasts, infectious microorganisms, Malassezia
• Microbial species bacteria, Staphylococcus aureus, mold spores, molds, noxae, bacterial toxins, delta-toxin, antibiotics, viruses, mycotoxins, components
• the at least one biobased noxa is peptide-based.
• Peptide-based in the context of the invention means that the bio-based Noxe is a compound or comprises at least one compound which comprises at least one peptide bond between at least two amino acids.
• epithelial tissue in particular surface epithelium, as the boundary between inner and outer surfaces and between functional units, outer epithelial tissue comprising skin, epidermis, scalp, epidermis, nail bed, nail plate (eponychium), cornea and conjunctiva, and more particularly mucous membrane, of the eye, outer ear, external auditory canal and lips,
• Transitional epithelial tissue comprising the oral cavity, oral mucosa, gums, tongue, tongue mucosa, upper respiratory tract, nasal cavity, paranasal sinuses, nasal mucosa, vocal folds, pharynx and genitalia and / or
• inner epithelial tissues comprising lower respiratory tract, trachea, bronchi, bronchial tree, lungs, inner endothelial tissue, continuous endothelium, in particular continuous endothelium of lung and heart, endothelium of cardiac, blood, lymphatic, esophagus, gastric mucosa and / or mucous membrane.
• Epithelial tissue is divided histologically according to the number of cell layers into a single-layer, multi-layered and multi-row epithelium. Further, the epithelium is classified into a flat epithelium, isoprismatic or cubic epithelium and highly prismatic or cylindrical epithelium according to the shape of the cells. The degree of keratinization is described as cornified or not horny. Depending on the localization and function of the epithelium, the epithelium has a characteristic histology.
• epithelial tissue encompassed within the meaning of the invention is summarized below, so that when the term "epithelial tissue" is used in the context of the invention, the following summary is authoritative, unless it is explicitly referred to a particular embodiment.
• Single-layered serous skins comprising pleura, lung pleura, pericardium, vaginal skin squamous epithelium of the testicle; Alveolar epithelium, endothelium, lungs (endothelium), endothelium of the heart, blood and lymph vessels; tongue mucosa
• Multilayer anterior corneal epithelium eye
• vocal fold vocal fold
• pharynx pharynx
• Esophagus anus, vagina, tongue mucosa (tongue top); Conjunctiva of the eye, cornea
• Multilayer epidermis (stratum basale, stratum spinosum, stratum granulosum), cornified epithelium nasal vestibule, external auditory canal, gums (outer junctional epithelium to the oral cavity),
• the epithelial tissues of Table 2 include as intercellular connections tight junction, Adherens junction and / or desmosomes.
• the tight junctions achieve the true paracellular barrier function of the epithelial tissue, in particular the selective permeability barrier, thereby enabling transcytosis and at the same time preventing the loss of body fluids. Furthermore, the paracellular penetration of molecules, ions, antigens, peptide-based Noxen and microorganisms is prevented.
• another object of the present invention is a compatible solute or solute mixture for use according to the invention, as described, wherein the at least one barrier defect of at least one epithelial tissue has a disturbed intercellular cell structure in at least one cell layer of the epithelial cells from the outer epithelial tissue, transitional epithelial tissue and / or inner epithelial tissue ,
• the at least one epithelial tissue comprises as intercellular connections tight junction, Adherens junction and / or desmosomes. Defects of the aforementioned compounds lead to structural weakening and thus to a disturbed and reduced selective permeability barrier.
• Tight junctions are the most important components in the maintenance of the barrier function of epithelial tissues due to their versatile functions. They enclose the epithelial cells ring-shaped at the apical end as intramembranous, continuous structure. Considering the spatial arrangement of intercellular junctions in epithelial tissues, tight junctions are most apically located in all epithelial tissues, followed by Adherens junction, desmosomes and gab junction as the basal intercellular junction. Thus, bio-based pollutants primarily affect tight junction. Only when these are damaged or defective and the bio-based Noxe can penetrate due to a lack of permeability barrier, the bio-based Noxe act on the Adherens junction, etc ..
• a further subject of the present invention is a compatible solute or solute mixture for use according to the invention, as described, wherein the at least one barrier defect of the at least one epithelial tissue damage the tight junction in at least one cell layer.
• damage to the tight junction leads to a disturbed and reduced selective permeability barrier, especially in the intercellular space.
• the at least one barrier defect in at least one epithelial tissue has a disturbed intercellular cell structure, in particular an increased permeability, in at least one cell layer of the epithelial cells from the outer epithelial tissue, transitional epithelial tissue and / or inner epithelial tissue on.
• the at least one barrier defect comprises damage to the tight junction in at least one cell layer of the at least one epithelial tissue.
• Damage to the tight junction may be reduced protein stability, modulation of the proteins, particularly the occludin and / or claudin protein family, partial degradation, or breaks in the trans-tight loops of the tight junction proteins, thereby impairing and permeating the cell structure. Impairment of the tight junction proteins results in the disruption and lowering of the selective permeability barrier of epithelial cells, which in turn results in increased paracellular flow of bio-based noxae (Example 2).
• the at least one barrier defect of the at least one epithelial tissue is a disrupted and diminished selective permeability barrier.
• a disrupted selective permeability barrier may be detected by a reduced transepithelial electrical resistance (TEER) as shown in Example 1 and by a lower expression of at least one claudin protein family protein as shown in Example 2.
• TEER transepithelial electrical resistance
• the at least one bio-based Noxe may be the cause of the disturbance of the barrier function and / or may already be predisposed epithelial tissues with impaired barrier function, for example in outer epithelial tissues such as the epidermis, horny and / or conjunctiva, to stronger barrier defects in epithelial tissues and resulting diseases.
• claudin-associated diseases with an altered selective permeability barrier comprising reduced claudin expression.
• Claudin-associated diseases include inflammatory bowel disease, kidney disease, bacterial and viral infections, and skin diseases.
