WO2008072905A1 - Composition comprising hyaluronic acid and/or its salts for treatment of atopic dermatitis - Google Patents
Composition comprising hyaluronic acid and/or its salts for treatment of atopic dermatitis Download PDFInfo
- Publication number
- WO2008072905A1 WO2008072905A1 PCT/KR2007/006486 KR2007006486W WO2008072905A1 WO 2008072905 A1 WO2008072905 A1 WO 2008072905A1 KR 2007006486 W KR2007006486 W KR 2007006486W WO 2008072905 A1 WO2008072905 A1 WO 2008072905A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- hyaluronic acid
- resveratrol
- atopic dermatitis
- composition according
- Prior art date
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Classifications
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- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- 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
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/34—Alcohols
- A61K8/347—Phenols
-
- 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
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
-
- 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
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
-
- 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
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
Definitions
- the present invention relates to a composition for prevention and treatment of atopic dermatitis, comprising hyaluronic add and/or a salt thereof, and a pharmaceutical composition comprising a therapeutically effective amount of the same.
- Atopic dermatitis is a deep-seated chronic disease which is accompanied by severe pruritus and a subsequent secondary infection of an inflammation. Incidence of atopic dermatitis is high among Western people, and particularly about 10% of children suffer from such a condition, while showing a gradual increase of morbidity thereof in recent years. Also in Korea, onset of atopic dermatitis has been rapidly increasing year by year. However, with high incurability and poor elucidation of pathogenic causes, most of therapeutic regimens have been made largely on symptomatic treatment of the disease. According to recent publication that atopic dermatitis is caused by immunological abnormalities, new medical therapies have been attempted to treat atopic dermatitis.
- Immunological abnormalities are characterized by manifestation of hypersensitivity which is an exaggerated or inappropriate immune response of the body to a foreign agent.
- An allergic reaction which is a type 1 hypersensitivity, is induced by antigen-specific IgE antibodies, but exposure of a subject to the same antigen may or may not provoke an allergic reaction, from person to person. For this reason, the allergic reaction is called atopy, meaning an idiosyncratic reaction of the body.
- atopic diseases may include allergic rhinitis, asthma, food allergy, atopic dermatitis, and the like.
- T-helper (Th) cells are in charge of immune functions in the body, and are divided into ThI cells and Th2 cells which show a reciprocal balance and secrete antagonistic substances against each other.
- Th T helper
- Thl/Th2 imbalance has been observed in atopic dermatitis patients.
- secretion of eosinophils implicated in allergic reactions, and secretion of interleukin (IL)-4, IL-5 and IL-10, which stimulate production of IgE antibodies, are increased among Th2 type cells, whereas secretion of substances which inhibit production of IgE is decreased among ThI type cells.
- Increased levels of IgE result in activation of basophils and mast cells. Binding of IgE to an IgE receptor (Fc ⁇ RI), followed by subsequent crosslinking of an allergen with the Fc ⁇ RI/IgE binding complex, brings about activation of basophils and mast cells, which consequently results in a process called degranulation.
- Fc ⁇ RI IgE receptor
- steroid and antihistamine medications are currently and widely used in the treatment of atopic dermatitis which is an allergic disease.
- a serious case involves administration of immunosuppressants.
- these drugs merely exhibit transient therapeutic effects and are highly susceptible to the oxurrence of adverse side effects such as osteoporosis, avascular necrosis, arteriosclerosis, glaucoma, tum- origenidty, and the like. Therefore, there is an urgent need for development of a novel therapeutic agent which is intended for symptomatic alleviation and treatment of atopic dermatitis and which is capable of providing high and long-lasting therapeutic effects in conjunction with minimum adverse side effects.
- IgE class antibodies serve as the principal mediator for atopic dermatitis as discussed above, suppression of excessive secretion of IgE antibodies elicits anti- itching and anti-inflammatory effects, which consequently can provide anti-atopic dermatitis effects. That is, a material with an IgE-suppressive activity can overcome the problems which are suffered by the aforementioned steroids, antihistamines and immunosuppressants, and can provide more fundamental approach affecting the basic underlying cause(s) of atopic dermatitis, thereby exhibiting excellent therapeutic effects on the disease.
- a composition comprising hyaluronic acid and/or a hyaluronic acid salt, and preferably res- veratrol exhibits significant effects on amelioration and treatment of atopic dermatitis.
- the present invention has proposed a composition for prevention and treatment of atopic dermatitis, comprising hyaluronic acid and/or a hyaluronic acid salt.
- Hyaluronic acid (HA) is a heteropolysaccharide consisting of alternating residues of
- HA is a linear polymer with a molecular weight of 2x10 5 Da or higher.
- HA is a biomaterial found in a variety of body fluids and tissues, cow's eyes, cockscombs, connective tissues of animals, placenta and umbilical cord.
- a high concentration of HA is found particularly in joint cartilages and eyes, so it is used for various medical applications such as an injectable anti-arthritic agent, an injection for assistance of ophthalmic surgery, a dry eye drug, and the like.
- a family of enzymes that degrade hyaluronic acid is present in the body, and HA absorbs several hundred times its weight in water to thereby form a gel.
- the thus- formed HA gel has a very high viscosity which consequently slows a release rate of a drug, so a great deal of research and study has been actively undertaken on utilization of hyaluronic add in the field of Drug Delivery Systems (DDSs) (see JP 1989-287041), USP 5416071, and US 2003/0064105).
- Hyaluronic add captures moisture to form a gel, and is therefore used for various cosmetic applications such as cosmetic moisturizers, cosmetic supplements for reduction of wrinkles, and the like (KR 2005-0048287, KR 2004-0024004, and KR 2003-0061447).
- a composition for prevention and treatment of atopic dermatitis comprising hyaluronic add and/or a hyaluronic add salt.