• the epithelial tissues especially in the early phase on a reduced selective permeability barrier, among other things, based on a down-regulated Claudin expression
• the regeneration of the above-described epithelial, selective permeability barrier for restoring the barrier function of epithelial tissues depends on the body's own vitality. However, after disease progression and potential side effects, it is often decreased and the body may be slow or unable to restore or maintain the barrier of epithelial tissues.
• the experiments described here demonstrate that ectoine can assist the body in the regeneration of the selective permeability barrier, as evidenced by the increase in claudin expression and increased TEER (Examples 1 to 3).
• the at least one epithelial tissue having at least one barrier defect, preferably in at least one cell layer, compared to non-damaged epithelial tissues, a reduced transepithelial electrical resistance (TEER), which in [Ohm ], as explained in Example 1.
• TEER transepithelial electrical resistance
• the action of at least one solute increases and / or stabilizes the TEER of the abovementioned epithelial tissue.
• TEER transepithelial electrical resistance
• the tightness of the selective paracellular permeability barrier is caused by tight junction.
• Adherens junction and desmosomes mechanically connect the cells with each other.
• the at least one epithelial tissue having at least one barrier defect, preferably in at least one cell layer, in comparison to non-damaged epithelial tissues, a higher permeability for at least one bio-based Noxe, as in Example 2 shown by the allergy prevention assay (APA).
• APA allergy prevention assay
• the at least one epithelial tissue having at least one barrier defect, preferably in at least one cell layer, compared to non-damaged epithelial tissues, a lower expression of at least one protein of the claudin protein family, such as shown in Example 3.
• the action of at least one solute increases and / or stabilizes claudin expression of the abovementioned epithelial tissues.
• human keratinocytes HaCat cells were used representatively for the outer epithelial tissue.
• Ectoin is able to promote the formation of tight junction by stimulating the expression of proteins of the Claudin protein family.
• the barrier function in particular the selective permeability barrier, is stabilized or restored in already damaged epithelial cells.
• Non-damaged epithelial tissues according to the invention correspond to the controls of the present examples and are epithelial tissues which have not been affected by the action of bio-based noxae.
• the aforementioned efficacies of ectoine for use in the prevention or treatment of barrier defects in epithelial tissues, in particular the stabilization and / or restoration of the selective permeability barrier is preferably greater than or equal to 10 mM to less than or equal to 1 M of at least one compatible solute, preferably ectoine, hydroxyectoine and / or its derivatives obtained, preferably greater than or equal to 10 mM to less than or equal to 750 mM, greater than or equal to 10 mM to less equal to 500 mM, greater than or equal to 25 mM to less than or equal to 500 mM, greater than or equal to 50 mM to less than or equal to 500 mM.
• ectoine and its derivatives are suitable for use in both prevention and treatment of barrier defects.
• diseases comprising at least one barrier defect in at least one epithelial tissue, which is associated with at least one, preferably peptide-based, bio-based Noxe (Table 1).
• epithelial tissue comprises exclusively outer epithelial tissues comprising the skin, epidermis, scalp, epidermis, nail bed, epochlorine, cornea and conjunctiva, and more particularly mucosa, the eye, outer ear, external auditory canal and lips, as well as transitional epithelial tissue comprising the oral cavity , Oral mucosa, gums, tongue, tongue mucosa, upper respiratory tract, nasal cavity, paranasal sinuses, nasal mucosa, vocal folds, pharynx and genitals.
• At least one compatible solute or solute mixture is selected from compounds of the formula I and / or the formula II, preferably ectoine and / or hydroxyectoine.
• outer epithelial tissue and transitional epithelial tissue are preferably outer epithelial tissue and transitional epithelial tissue, which each have tight junction.
• Tigt junction and desmosomes are strongly represented and form the most important barrier for humans for biobased, especially peptide-based, noxious.
• Barrier defects in this case have a reduced transepithelial electrical resistance (TEER), a higher permeability (APA) and / or a lower expression of at least one protein of the Claudin protein family, in each case in comparison to non-damaged epithelial tissue with an intact barrier function.
• the barrier defects are present at the border between apical and basolateral membrane of epithelial cells.
• the at least one solute or solute mixture protects and / or stabilizes the barrier function of the at least one epithelial tissue, in particular the selective permeability barrier, inhibits and / or at least reduces the disruption of the barrier function, in particular in at least one epithelial tissue, and / or at least partially restores it (see above, Example 1 -3).
• the at least one solute or solute mixture at a concentration greater than or equal to 1 mM to less than or equal to 1 M has at least a protective effect on the barrier function of Epithelial cells of the outer epithelial tissues (preferably skin, epidermis), transitional epithelial tissue (preferably oral and nasal mucosa) and / or inner epithelial tissue (preferably lung, bronchial and gastric epithelium) inhibit and / or at least inhibit barrier function partially restored the aforementioned epithelial cells.
• the outer epithelial tissues preferably skin, epidermis
• transitional epithelial tissue preferably oral and nasal mucosa
• / or inner epithelial tissue preferably lung, bronchial and gastric epithelium
• the concentration of the at least one compatible solute, preferably ectoine, hydroxyectoine and / or its derivatives, is greater than or equal to 1 mM to less than or equal to 1 M, greater than or equal to 5 mM, greater than or equal to 10 mM, greater than or equal to 15 mM, greater than or equal to 20 mM.
• concentration ranges are greater than or equal to 10 mM to less than or equal to 1 M, greater than or equal to 10 mM to less than or equal to 750 mM, greater than or equal to 10 mM to less than or equal to 500 mM, greater than or equal to 25 mM to less than or equal to 500 mM, greater than or equal to 50 mM or less equal to 500 mM each of at least one compatible solute, preferably ectoine, hydroxyectoine and / or its derivatives.
• Barrier defects may also be the result of a disease (skin condition, skin disease), inflammatory reaction due to infections and / or allergies, infection (superficial, internal) and / or an allergy. This shows a disturbed barrier function each affected epithelial tissue different symptoms (synonymous phenotype or phenotypic). These can occur sporadically, locally restricted, distributed selectively or over a large area.