- the inventors of the present invention conducted an ear edema test in conjunction with a measurement of a blood IgE level, using an animal model of atopic dermatitis. As a result, it was confirmed that the aforesaid composition exhibits excellent therapeutic effects on atopic dermatitis.
- Hyaluronic acid is a naturally occurring biopolymer and is a colorless and transparent linear polysaccharide having a high viscosity and a molecular weight of 5xlO 4 to 13xlO 6 Dalton and containing alternating N-acetyl-D-glucosamine and D- glucuronic acid monosaccharide as repeat units.
- Hyaluronic acid may be extracted and purified from various and diverse organisms and tissues such as vitreous humor, joint synovial fluid, cockscomb, and the like, by a conventional method known in the art, such as acid solubilization, alkaline solubilization, neutral solubilization and enzymatic solubilization.
- the composition of the present invention may employ hyaluronic acid as well as a hyaluronic acid salt.
- Preferred examples of the hyaluronic acid salts may include, but are not limited to, sodium hyaluronate, potassium hya- luronate, ammonium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, cobalt hyaluronate, and any combination thereof.
- IVbre preferred is sodium hyaluronate.
- Hyaluronic acid or its salts may have various ranges of a molecular weight, depending upon extraction and purification methods, determination methods, etc. As the molecular weight increases, hyaluronic acid or a salt thereof is likely to form a gel even with a small amount thereof.
- a preferred content of hyaluronic acid in a hyaluronic acid composition is more than 2% by weight when the molecular weight of hyaluronic acid is 1x10 6 Da, and is more than 0.5% by weight when the molecular weight of hyaluronic acid is 3x10 6 Da.
- the molecular weight and content of hyaluronic acid or a salt thereof in the composition of hyaluronic acid and/or a salt thereof should be sufficient to form a hyaluronic acid gel.
- the molecular weight of hyaluronic acid is preferably 2x10 5 Da or higher and more preferably IxIO 6 to IxIO 7 Da, and the preferred content of hyaluronic acid is in a range of 0.5 to 50% by weight, based on the total weight of the composition.
- the aforesaid composition may further comprise resveratrol, in addition to hyaluronic acid and/or a salt thereof.
- resveratrol in addition to hyaluronic acid and/or a salt thereof.
- Resveratrol is a polyphenol antioxidant having a structure of
- resveratrol is known to have various beneficial effects such as anti-cancer activity, antioxidative activity, anti-inflammatory activity, cholesterol-lowering activity, prophylactic effects on cardiovascular diseases, and the like (WbI. Nutr. Food Res., 49, 405-430, 2005; Biomed.
- Resveratrol exists in two isoforms; trans-resveratrol and ds-resveratrol where the trans-isomer is the more stable form in nature.
- trans-resveratrol As the naturally occurring trans- resveratrol was reported to inhibit the primary stages of carcinogenesis and have an anticancer activity (Science, 275, 218-220, 1997), a great deal of research and study has been actively focused on utilization of resveratrol.
- trans-resveratrol trans-3,5,4'-trihyiroxystilbene
- a resveratrol source there may be used a resveratrol-containing extract, resveratrol which is obtained from any suitable plant species, or synthetic resveratrol. Typical examples of such a plant species may include gymnospermous plants and dicotyledonous plants.
- resveratrol may be extracted and purified from grape fruits, rinds, seeds, stems and leaves, particularly of Vitis vinifera, Vitis rotundifolia and Vitis labrusca grapes, Polygonum cuspidatum, eucalyptus, Spruce, Scottish pine, peanut, lily, and the like.
- extracts of the above-mentioned plant species may be used alone or in any combination thereof, or otherwise an extract containing a small amount of resveratrol may be used. It is preferred to use a purified resveratrol extract with a high purity of more than 90%.
- the content of resveratrol may be in a range of preferably 0.01 to 50% by weight and more preferably 0.01 to 10% by weight.
- the composition may be a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or vehicles.
- the pharmaceutical composition may further comprise additional ingredients such as a solvent, an oil, an emulsifying agent, or the like, in order to increase the solubility of resveratrol.
- additional materials may be used alone or in any combination thereof, and may be easily and appropriately selected upon preparation of the composition.
- Examples of the solvent that can be used in the present invention may include water, ethanol, isopropanol, 1,3-butylene glycol, propylene glycol, glycerol, and the like.
- the oil used in the present invention may be at least one selected from the group consisting of corn oil, sesame oil, cotton seed oil, soybean oil, peanut oil, mono-, di- and tri-glyceride, mineral oil, squalene, jojoba oil, olive oil, evening primrose oil, borage oil, grape seed oil and any combination thereof.
- emulsifying agent there may be used, for example lecithin, organic monoglyceride, sorbitan fatty acid ester, polyoxyethylene fatty add ester, sorbitan stearate, and the like.
- the composition may be preferably formulated into a cosmetic composition comprising one or more cosmetically acceptable carriers or vehicles. That is, the composition may be prepared into a composition for prevention and treatment of atopic dermatitis in the form of a cosmetic or cosmetic additive.
- the cosmetically acceptable carriers or vehicles may be identical with or different from the pharmaceutically acceptable carriers or vehicles.
- composition of the present invention when it is desired to use the composition of the present invention as a cosmetic raw material, the composition can be added by itself or can be used in conjunction with other cosmetic ingredients, or may be used appropriately according to other conventional methods.
- Cosmetics include, but are not limited to, aftershaves, lotions, creams, packs and color cosmetics.
- the cosmetic composition may be formulated into various forms of the compositions such as a gel, a cream, an ointment, and the like.
- the gel, cream, and ointment type compositions may be appropriately prepared using a known method, by adding conventional softening agents, emulsifying agents and thickening agents or other materials known in the art, depending upon a desired dosage form of the composition.