• the at least one barrier defect of at least one epithelial tissue therefore comprises phenotypically itching, skin discoloration, heat, heat development, fever, reddening, dry skin (xerodermia).
• ring-shaped lesions blisters, blisters, pustules, papules, pimples, with or without pus, abscesses, fistulas, rash, crusts, bumps, swelling, scratches, stings, sloughing, scaling, hives, angioedema, Quincke's edema, Hives, plaques, ulcers, boils, carbuncles, eczema and / or oriental bumps.
• the barrier defect of epithelial tissues of the type described above comprising in particular diseases having at least one barrier defect, associated with at least one biobased, preferably peptide-based, noxious, parasitic, bacterial and / or viral diseases, mycoses, lesions, dryness, irritation, inflammation, hypersensitivity and / or allergic reactions of each of the outer epithelial tissue, transitional epithelial tissue and / or inner epithelial tissue.
• the barrier defects preferably have a damage to the tight junction (see above) in at least one cell layer of the epithelial tissue.
• Allergic reactions include allergic reactions to the fiction-based noxa (Table 1), cross-allergies and contact allergies, preferably the outer epithelial tissue comprising skin, epidermis, Scalp, epidermis, nail bed, nail plate (eponychium), cornea and conjunctiva, and more particularly mucous membrane, eye, outer ear, external auditory canal and lips, and transitional epithelial tissues including oral cavity, oral mucosa, gums, tongue, tongue mucosa, upper respiratory tract, nasal cavity, paranasal sinuses, nasal mucosa , Vocal folds, throat and genitals.
• Table 1 the outer epithelial tissue comprising skin, epidermis, Scalp, epidermis, nail bed, nail plate (eponychium), cornea and conjunctiva, and more particularly mucous membrane, eye, outer ear, external auditory canal and lips
• transitional epithelial tissues including oral cavity, oral mucosa, gums, tongue, tongue mucosa,
• At least one compatible solute or solute mixture is selected from compounds of the formula I and / or the formula II, preferably ectoine and / or Hydroxyectoine, used.
• the described preferred concentration ranges for the at least one solute apply here accordingly.
• a contact allergy is an onset within 48-72 hours of reaction to contact with an allergen, in which the allergen, especially the bio-based Noxe and biogenic agents (Ex: latex, in agriculture, forestry and fisheries), the epithelial tissue , preferably the epidermis, intruded and / or penetrated.
• the allergen especially the bio-based Noxe and biogenic agents (Ex: latex, in agriculture, forestry and fisheries)
• the epithelial tissue preferably the epidermis, intruded and / or penetrated.
• contact allergic reactions are manifested by the symptoms already described.
• barrier defects of the epidermis which are in the stratum granulosum and stratum spinosum respectively Tigt junction and desmosomes increasingly has and forms the most important barrier for human biobased, especially peptide-based, noxious.
• Barrier defects in this case have a reduced transepithelial electrical resistance (TEER), a higher permeability (APA) and / or a lower expression of at least one protein of the Claudin protein family, in each case compared to non-damaged epithelial tissues with an intact barrier function.
• TEER transepithelial electrical resistance
• APA higher permeability
• / or a lower expression of at least one protein of the Claudin protein family in each case compared to non-damaged epithelial tissues with an intact barrier function.
• the preferred concentration ranges for the at least one solute apply here accordingly.
• At least one barrier defect is present in the case of diseases, in each case
• outer epithelial tissues comprising diseases of the skin and subcutaneous tissue, skin lesions, infections of the skin and / or subcutaneous tissue, mycoses, dry skin, in particular dry epidermis of the extremities / limbs, such as legs, feet, arms, Hands, armpits, knees, face, head and neck, contact allergies, dermatitis, eczema, neurodermatitis, psoriasis, urticaria, herpes, cold sores, diseases of the eye, inflammation of the conjunctiva and / or cornea, conjunctivitis, keratitis, dry conjunctiva, diseases of the external ear, inflammation of the outer ear and / or the external auditory canal, otitis externa, physical disorders and / or damage to the skin structure comprising injuries, punctures, cuts, scratches, abrasions, burns and / or chemical burns respectively caused by contact with at least one bio-based, preferably peptide-based, Noxe
• Transitional epithelial tissues (Table 2) comprising allergic reactions of the nasal mucosa, allergic reactions of at least one mucous membrane of the oral cavity
• Throat, nose and / or genitals in particular skin of the penis, the glans, the scrotum, the prepuce, the glans layer, clitoral hood, clitoris, outer and inner labia, physical disorders and / or damage to the skin structure, including injuries, stitches, cuts, Scratches, abrasions, burns and / or caustic each triggered by contact with at least one bio-based, preferably peptide-based, Noxe, and / or
• Table 2 Internal epithelial tissues (Table 2) comprising diseases of the digestive system, inflammation of the gastric mucosa and / or small intestinal mucosa, Crohn's disease, ulcerative colitis, diverticulosis, claudin-associated diseases, diseases of the lower respiratory tract, inflammation of the lung and / or bronchi and / or Asthma.
• Skin lesions include redness of the skin (erythema), skin discoloration, annular lesions, blisters or blisters (with or without pus), pustules, pimples, crusts, bumps, sloughing, etc., severe itchy wheals (eg in the form of urticaria), acne, plaques ( psoriasis), ulcers, furuncles, carbuncles, oriental bumps (cutaneous leishmaniasis, cutaneous leishmaniasis), eyelid swelling.
• the conjunctiva may be inflamed by various bio-based noxae, such as viruses, bacteria, plant noxae, pollen or allergens (see Table 1).
• An allergic disease in the conjunctiva is allergic rhinoconjunctivitis.
• the epithelial tissues are particularly in the early Phase on a reduced selective permeability barrier, among other things, based on a down-regulated Claudin expression.