- the gel type composition may be prepared, for example, by addition of softening agents such as trimethylolpropane, polyethylene glycol and glycerin, solvents such as propylene glycol, ethanol and isocetyl alcohol, and purified water.
- softening agents such as trimethylolpropane, polyethylene glycol and glycerin
- solvents such as propylene glycol, ethanol and isocetyl alcohol
- the cream type composition may be prepared, for example, by addition of fatty alcohols such as stearyl alcohol, myristyl alcohol, behenyl alcohol, arachidic alcohol, isostearyl alcohol and isocetyl alcohol; emulsifying agents such as lipids, e.g.
- lecithin phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phos- phatidylinositol, and derivatives thereof, glyceryl stearate, sorbitan palmitate, sorbitan stearate and the like; natural fats and oils such as avocado oil, apricot oil, babassu oil, borage oil, camellia oil and the like; lipid compositions such as ceramide, cholesterol, fatty acid, phytosphingosine, lecithin, and the like; solvents such as propylene glycol and the like; and purified water.
- natural fats and oils such as avocado oil, apricot oil, babassu oil, borage oil, camellia oil and the like
- lipid compositions such as ceramide, cholesterol, fatty acid, phytosphingosine, lecithin, and the like
- solvents such as propylene glycol and the like
- purified water
- the ointment type composition may be prepared, for example, by addition of softening agents, emulsifying agents and waxes such as microcrystalline wax, paraffin, ceresin, beeswax, spermaceti wax, Vaseline and the like.
- a pharmaceutical preparation for prevention and/or treatment of atopic dermatitis comprising the above-mentioned composition as an active ingredient, and one or more pharmaceutically acceptable carriers or vehicles.
- the above-mentioned preparation may contain pharmaceutically acceptable carriers, diluents, vehicles or any combination thereof, if necessary. These components facilitate administration of the active ingredient into the organism.
- the carrier is defined as a compound that facilitates addition of a compound or substance of interest into target cells or tissues.
- the carrier may be preferably one conventionally used in the art depending upon desired formulations, for example at least one selected from the group consisting of solid carriers such as starch, lactose, mannitol, carboxymethylcellulose, corn starch and inorganic salts; liquid carriers such as distilled water, physiological saline, aqueous gluoose solutions, alcohols such as ethanol, propylene glycol, and polyethylene glycol; and oily carriers such as various animal and vegetable oils, white Vaseline, paraffin and wax.
- solid carriers such as starch, lactose, mannitol, carboxymethylcellulose, corn starch and inorganic salts
- liquid carriers such as distilled water, physiological saline, aqueous gluoose solutions, alcohols such as ethanol, propylene glycol, and polyethylene glycol
- oily carriers such as various animal and vegetable oils, white Vas
- Examples of vehicles may include fillers such as lactose, sucrose, mannitol and sorbitol, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, hjdroxypropylmethylcellulose, sodium carboxymethylcellulose, and/ or cellulosic materials such as polyvinylpyrrolidone (PVP).
- fillers such as lactose, sucrose, mannitol and sorbitol
- corn starch wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, hjdroxypropylmethylcellulose, sodium carboxymethylcellulose, and/ or cellulosic materials such as polyvinylpyrrolidone (PVP).
- PVP polyvinylpyrrolidone
- the pharmaceutical formulation may be a parenteral preparation. Preparation of the composition into the parenteral formulation may be carried out by a conventional method known in the art, using a sterile aqueous solution, a non-aqueous solvent, a suspension, an emulsion, or a ljophilizate, as a base material.
- the pharmaceutical formulation may be an oral preparation.
- the oral preparation may be formulated into a capsule, suspension, emulsion, syrup or aerosol form by a conventional method known in the art.
- the pharmaceutical formulation may include other dosage forms such as a suppository.
- Resveratrol purity: more than 99%, available from Sigma was dissolved to a 0.1%
- the ear edema model is an animal model in which an ear of an mouse is sensitized with a hapten (a low-molecular weight substance which combines with a protein to thereby become an allergen) to induce an atopic reaction, and a thickness of the ear swollen with the passage of time is measured to confirm therapeutic effects against atopic dermatitis (Journal of Dermatological Science, 36, 1-9, 2004; and Journal of Dermatological Science, 37, 159-167, 2005).
- a hapten a low-molecular weight substance which combines with a protein to thereby become an allergen
- This experiment employed Balb/C mice (male, 5 weeks old) and 2,4-dinitro-l-chloro-benzene (DNCB, Sigma) as a hapten.
- Each animal group consisted of 5 mice.
- 30 ⁇ i of a 1% DNCB solution in acetone was applied to a right ear of mice to cause ear sensitization.
- 30 ⁇ i of a 1% DNCB solution was applied daily to the animals to cause atopic dermatitis.
- 30 ⁇ i of the hyaluronic acid gel of Example 1 and 30 ⁇ i of the resveratrol solution of Comparative example 1 were applied twice daily to a right ear of mice of each group.
- mice of Example 1 exhibited a significant difference of more than 40 ⁇ m, upon comparing with that of the control group, thus confirming excellent inhibitory effects of the hyaluronic acid gel on atopic dermatitis, and further confirming superior inhibitory effects to Comparative Example 1 with treatment of resveratrol. From these results, it can be seen that hyaluronic acid and resveratrol have therapeutic effects on atopic dermatitis, and particularly hyaluronic acid is remarkably effective for treatment of atopic dermatitis.
- resveratrol purity: more than 99%, available from Sigma
- resveratrol purity: more than 99%, available from Sigma
- mice In order to confirm therapeutic effects of a resveratrol-containing hyaluronic acid gel on atopic dermatitis, induction of atopic dermatitis on the back of mice was carried out as an animal model of atopic dermatitis.