• the aforementioned diseases can also occur as occupational diseases due to increased exposure to biobased noxa (Table 1) in the workplace and / or due to increased human sensitivity.
• the at least one bio-based, preferably peptide-based, noxa intrudes the outer epithelial tissue, in particular the epidermis, preferably the surface epithelium of the skin, the multilayered epithelium of the skin Oral mucosa, the tongue mucosa, the nasal mucosa, the cornea or the conjunctiva of the eye.
• the above-described compatible solute or solute mixture preferably ectoine and / or hydroxyectoine, is particularly suitable for use in the prevention or treatment of epithelial tissue diseases (Table 2) caused by at least one biobased noxa (Table 1)
• infections include, in particular, infections of the outer epithelial tissues, such as skin infections including erythrasma, impetigo contiaguisa (lichen), herpes labialis, phlegmon, boils, skin tuberculosis and tinea pedis (athlete's foot); Transitional epithelial tissue infections, such as upper respiratory tract and oral cavity, including infectious sinusitis, infectious gingival infections, bacterial periodontitis; the internal epithelial tissue, such as respiratory infections, including infectious bronchitis, bronchiolitis and / or alveolitis;
• allergies triggering an immune response of the body to non-infectious noxae (antigens or allergens) (Table 1) with inflammatory signs, including allergies of the outer epithelial tissues, such as urticaria, contact dermatitis, atopic dermatitis and allergic conjunctivitis; the transitional epithelial tissues, such as rhinitis allergica, allergic rhinopathy and sinusitis; the internal epithelial tissue, such as bronchial asthma, and
• Primary impairments and / or damage to the barrier function of epithelial tissues in the context of the invention are those which occur first, are not necessarily noted phenotypically and are not pathological.
• a cosmetic or medical device may be suitable.
• Secondary impairments and / or damage to the barrier function of epithelial tissues can arise from such primary barrier defects.
• Secondary barrier defects in the sense of the invention are those which follow a primary barrier defect and lead to further damage to the barrier function, which can be clearly recognized and characterized phenotypically. This is often the case when environmental noxae cause mechanical lesions according to group (3) described above and subsequently cause infections by infectious noxae (see group (1) above) or non-infectious noxae (see group (2) above) become.
• secondary barrier defects are pathological and must be treated with a medical device or drug.
• secondary barrier defects can also occur without primary barrier defects.
• the occurring symptoms and phenotypic symptoms have already been described above.
• the preferred embodiments of the at least one compatible solute, solute mixture and / or compositions as well as concentrations described below apply accordingly.
• the at least one compatible solute or solute mixture is selected from S-ectoine, R-ectoine, (S, S) -hydroxyectoine, (S, R) -hydroxyectoine, (R, S) -hydroxyectoine, (R, R ) -Hydroxyectoine and S-homoectin, the physiologically acceptable salts of S-ectoine, R-ectoine, (S, S) -hydroxyectoine, (S, R) -hydroxyectoine, (R, S) -hydroxyectoine, (R, R) Hydroxyectoine and S-homoectoine, the amides and esters of the abovementioned compounds or a solute mixture of at least two of the abovementioned compounds.
• a compatible solute or a solute mixture comprising at least two of the compounds of the preceding definition, where the at least one compound is selected from S-ectoine, R-ectoine, (S, S) -hydroxyectoine, (S, R) -hydroxyectoine, (R, S) - Hydroxyectoine, (R, R) -hydroxyectoine and S-homoectoine, the physiologically acceptable salts of S-ectoine, R-ectoine, (S, S) -hydroxyectoine, (S, R) -hydroxyectoine, (R, S) -hydroxyectoine and S-homoectoine, the amides and esters of the aforementioned compounds or a solute mixture of at least two of the aforementioned compounds.
• An S enantiomer according to CIP rule corresponds to the L enantiomer according to the Fischer projection and an R enantiomer according to CIP rule corresponds to the D enantiomer according to the Fischer projection.
• Particularly preferred compounds of the formula I and of the formula II for use in the prevention or treatment of barrier defects of epithelial tissues associated with at least one bio-based noxious agent, in particular of diseases comprising at least one barrier defect in at least one cell layer of at least one epithelial tissue, are the abovementioned solutes.
• the at least one compatible solute is in pure form enantiomer with a purity greater than or equal to 90%, preferably greater than or equal to 95%. greater than or equal to 97%, greater than or equal to 99%, especially preferred equal to 100%.
• Enantiomerically pure forms of the solute or of the solute mixture according to the invention particularly preferably have S and / or (S, S) -silomers.
• Preferred forms of the sol of the invention are S (L) -ectin, R (D) -ctoine, (S, S) -hydroxyectoine, (S, R) -hydroxyectoine, (R, S) -hydroxyectoine and (R, R) - Hydroxyectoine and solute mixtures of at least two of the aforementioned compounds.
• a preferred enantiomer pure solute mixture are S-ectoine and (S, S) - hydroxyectoein each with a purity greater than or equal to 90%, greater than or equal to 95%, preferably greater than or equal to 97%, greater than or equal to 99%, particularly preferably equal to 100%.
• this solute mixture preferably has in each case less than or equal to 10% less than or equal to 5%, preferably less than or equal to 3%, less than or equal to 1%, particularly preferably equal to 0% R-ectoine or (R, S) - / (S, R) - or ( R, R) -hydroxyectoine.
• racemates are preferred:
• the solute mixture according to the invention comprises at least two compounds of formula I and / or formula II and / or their respective enantiomers.
• the above-described solute mixture according to the invention for use in the prevention or treatment of biobased, preferably peptide-based, noxious, associated barrier defects of epithelial tissues comprises, based on the sum of all compounds in the solute mixture with a total content of 100% by weight,
• the proportion of S-ectoine is less than or equal to 70% by weight, preferably less than or equal to 65% by weight, less than or equal to 60% by weight, less than or equal to 55% by weight, particularly preferably greater than or equal to 50% by weight
• the solute mixture comprises a mixture of two compounds of the formula I and / or of the formula II in each case greater than or equal to 60% by weight of the first compound to less than or equal to 40% by weight of the second compound.