- the mouse back dermatitis-induced model is an animal model in which the shaved back of an animal is subjected to hapten sensitization, followed by atopic induction for 4 to 5 weeks, a therapeutic drug is applied to the animal back for several days, and a level of IgE in blood is measured to confirm therapeutic effects against atopic dermatitis (Journal of Dermatological Science, 36, 1-9, 2004).
- Such an animal model is a beneficial model by which therapeutic effects against atopic dermatitis can be more directly confirmed because inhibitory effects of the drug on the IgE level are measured by determination of the blood IgE level.
- DNCB 2,4-dinitro-l-chloro-benzene
- Example 2 On Day 2 of treatment, the gel of Example 2 exhibited IgE level- inhibitory effects about 20% or more higher than the control group and about 10% or more higher than the lidomex group, thus representing that the resveratrol-containing hyaluronic acid gel of Example 2 has remarkable therapeutic effects on atopic dermatitis.
- use of only resveratrol exhibited anti-atopic dermatitis effects lower than use of only hyaluronic acid.
- a combined use of resveratrol with hyaluronic acid was found to exert significantly improved therapeutic effects, resulting from the complementary interaction therebetween, as compared to separate use of each compound.
- a pharmaceutical preparation containing hyaluronic acid is more therapeutically effective for treatment of atopic dermatitis than conventional steroid preparations.
- hyaluronic acid and resveratrol exerts pronounced therapeutic effects on atopic dermatitis.
- Example 3 Preparation of gel containing resveratrol and hyaluronic acid [72] 1% (w/w) sodium hyaluronate having a molecular weight of 3xlO 6 Da, 0.1% (w/w) resveratrol, 5% (w/w) glycerin, 3% (w/w) propylene glycol and a balance of purified water were mixed to prepare a gel.
- a composition comprising hyaluronic acid and/or a salt thereof in accordance with the present invention may be formulated into a pharmaceutical composition, a cosmetic composition or a pharmaceutical preparation which is thereby used for prevention and treatment of atopic dermatitis.
- resveratrol further incorporation of resveratrol into the aforesaid composition results in significantly excellent prophylactic and therapeutic effects on atopic dermatitis.
Abstract
Provided is a composition for prevention and treatment of atopic dermatitis, comprising hyaluronic acid and/or a salt thereof, and preferably resveratrol. The composition has therapeutic effects on amelioration and treatment of atopic dermatitis which is an allergic disease.
Description
Description
COMPOSITION COMPRISING HYALURONIC ACID AND/OR ITS SALTS FOR TREATMENT OF ATOPIC DERMATITIS
Technical Field
[1] The present invention relates to a composition for prevention and treatment of atopic dermatitis, comprising hyaluronic add and/or a salt thereof, and a pharmaceutical composition comprising a therapeutically effective amount of the same. Background Art
[2] Atopic dermatitis is a deep-seated chronic disease which is accompanied by severe pruritus and a subsequent secondary infection of an inflammation. Incidence of atopic dermatitis is high among Western people, and particularly about 10% of children suffer from such a condition, while showing a gradual increase of morbidity thereof in recent years. Also in Korea, onset of atopic dermatitis has been rapidly increasing year by year. However, with high incurability and poor elucidation of pathogenic causes, most of therapeutic regimens have been made largely on symptomatic treatment of the disease. According to recent publication that atopic dermatitis is caused by immunological abnormalities, new medical therapies have been attempted to treat atopic dermatitis.
[3] Immunological abnormalities are characterized by manifestation of hypersensitivity which is an exaggerated or inappropriate immune response of the body to a foreign agent. An allergic reaction, which is a type 1 hypersensitivity, is induced by antigen- specific IgE antibodies, but exposure of a subject to the same antigen may or may not provoke an allergic reaction, from person to person. For this reason, the allergic reaction is called atopy, meaning an idiosyncratic reaction of the body. Examples of atopic diseases may include allergic rhinitis, asthma, food allergy, atopic dermatitis, and the like.
[4] A specific action mechanism of the antigen- specific IgE class antibodies which are responsible for the incidence of allergic diseases will be illustrated as follows. T-helper (Th) cells are in charge of immune functions in the body, and are divided into ThI cells and Th2 cells which show a reciprocal balance and secrete antagonistic substances against each other. However, due to a polarization of T helper (Th) cells towards a dominance of Th2, Thl/Th2 imbalance has been observed in atopic dermatitis patients. That is, secretion of eosinophils implicated in allergic reactions, and secretion of interleukin (IL)-4, IL-5 and IL-10, which stimulate production of IgE
antibodies, are increased among Th2 type cells, whereas secretion of substances which inhibit production of IgE is decreased among ThI type cells. Increased levels of IgE result in activation of basophils and mast cells. Binding of IgE to an IgE receptor (FcεRI), followed by subsequent crosslinking of an allergen with the FcεRI/IgE binding complex, brings about activation of basophils and mast cells, which consequently results in a process called degranulation. At this time, physiologically active substances such as histamine are secreted extracellularly to thereby cause symptoms of atopic dermatitis such as intense itching, erythema, edema, inflammation, and the like. In fact, 80 to 90% of atopic dermatitis patients showed an increased level of serum IgE, and such an increased serum IgE level is known to have a high probability of allergic diseases (Cellular and Molecular Immunology, Abbas et al., 2 nd Edition, Saunders, Philadelphia; and Journal of Dermatological Science, 36, 1-9, 2004).