• This solute mixture preferably contains greater than or equal to 60% by weight, particularly preferably greater than or equal to 70% by weight of S-ectoine and less than or equal to 40% by weight, particularly preferably less than or equal to 30% by weight of (S, S) -hydroxyectoine.
• the solute mixture comprises a mixture of two compounds of the formula I and / or of the formula II with a content of 50% by weight, S-ectoine and 50% by weight of (S, S) -hydroxyectoine.
• the at least one solute of formula I and / or formula II or the solute mixture containing at least two solutes is Formula I and / or Formula II biobased and is therefore of biological origin.
• Biobased or biological origin in the sense of the invention means that the compound of the formula I and / or of the formula II is produced by or in an organism.
• the organism is a microorganism, and more preferably the microorganism is a halophilic bacterium comprising Ectothiorhodospira halochloris, Halomonas elongata, Marinococcus halophilus, Brevibacterium linens, Halomonas SPC1, Volcaniella eurihalina, Deleya salina, Bacillus pantothenticus, Bacillus halophilus, Vibrio costicola and Streptomyces parvulus
• the bio-based solute of the formula I and / or of the formula II or the already described solute mixture, preferably S- / R-ectoine and / or (S, S) - / (S, R) - / (R, S) - / (R, R) -
• a further subject of the present invention is a pharmaceutical composition containing at least one compatible solute, in particular of the type described above, or a solute mixture comprising at least two compatible solutes for use in the prevention or treatment of at least one bio-based, preferably peptide-based, noxa (Table 1). associated barrier defects of epithelial tissues, in particular diseases comprising at least one barrier defect, preferably in at least one cell layer, in at least one epithelial tissue.
• the compatible solute or the solute mixture comprises at least one compound selected from compounds of the formula I, the formula II, the physiologically acceptable salts of the formula I and formula II, the stereoisomeric forms of the compounds of the formula I, formula II and the physiologically acceptable salts of stereoisomeric forms or a mixture of at least two of the aforementioned compounds.
• the definition of the formula I and formula II and their radicals R 1, R 2, R 3, R 4 and R 5 as well as n and alkyl have already been defined above.
• the definitions and preferred radicals, preferred compounds and combinations apply to the composition accordingly.
• the at least one compatible solute preferably ectoine and / or hydroxyectoine, or the solute mixture is present in a proportion of greater than or equal to 0.0001% by weight to less than or equal to 50% by weight Composition before, based on the total content of the composition.
• compositions contain the at least one compatible solute or the solute mixture, preferably S (L) -ctoine, R (D) -ctoine, (S, S) -hydroxyectoine, (S, R) -hydroxy-ectoine, (R, S) -Hydroxyectoine and / or (R, R) -hydroxyectoine, having a proportion of greater than or equal to 0.0001% by weight to less than or equal to 50% by weight in the composition, based on the total content of the composition.
• Particularly preferred is a range greater than or equal to 0.001 wt .-%, greater than or equal to 0.01 wt .-%, greater than or equal to 0.1 wt .-%, particularly preferably greater than or equal to 1, 0 wt .-% to less than or equal to 40 wt. %, less than or equal to 30% by weight, less than or equal to 20% by weight, particularly preferably less than or equal to 10% by weight
• the at least one compatible solute or mixture is preferably S (L) -ectoine, R (D) -ctoine, (S, S) -hydroxyectoine, (S, R) -hydroxyectoine , (R, S) - hydroxyectoine and / or (R, R) -hydroxyectoine, in a proportion of greater than or equal to 0.0001% by weight to less than or equal to 10% by weight in the composition, based on the total content of Composition.
• the at least one compatible solute or the solute mixture in a proportion greater than or equal to 0.0001 wt .-% to less than or equal to 10 wt .-% in the composition before, based on the total content of the composition, preferably greater than or equal 0.001 wt .-% to less than or equal to 8 wt .-%, preferably to less than or equal to 6 wt .-%, more preferably less than or equal to 5 wt .-%.
• composition according to the invention preferably comprises at least one compound of the formula I and / or of the formula II selected from S-ectoine, R-ectoine, (S, S) -hydroxyectoine, (S, R) -hydroxyectoine, (R, S) -hydroxyectoine , (R, R) -hydroxyectoine and S-homoectoin, the physiologically acceptable salts of S-ectoine, R-ectoine, (S, S) -hydroxyectoine, (S, R) -hydroxyectoine, (R, S) -hydroxyectoine, (R, R) -hydroxyectoine and S-homoectoine, the amides and esters of the aforementioned compounds or a solute mixture of at least two of the aforementioned compounds.
• the solute, solute mixture and / or the composition in particular for use in the prevention or treatment of barrier defects of epithelial tissues associated with at least one bio-based noxious agent, is as Medicament, medical device, cosmetic, as an additive to one of the aforementioned products and / or preferably as part of in vitro diagnostic products (IVD).
• the solute or solute mixture can be incorporated into existing formulations and / or formulations of existing drugs to add the stabilizing, protective (preventive) and / or promoting (therapeutic) effects of the solute to the barrier function of the epithelial tissues.
• the solute, solute mixture or the composition is in solid or liquid form or as a mixture before, selected from i) solid forms comprising powder, lyophilisate, tablets, granules, film-coated tablet, dragee, capsules, effervescent tablets, powder and soap,
• liquid forms comprising solution, injection, infusion, tincture, dripping solution, suspension, emulsion, gel, foam and cream, and / or
• mixtures comprising spray, aerosols, ointment, paste and capsule, and especially semi-solid forms.
• These forms preferably contain at least one sol of the formula I and / or of the formula II, preferably S-ectoine and / or (S, S) -hydroxyectoine, particularly preferably with a proportion greater than or equal to 0.0001% by weight to less than or equal to 10 wt .-% in the composition, based on the total content of the composition.
• composition of the invention for oral administration for uptake via the gastrointestinal tract by swallowing the composition of the invention, and preferably for use in the prevention or treatment of diseases of the inner epithelial tissues of gastric and / or intestinal mucosa comprising at least one barrier defect, i) are particularly preferred Forms comprising powder, in particular after mixing with a drink or water, capsules, tablets, granules, film-coated tablets, dragee and effervescent tablets, or ii) liquid forms comprising solution, dripping solution, tincture, syrup, juice and oil.
• Liquid formulations preferably solutions, tinctures, rinses, gargle solutions and dripping solutions and / or mixtures, such as sprays, are preferred for use in the prevention or treatment of transitional diseases.
• epithelial tissue of the oral cavity, nasal cavity, pharynx and palate each comprising at least one barrier defect used.
• solid forms such as powders, powders, soaps or mixtures such as ointments, creams, gels, hydrogels are preferably used.
• composition of the invention may contain excipients known in the art from the prior art formulation.
• Excipients include carriers, preservatives, antioxidants, stabilizers, solubilizers, vitamins, colorants, odor improvers.
• Carriers in particular for cosmetic formulations and / or medical products, include animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of at least two of the aforementioned substances.
• the abovementioned carriers are particularly suitable for ointments, pastes, creams and gels containing at least one sol of the formula I or of the formula II, preferably S-ectoine and / or (S, S) -hydroxyectoine.
• Carriers for powders or sprays comprising at least one solut of the formula I or of the formula II, preferably S-ectoine and / or (S, S) -hydroxyectoine include lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of at least two the aforementioned substances.
• Sprays may additionally contain the usual propellants, e.g. Chlorofluorocarbons, propane / butane or dimethyl ether.
• Solutions and emulsions comprising at least one sol of the formula I or of the formula II, preferably S-ectoine and / or (S, S) -hydroxyectoine, may comprise the usual excipients, such as solvents, solubilizers and emulsifiers, eg water, ethanol, isopropanol, Ethyl carbonate, ethyl acetate, benzyl alcohol, Benzytbenzoat, propylene glycol, 1, 3-butyl glycol, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol fatty acid esters, polyethylene glycols and fatty acid esters of sorbitan or mixtures of at least two of the aforementioned substances.
• solvents such as solvents, solubilizers and emulsifiers, eg water, ethanol, isopropanol, Ethyl carbonate, ethyl acetate,
• Suspensions containing at least one sol of the formula I or of the formula II, preferably S-ectoine and / or (S, S) -hydroxyectoine include customary carriers, such as liquid diluents, for example water, ethanol or propylene glycol, suspending agents, for example ethoxylated iso-stearyl alcohols , Polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar agar and tragacanth or mixtures of at least two of the aforementioned substances.
• customary carriers such as liquid diluents, for example water, ethanol or propylene glycol, suspending agents, for example ethoxylated iso-stearyl alcohols , Polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar agar and trag
• soaps and lotions containing at least one solut of the formula I or of the formula II, preferably S-ectoine and / or (S, S) -hydroxyectoine, suitable excipients, such as alkali metal salts of fatty acids, salts of fatty acid monoesters, Fatty acid protein hydrolysates, isothionates, lanolin, fatty alcohol, vegetable oils, plant extracts, glycerol, sugars or mixtures of at least two of the aforementioned substances.
• suitable auxiliaries for the respective formulation are known to the person skilled in the art.
• barrier defects of epithelial tissues associated with at least one bio-based noxious agent in particular diseases comprising at least one barrier defect, are used
• cosmetic formulations comprising mixtures of lipstick, lip balm, powder, sunscreen, body lotion and / or
• compositions preferably containing S-ectoine and / or (S, S) -hydroxyectoine, in solid or liquid form, wherein formulation is selected from
• solid forms comprising powders, tablets, granules, film-coated tablets, dragées, capsules,
• liquid forms comprising solution, injection, infusion, tincture, dripping solution, suspension, syrup, juice, emulsion, gel, foam, cream, lotion, surfactant-containing cleansing preparation, oil and / or
• mixtures comprising spray, aerosols, inhalant, ointment, paste, gels and hydrogels.
• Preferred formulations according to the invention for the prevention or treatment of barrier defects of epithelial tissues associated with at least one bio-based noxa, preferably containing S-ectoine and / or (S, S) -hydroxyectoine, are for topical administration to the skin surface, to the eye, suitable formulations for the oral and nasal mucosa.
• suitable formulations for the oral and nasal mucosa are particularly preferably comprise S-ectoine and / or (S, S) -hydroxyectoine, with a proportion greater than or equal to 0.0001% by weight to less than or equal to 10% by weight in the composition, based on the total content of the composition.
• Medical products within the meaning of the invention are the formulations described herein comprising at least one solut of the formula I or of the formula II or the solute mixture of at least two of the abovementioned compounds, preferably S-ectoine and / or (S, S) - Hydroxyectoine for use in the prevention or treatment of humans for medical therapeutic purposes.
• the medical devices according to the invention preferably fulfill the definition and requirements of Directive 93/42 / EEC and / or the corresponding regulations in the USA.
• In vitro diagnostic products comprise at least one sol of the formula I or formula II or the solute mixture of at least two of the aforementioned compounds as an additive (synonymous constituent) and preferably meet the definition and requirements of Directive 98/79 / EC and / or US regulations "US man regulations Title 21: Food and Drugs PART 809 - IN VITRO DIAGNOSTIC PRODUCTS FOR HUMAN USE Subpart A - ⁇ 809.3 Definitions ".
• Preferred excipients for the composition of medical devices and pharmaceutical formulations for the prevention or treatment of diseases comprising at least one barrier defect in epithelial tissues in solid or liquid form include lactose, sucrose, dextrose, mannitol, sorbitol, starch, gelatin, tragacanth, pectin, cellulose, methylcellulose, hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose sodium, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid, polyethylene glycol, polyethylene oxide, sodium dodecylsulfate, sodium cetylstearylsulfate and sodium dioctylsulfosuccinate (also K, Ca salts).