[5] Meanwhile, steroid and antihistamine medications are currently and widely used in the treatment of atopic dermatitis which is an allergic disease. A serious case involves administration of immunosuppressants. Unfortunately, these drugs merely exhibit transient therapeutic effects and are highly susceptible to the oxurrence of adverse side effects such as osteoporosis, avascular necrosis, arteriosclerosis, glaucoma, tum- origenidty, and the like. Therefore, there is an urgent need for development of a novel therapeutic agent which is intended for symptomatic alleviation and treatment of atopic dermatitis and which is capable of providing high and long-lasting therapeutic effects in conjunction with minimum adverse side effects.
[6] Since IgE class antibodies serve as the principal mediator for atopic dermatitis as discussed above, suppression of excessive secretion of IgE antibodies elicits anti- itching and anti-inflammatory effects, which consequently can provide anti-atopic dermatitis effects. That is, a material with an IgE-suppressive activity can overcome the problems which are suffered by the aforementioned steroids, antihistamines and immunosuppressants, and can provide more fundamental approach affecting the basic underlying cause(s) of atopic dermatitis, thereby exhibiting excellent therapeutic effects on the disease.
[7] In this connection, the inventors of the present invention have discovered that a composition comprising hyaluronic acid and/or a hyaluronic acid salt, and preferably res- veratrol exhibits significant effects on amelioration and treatment of atopic dermatitis. Based on this fact, the present invention has proposed a composition for prevention and treatment of atopic dermatitis, comprising hyaluronic acid and/or a hyaluronic acid salt.
[8] Hyaluronic acid (HA) is a heteropolysaccharide consisting of alternating residues of
D-glucuronic acid and N-acetylgluoosamine. HA is a linear polymer with a molecular weight of 2x105 Da or higher. HA is a biomaterial found in a variety of body fluids and tissues, cow's eyes, cockscombs, connective tissues of animals, placenta and umbilical cord. A high concentration of HA is found particularly in joint cartilages and eyes, so it is used for various medical applications such as an injectable anti-arthritic agent, an injection for assistance of ophthalmic surgery, a dry eye drug, and the like. Further, a family of enzymes that degrade hyaluronic acid is present in the body, and HA absorbs several hundred times its weight in water to thereby form a gel. The thus- formed HA gel has a very high viscosity which consequently slows a release rate of a drug, so a great deal of research and study has been actively undertaken on utilization of hyaluronic add in the field of Drug Delivery Systems (DDSs) (see JP 1989-287041), USP 5416071, and US 2003/0064105). Hyaluronic add captures moisture to form a gel, and is therefore used for various cosmetic applications such as cosmetic moisturizers, cosmetic supplements for reduction of wrinkles, and the like (KR 2005-0048287, KR 2004-0024004, and KR 2003-0061447).
[9] However, there is no case reporting that hyaluronic add and/or a hyaluronic add salt is therapeutically effective for alleviation and treatment of atopic dermatitis. Further, to the best of our knowledge, no attempt has been made in the art in which a composition comprising hyaluronic add and/or a hyaluronic add salt in conjunction with resveratrol was used for prevention and treatment of atopic dermatitis. Disclosure of Invention Technical Problem
[10] Accordingly, it is an object of the present invention to solve the above problems, and other technical problems that have yet to be resolved.
[11] As a result of a variety of extensive and intensive studies and experiments to solve the problems as described above, the inventors of the present invention have discovered that a composition comprising hyaluronic add and/or a hyaluronic add salt has significant effects on prevention and treatment of atopic dermatitis. The present invention has been completed based on these findings. Technical Solution
[12] In accordance with an aspect of the present invention, the above and other objects can be accomplished by the provision of a composition for prevention and treatment of atopic dermatitis, comprising hyaluronic add and/or a hyaluronic add salt.
[13] In order to confirm prophylactic and therapeutic effects of the aforesaid composition on atopic dermatitis, the inventors of the present invention, as will be illustrated in following Experimental Examples, conducted an ear edema test in conjunction with a measurement of a blood IgE level, using an animal model of atopic dermatitis. As a result, it was confirmed that the aforesaid composition exhibits excellent therapeutic effects on atopic dermatitis.
[14] Hyaluronic acid (HA) is a naturally occurring biopolymer and is a colorless and transparent linear polysaccharide having a high viscosity and a molecular weight of 5xlO4 to 13xlO6 Dalton and containing alternating N-acetyl-D-glucosamine and D- glucuronic acid monosaccharide as repeat units. Hyaluronic acid may be extracted and purified from various and diverse organisms and tissues such as vitreous humor, joint synovial fluid, cockscomb, and the like, by a conventional method known in the art, such as acid solubilization, alkaline solubilization, neutral solubilization and enzymatic solubilization.
[15] As defined hereinbefore, the composition of the present invention may employ hyaluronic acid as well as a hyaluronic acid salt. Preferred examples of the hyaluronic acid salts may include, but are not limited to, sodium hyaluronate, potassium hya- luronate, ammonium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, cobalt hyaluronate, and any combination thereof. IVbre preferred is sodium hyaluronate.
[16] Hyaluronic acid or its salts may have various ranges of a molecular weight, depending upon extraction and purification methods, determination methods, etc. As the molecular weight increases, hyaluronic acid or a salt thereof is likely to form a gel even with a small amount thereof. For example, a preferred content of hyaluronic acid in a hyaluronic acid composition is more than 2% by weight when the molecular weight of hyaluronic acid is 1x10 6 Da, and is more than 0.5% by weight when the molecular weight of hyaluronic acid is 3x10 6 Da.
[17] Meanwhile, the molecular weight and content of hyaluronic acid or a salt thereof in the composition of hyaluronic acid and/or a salt thereof should be sufficient to form a hyaluronic acid gel. Accordingly, the molecular weight of hyaluronic acid is preferably 2x105 Da or higher and more preferably IxIO6 to IxIO7 Da, and the preferred content of hyaluronic acid is in a range of 0.5 to 50% by weight, based on the total weight of the composition.