• Preferred excipients for solutions and suspensions according to the invention include dextrose, mannitol, tragacanth, pectin, methylcellulose, hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid, polyethylene glycol, polyethylene oxide, sodium dodecylsulfate, sodium cetylstearylsulfate, sodium dioctylsulfosuccinate (also K, Ca salts) and especially for suspensions also cellulose.
• Semi-solid forms or mixtures within the meaning of the invention preferably comprise hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose sodium, polyethylene glycol, polyethylene oxide, sodium dodecylsulfate, sodium cetylstearylsulfate and pectin.
• HPMC hydroxypropylmethylcellulose
• carboxymethylcellulose sodium polyethylene glycol
• polyethylene oxide polyethylene oxide
• sodium dodecylsulfate sodium cetylstearylsulfate
• pectin pectin
• a preferred composition of a medical device and / or a medicament containing the erfindungsffleße a solute of formula I or formula II or the solute mixture of at least two of the aforementioned solutes, preferably S-ectoine and / or (S, S) -hydroxyectoine, for the prevention or Treatment of barrier defects associated with at least one bio-based noxious agent in epithelial tissues includes formulations for application, application, massaging, spraying and / or application to the affected epithelial surface.
• Such products include nasal spray, nasal drops, nasal balm, eye drops, Artificial tear fluid (dry eyes), contact lenses, eye pads (pads), eye gel, mouthwash, mouth spray, gum gums, ear drops, solution, conditioner, suspension, ointment, cream, lotion, paste, spray, jelly, aerosol, emulsions (W / O, OW), hydrogel, liposomes, microsomal capsules, steam bath concentrate.
• dermatological products for the prevention or treatment of diseases comprising at least one barrier defect of outer epithelial tissues and / or transitional epithelial tissues.
• Fig. 1 Experimental set-up for the determination of transepithelial resistance (TEER);
• a cell culture medium (2) is an insert (3) with a transparent ThinCerts membrane, pore size 0.4 ⁇ arranged.
• On the membrane is a single layer cell layer of a cell culture (4), wherein the membrane is covered with the cells from the cell culture medium.
• the single-layer cell layer (4) is arranged between the two electrodes E1 and E2, wherein a defined strength (U) of a direct current (DC) is applied between the electrodes E1 and E2, so that the applied direct current (DC) flows through the cells.
• U defined strength
• DC direct current
• FIG. 2 TEER values [ohms] of oral mucosal cell epithelial cells (TR146) after incubation with 50 mM ectoine, 0.01% lecithin or PBS for 12 hours (h).
• FIG. 3 TEER values [ohms] of oral mucosal cell epithelial cells (TR146) after incubation with 50 mM ectoine, 0.01% lecithin or PBS overnight and subsequent treatment with 0.005% SDS.
• Fig. 4 TEER values [ohms] of porcine renal epithelial cells (LLC-PK1) after incubation with 50 mM ectoine, 0.01% lecithin or PBS overnight and subsequent treatment with 0.001% BAK.
• FIG. 6 Experimental setup for the allergy prevention assay (APA): An insert (1) with a transparent ThinCerts membrane (3) with a pore size of 0.4 ⁇ m is arranged in a test vessel (6) with cell culture medium in an outer reservoir (5). On the membrane (3) is a closed single-layered epithelial cell layer (2). The insert separates an inner reservoir (7) above the cell layer (3).
• the allergen (5) is eg OVA.
• the following examples show the influence of ectoine on various epithelial tissues and on the barrier function of the epithelial cells or epithelial tissue. Ectoin is shown to be effective in the prevention and treatment of biobased noxious barrier epithelial tissue defects. Ectoin acts structurally on the epithelial tissues.
• a diffusion barrier or membrane integrity is characterized by epithelial cells and endothelial cells which have intercellular connections. These intercellular junctions separate the apical (lumen) side from the basolateral (ablumenal) side of the cells and, through their complex geometries, form a diffusion barrier for a variety of molecules in the paracellular passageway between the apical (luminal) and basolateral (abluminal) compartments as well as for the Passage via the intracellular transport route.
• This diffusion barrier is provided by so-called tight junctions (intercellular junctions) that connect adjacent cells (Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier.) Nat Rev Neurosci, 7: 41 - 53).
• Tight junctions are complex and composed of a variety of components, including integral membrane proteins (claudins, occludins, and junctional adhesion molecules, JAMs) and peripheral membrane proteins
• the Claudin protein family currently comprises 24 described members of different cell types, of which 21 are components Known as tight junction in epithelial membranes of the kidney, liver, brain and intestinal tissue, claudins are found in homo- and heterotypic arrangements in single tight junctions and can be divided into two main categories: pore-sealing and pore-sealing.
• Claudin-1, -3, -4, -5, -7 and -19 are known as Claudine pore-sealing.
• Increased expression of pore-sealing claudins results in an increase in the density of epithelial tissues, and increased transepithelial electrical resistance (TEER) and decreasing permeability of the epithelial tissues (Khan N, Asif, AR (2015) Transcriptional Regulators of Claudins in Epithelial Tight Junctions, Mediators Inflamm, Volume 2015, Article ID 219843, doi: 10.1 155/2015/219843). Based on this scheme, experiments were performed to detect the effects of ectoine on epithelial tissue.
• the OECD Guidance Document 28 recommends the determination, for example by means of transepithelial electrical resistance (TEER), as shown in Fig. 1.
• TEER transepithelial electrical resistance
• Example 1 Influence of compatible solutes on the transepithelial electrical
• TEER a defined thickness (U) of a direct current (DC) is applied between two electrodes E1 and E2, the monolayer being arranged between the two electrodes (FIG. 1), so that the applied direct current (DC) flowing through the cells.
• the measurement of TEER takes place with an epithelial voltometer (EVOM2).
• EVOM2 epithelial voltometer
• a decrease in the transepithelial electrical resistance [ohms] indicates a defective barrier function of the epithelial cells and thus a lower membrane integrity.