[18] In a preferred embodiment of the present invention, the aforesaid composition may further comprise resveratrol, in addition to hyaluronic acid and/or a salt thereof.
[19] According to the study conducted by the present inventors, even though each of hyaluronic acid and/or a hyaluronic acid salt and resveratrol may exhibit therapeutic effects on atopic dermatitis, a combined use of them was found to exert unexpectedly improved therapeutic effects, as compared to independent use of each compound. IVbre specifically, a specific combination of hyaluronic acid and/or a hyaluronic acid salt with resveratrol exerts significantly excellent therapeutic effects on atopic dermatitis by the complementary interaction without causing a competitive reaction therebetween. These facts will be experimentally verified in Examples and Experimental Examples which will follow hereinafter.
[20] Resveratrol is a polyphenol antioxidant having a structure of
3,5,4'-trihyiroxystilbene and is widely found in gymnospermous plants and dicotyledonous plants. Even though it may be present as both free and glycoside forms, resveratrol mostly exists in a glycoside form wherein a nonsugar component resveratrol is attached to a sugar component (J. Prog. Phytochem., 6, 203-209, 1980). Resveratrol is known to have various beneficial effects such as anti-cancer activity, antioxidative activity, anti-inflammatory activity, cholesterol-lowering activity, prophylactic effects on cardiovascular diseases, and the like (WbI. Nutr. Food Res., 49, 405-430, 2005; Biomed. Pharmacother., 56, 84-87, 2002; AJH, 18, 864-870, 2005; and Food Chemistry, 101, 449-457, 2007). Therefore, a great deal of research and study has been made on the feasibility of various applications such as antiinfluenza agents (KR 2005-0071627), anti-aging and skin- whitening components of cosmetics (KR 2004-0101665, and KR 2005-0039927), a functional health food (KR 2006-0015737), and the like.
[21] Resveratrol exists in two isoforms; trans-resveratrol and ds-resveratrol where the trans-isomer is the more stable form in nature. As the naturally occurring trans- resveratrol was reported to inhibit the primary stages of carcinogenesis and have an anticancer activity (Science, 275, 218-220, 1997), a great deal of research and study has been actively focused on utilization of resveratrol.
[22] According to the present invention, trans-resveratrol (trans-3,5,4'-trihyiroxystilbene) present in nature is preferred among ds and trans isomers. As a resveratrol source, there may be used a resveratrol-containing extract, resveratrol which is obtained from any suitable plant species, or synthetic resveratrol. Typical examples of such a plant species may include gymnospermous plants and dicotyledonous plants. Preferably, resveratrol may be extracted and purified from grape fruits, rinds, seeds, stems and leaves, particularly of Vitis vinifera, Vitis rotundifolia and Vitis labrusca grapes,
Polygonum cuspidatum, eucalyptus, Spruce, Scottish pine, peanut, lily, and the like.
[23] As a raw material for resveratrol, extracts of the above-mentioned plant species may be used alone or in any combination thereof, or otherwise an extract containing a small amount of resveratrol may be used. It is preferred to use a purified resveratrol extract with a high purity of more than 90%.
[24] The content of resveratrol may be in a range of preferably 0.01 to 50% by weight and more preferably 0.01 to 10% by weight.
[25] Preferably, the composition may be a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers or vehicles.
[26] If necessary, the pharmaceutical composition may further comprise additional ingredients such as a solvent, an oil, an emulsifying agent, or the like, in order to increase the solubility of resveratrol. These additional materials may be used alone or in any combination thereof, and may be easily and appropriately selected upon preparation of the composition.
[27] Examples of the solvent that can be used in the present invention may include water, ethanol, isopropanol, 1,3-butylene glycol, propylene glycol, glycerol, and the like.
[28] The oil used in the present invention may be at least one selected from the group consisting of corn oil, sesame oil, cotton seed oil, soybean oil, peanut oil, mono-, di- and tri-glyceride, mineral oil, squalene, jojoba oil, olive oil, evening primrose oil, borage oil, grape seed oil and any combination thereof.
[29] As the emulsifying agent, there may be used, for example lecithin, organic monoglyceride, sorbitan fatty acid ester, polyoxyethylene fatty add ester, sorbitan stearate, and the like.
[30] However, the above-mentioned materials are provided only for exemplification, and so other equivalent materials may also be used.
[31] Further, the composition may be preferably formulated into a cosmetic composition comprising one or more cosmetically acceptable carriers or vehicles. That is, the composition may be prepared into a composition for prevention and treatment of atopic dermatitis in the form of a cosmetic or cosmetic additive. The cosmetically acceptable carriers or vehicles may be identical with or different from the pharmaceutically acceptable carriers or vehicles.
[32] When it is desired to use the composition of the present invention as a cosmetic raw material, the composition can be added by itself or can be used in conjunction with other cosmetic ingredients, or may be used appropriately according to other conventional methods. Cosmetics include, but are not limited to, aftershaves, lotions,
creams, packs and color cosmetics.
[33] The cosmetic composition may be formulated into various forms of the compositions such as a gel, a cream, an ointment, and the like. The gel, cream, and ointment type compositions may be appropriately prepared using a known method, by adding conventional softening agents, emulsifying agents and thickening agents or other materials known in the art, depending upon a desired dosage form of the composition.
[34] The gel type composition may be prepared, for example, by addition of softening agents such as trimethylolpropane, polyethylene glycol and glycerin, solvents such as propylene glycol, ethanol and isocetyl alcohol, and purified water.
[35] The cream type composition may be prepared, for example, by addition of fatty alcohols such as stearyl alcohol, myristyl alcohol, behenyl alcohol, arachidic alcohol, isostearyl alcohol and isocetyl alcohol; emulsifying agents such as lipids, e.g. lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phos- phatidylinositol, and derivatives thereof, glyceryl stearate, sorbitan palmitate, sorbitan stearate and the like; natural fats and oils such as avocado oil, apricot oil, babassu oil, borage oil, camellia oil and the like; lipid compositions such as ceramide, cholesterol, fatty acid, phytosphingosine, lecithin, and the like; solvents such as propylene glycol and the like; and purified water.
[36] The ointment type composition may be prepared, for example, by addition of softening agents, emulsifying agents and waxes such as microcrystalline wax, paraffin, ceresin, beeswax, spermaceti wax, Vaseline and the like.
[37] In accordance with another aspect of the present invention, there is provided a pharmaceutical preparation for prevention and/or treatment of atopic dermatitis, comprising the above-mentioned composition as an active ingredient, and one or more pharmaceutically acceptable carriers or vehicles.
[38] Therefore, the above-mentioned preparation may contain pharmaceutically acceptable carriers, diluents, vehicles or any combination thereof, if necessary. These components facilitate administration of the active ingredient into the organism.
[39] The carrier is defined as a compound that facilitates addition of a compound or substance of interest into target cells or tissues. Although there is no particular limit to kinds of carriers, the carrier may be preferably one conventionally used in the art depending upon desired formulations, for example at least one selected from the group consisting of solid carriers such as starch, lactose, mannitol, carboxymethylcellulose, corn starch and inorganic salts; liquid carriers such as distilled water, physiological saline, aqueous gluoose solutions, alcohols such as ethanol, propylene glycol, and
polyethylene glycol; and oily carriers such as various animal and vegetable oils, white Vaseline, paraffin and wax.
[40] Examples of vehicles may include fillers such as lactose, sucrose, mannitol and sorbitol, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, hjdroxypropylmethylcellulose, sodium carboxymethylcellulose, and/ or cellulosic materials such as polyvinylpyrrolidone (PVP).
[41] In one preferred embodiment of the present invention, the pharmaceutical formulation may be a parenteral preparation. Preparation of the composition into the parenteral formulation may be carried out by a conventional method known in the art, using a sterile aqueous solution, a non-aqueous solvent, a suspension, an emulsion, or a ljophilizate, as a base material.
[42] In another preferred embodiment of the present invention, the pharmaceutical formulation may be an oral preparation. The oral preparation may be formulated into a capsule, suspension, emulsion, syrup or aerosol form by a conventional method known in the art.
[43] Alternatively, the pharmaceutical formulation may include other dosage forms such as a suppository. Mode for the Invention
[44] Now, the present invention will be described in more detail with reference to the following Examples. These examples are provided only for illustrating the present invention and should not be construed as limiting the scope and spirit of the present invention.
[45]
[46] Example 1 : Preparation of hyaluronic acid gel
[47] 1 g of sodium hyaluronate having a molecular weight of 3x106 Da was dissolved to a
1% (w/w) concentration in a balance of purified water to thereby prepare a hyaluronic acid gel.
[48]
[49] Comparative Example 1 : Preparation of resveratrol solution
[50] Resveratrol (purity: more than 99%, available from Sigma) was dissolved to a 0.1%
(w/w) concentration in ethanol to prepare a resveratrol solution.
[51]
[52] Experimental Example 1 : Ear edema test in mice
[53] In order to confirm prophylactic and therapeutic effects of a drug on atopic dermatitis, an experiment was carried out using an ear edema model as an animal
model of atopic dermatitis. The ear edema model is an animal model in which an ear of an mouse is sensitized with a hapten (a low-molecular weight substance which combines with a protein to thereby become an allergen) to induce an atopic reaction, and a thickness of the ear swollen with the passage of time is measured to confirm therapeutic effects against atopic dermatitis (Journal of Dermatological Science, 36, 1-9, 2004; and Journal of Dermatological Science, 37, 159-167, 2005).
[54] This experiment employed Balb/C mice (male, 5 weeks old) and 2,4-dinitro-l-chloro-benzene (DNCB, Sigma) as a hapten. Each animal group consisted of 5 mice. 30 μi of a 1% DNCB solution in acetone was applied to a right ear of mice to cause ear sensitization. One week later, 30 μi of a 1% DNCB solution was applied daily to the animals to cause atopic dermatitis. At the same time, 30 μi of the hyaluronic acid gel of Example 1 and 30 μi of the resveratrol solution of Comparative example 1 were applied twice daily to a right ear of mice of each group. Prior to DNCB sensitization, and on Days 1 and 3 after atopic induction, an ear thickness of animals was measured using a digital micrometer (Digitrix, NSK, Japan). The thus- obtained results showing an increase in the ear thickness after atopic induction are given in Table 1 below.
[55] [Table 1] Increased ear thickness (μm) [56]
[57] As can be seen from Table 1, the control (non-treatment) group exhibited a significant increase in the ear thickness of animals with the passage of atopic induction time. On Day 3, it can be seen that an increase in the ear thickness of atopy-induced mice of Example 1 and Comparative Example 1 is significantly lower, as compared to atopy-induced mice of the control (non-treatment) group, thus representing inhibitory effects of the drug on ear edema. In particular, an increased ear thickness in mice of Example 1 exhibited a significant difference of more than 40 μm, upon comparing with that of the control group, thus confirming excellent inhibitory effects of the hyaluronic acid gel on atopic dermatitis, and further confirming superior inhibitory effects to Comparative Example 1 with treatment of resveratrol. From these results, it can be seen that hyaluronic acid and resveratrol have therapeutic effects on atopic dermatitis, and particularly hyaluronic acid is remarkably effective for treatment of atopic
dermatitis.