• PBS untreated epithelial cells
• SDS treated epithelial cells
• BAK air drying with and without ectoine
• epithelial cells were seeded on special cell culture carriers with a membrane (ThinCerts, pore size 0.4 ⁇ ) in in vitro experiments and cultured to a closed, single-layer cell layer (synonymous epithelial monolayer) on the membrane (Fig. 1).
• the intact epithelial monolayer was in each case controlled by a TEER measurement.
• the epithelial cells formed an intact epithelial monolayer with an intact epithelial barrier (selective permeability barrier).
• selective permeability barrier selective permeability barrier.
• TR146 cells of an intact epithelial monolayer were incubated for 12 hours (h) in cell culture medium with PBS (control), 50 mM ectoine and 0.1% lecithin (positive control) , Immediately after the incubation, the TEER was measured as shown in FIG.
• LLC-PK1 porcine renal epithelial cells
• HaCat human keratinocytes
• PBS control
• 50 mM ectoine 50 mM ectoine
• 100 mM ectoine 100 mM ectoine incubated.
• a stress treatment was carried out by air drying for 5 min at room temperature (RT) under the sterile bench (FIG. 5). After air drying at RT under sterile conditions, the cells were again covered with medium including OVA-allergen (250 ⁇ g ml) and incubated for 24 h at 37 ° C in an incubator and then the TEER value was measured.
• OVA-allergen 250 ⁇ g ml
• the measurement of the TEER is a direct way to obtain information about the functionality of the barrier of epithelial tissues, in particular for membrane integrity and stability.
• a decrease in the TEER directly points to a disturbed membrane, in particular a defective barrier.
• Chemicals such as SDS and B ⁇ K are capable of destroying the membrane, which shows in decreasing TEER values. At too high a concentration of these chemicals, the affected epithelial cells can not recover and die.
• the in vitro experiments described above demonstrate a protective and stabilizing effect of ectoine on the membrane stability or on the barrier function of the epithelial cells based on TEER values of different epithelial cell lines.
• the TEER values [ohms] were each higher than the TEER values of the control without ectoin (PBS).
• the tests show a protective effect of ectoine against detergents and preservatives.
• the cell culture vessel (6) comprises an inner (7) and an outer (5) reservoir, wherein both compartments are separated by a transparent, ThinCert membrane (3) with a pore size of 0.4 ⁇ m.
• This pore size allows for cytokine and protein movement between the outer and inner reservoirs ( Figure 6).
• Eukaryotic cells can not penetrate this membrane and therefore form a single layer closed cell layer which covers the entire membrane.
• an arrangement is achieved in this experimental set-up which reflects the apical side (outer reservoir) and basolateral side (inner reservoir within the insert) of the epithelial cells.
• allergens e.g. the ovalbumin (OVA) due to their small molecule size, the membrane pass without problems.
• OVA ovalbumin
• OVA can pass this membrane barrier only from the apical to the basolateral side by gaps, tight junction or trancytosis (Ding L, Zhang Y, Jiang Y, Wang L, Liu B, Liu J (2014 ) Transport of egg white ACE inhibitory peptides, Gln-Ile-Gly-Leu-Phe, in human intestinal Caco-2 cell monolayers with cytoprotective effect J Agric Food Chem (Epub ahead of print)).
• the cells of the respective cell line were cultured on a membrane (3) (FIG. 6) until the formation of a closed monolayer cell layer (2) (synonymous epithelial monolayer).
• the epithelial monolayer was pretreated with ectoine (10, 50, 100 mM) for 6 hours in cell culture medium.
• the epithelial monolayer was incubated with 250 ⁇ g ml of the allergen OVA ( Figure 6), (4) overnight.
• the OVA content in the inner and outer reservoirs was measured by OVA specific ELISA and the relative penetration of the epithelial monolayer with OVA in pretreated and untreated cells was determined.
• the epithelial monolayer on the membrane was stressed for 5 minutes by air drying and fluid loss. For this, the cell culture supernatant was removed and the epithelial monolayer was fixed diagonally in a new 12-well plate, so that the liquid could flow off. After drying, the epithelial monolayer was transferred again into the cell culture medium and treated with ectoine and allergen analogously to 2.1.1. 2.2 results
• Ectoin has been shown to be able to stabilize the membrane structure and barrier function of epithelial tissues and to inhibit the penetration of allergens.
• ectoine and its derivatives as compatible solutes according to the invention are suitable both for use in the prevention and treatment of barrier defects in epithelial tissues, in particular diseases with at least one barrier defect in at least one cell layer of at least one epithelial tissue.
• these tests were not carried out in the present case, it is to be expected that experiments with artificial skin models (eg Phenion model, Henkel) or in animal experiments will confirm the results.
• the HaCat cell line was cultured in a plastic cell culture vessel until a closed single layer cell layer (HaCat monolayer) was formed. Subsequently, the monolayer was pretreated with 50 mM or 100 mM ectoine for 6 hours (h) in the cell culture medium. After the pretreatment, a temperature treatment of the cells was carried out at 44 ° C for 30 min. After the heat stress, the monolayer was incubated again at 37 ° C. in the incubator for 24 hours. Subsequently, the HaCat monolayer was harvested and after lysis by cryoshock (freezing, thawing and scraping with spatula) the lysate was analyzed for claudin-1 by ELISA.
• cryoshock freezing, thawing and scraping with spatula
• HaCat human keratinocytes
• ectoine induces increased expression of claudin-1 after heat stress.
• the increased expression of claudin-1 is expected to correlate with an increase in TEER, demonstrating the strengthening of the barrier function of HaCat cells following a drying stress.
• compatible solutes such as ectoine and its derivatives, stabilize the cell membrane and thus strengthen the barrier function of the respective epithelial cells, in particular epithelial tissue.
• ectoine inhibits the penetration of bio-based noxae (Table 1) such as toxins and allergens.

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