[38]
[39] Example 2: Preparation of hyaluronic add gel containing resveratrol
[60] 1 g of sodium hyaluronate having a molecular weight of 3xlO6 Da was dissolved to a
1% (w/w) concentration in a balance of purified water to thereby prepare a hyaluronic acid gel. Thereafter, resveratrol (purity: more than 99%, available from Sigma) was added to a 0.1% (w/w) concentration in the hyaluronic acid gel to thereby prepare a hyaluronic acid gel containing resveratrol.
[61]
[62] Experimental Example 2: Induction of atopic dermatitis on back of mice
[63] In order to confirm therapeutic effects of a resveratrol-containing hyaluronic acid gel on atopic dermatitis, induction of atopic dermatitis on the back of mice was carried out as an animal model of atopic dermatitis. The mouse back dermatitis-induced model is an animal model in which the shaved back of an animal is subjected to hapten sensitization, followed by atopic induction for 4 to 5 weeks, a therapeutic drug is applied to the animal back for several days, and a level of IgE in blood is measured to confirm therapeutic effects against atopic dermatitis (Journal of Dermatological Science, 36, 1-9, 2004). Such an animal model is a beneficial model by which therapeutic effects against atopic dermatitis can be more directly confirmed because inhibitory effects of the drug on the IgE level are measured by determination of the blood IgE level.
[64] This experiment employed Balb/C mice (male, 5 weeks old) and
2,4-dinitro-l-chloro-benzene (DNCB, Sigma) as a hapten. Each animal group consisted of 5 mice. 200 jΛ of a 1% DNCB solution in acetone (acetone :olive oil = 3:1) was applied to the shaved back of mice to cause hapten sensitization. One week later, 200 jΛ of a 0.5% DNCB solution was applied once every two days to the animals for 5 weeks to thereby cause atopic dermatitis. After induction of atopic dermatitis was complete, 200 μJl of each hyaluronic acid gel of Examples 1 and 2 and 200 μJl of a lidomex cream (ingredient: Prednisolone Valerate Acetate, Sama Pharmaceutical Co., Ltd., Korea) as a steroid drug (positive control) were applied twice daily to the dermatitis-induced back of mice, for 5 days. A control group was non-treated. Prior to administration of the drug, and on Days 2 and 5 after administration of the drug, blood was collected from tails of mice. Sera were separated and then a blood IgE level was measured by IVbuse IgE ELISA (Alpha Diagnostic International). Based on a blood IgE level prior to administration of the drug, the blood IgE levels after treatment of the drug on mice were calculated. The results thus obtained are given in Table 2 below.
[65] [Table 2] [66]
[67] As can be seen from Table 2, it was confirmed that the steroid drug lidomex and gels of Examples 1 and 2 exhibit higher inhibitory effects on IgE levels in atopy- induced mice, as compared to the control group. IVbre surprisingly, the hyaluronic add gel of Example 1 and the resveratrol-containing hyaluronic acid gel of Example 2 were significantly superior in IgE level-inhibitory effects, as compared to the steroid drug which is currently used in atopic treatment. As discussed hereinbefore, it is possible to understand direct therapeutic effects of the drug on atopic dermatitis from a degree of inhibition on the IgE level. Therefore, it can be seen that both drugs of Examples 1 and 2 exhibit superior therapeutic effects on atopic dermatitis, as compared to the steroid drug.
[68] In particular, on Day 2 of treatment, the gel of Example 2 exhibited IgE level- inhibitory effects about 20% or more higher than the control group and about 10% or more higher than the lidomex group, thus representing that the resveratrol-containing hyaluronic acid gel of Example 2 has remarkable therapeutic effects on atopic dermatitis. As can be seen from the results of the aforementioned Experimental Example 1, use of only resveratrol exhibited anti-atopic dermatitis effects lower than use of only hyaluronic acid. However, a combined use of resveratrol with hyaluronic acid, as can be seen from the results of Table 2, was found to exert significantly improved therapeutic effects, resulting from the complementary interaction therebetween, as compared to separate use of each compound.
[69] In conclusion, a pharmaceutical preparation containing hyaluronic acid is more therapeutically effective for treatment of atopic dermatitis than conventional steroid preparations. In particular, it was demonstrated that the simultaneous incorporation of hyaluronic acid and resveratrol exerts pronounced therapeutic effects on atopic dermatitis.
[70] [71] Example 3: Preparation of gel containing resveratrol and hyaluronic acid [72] 1% (w/w) sodium hyaluronate having a molecular weight of 3xlO6 Da, 0.1% (w/w)
resveratrol, 5% (w/w) glycerin, 3% (w/w) propylene glycol and a balance of purified water were mixed to prepare a gel.
[73]
[74] Example 4: Preparation of cream containing resveratrol and hyaluronic acid
[75] 1% (w/w) sodium hyaluronate having a molecular weight of 3xlO6 Da, 0.1% (w/w) resveratrol, 2.5% (w/w) stearyl alcohol, 2.5% (w/w) sorbitan stearate, 5% (w/w) camellia oil, 0.1% (w/w) ceramide, 3% (w/w) propylene glycol and a balance of purified water were mixed to prepare a cream.
[76]
[77] Example 5: Preparation of ointment containing resveratrol and hyaluronic acid
[78] 50% of a gel containing 1% (w/w) sodium hyaluronate having a molecular weight of
3xlO6 Da, 0.1% (w/w) resveratrol, 5% (w/w) glycerin, 1% (w/w) sorbitan stearate, and a balance of Vaseline were mixed to prepare an ointment. Industrial Applicability
[79] As apparent from the above description, a composition comprising hyaluronic acid and/or a salt thereof in accordance with the present invention may be formulated into a pharmaceutical composition, a cosmetic composition or a pharmaceutical preparation which is thereby used for prevention and treatment of atopic dermatitis. In particular, further incorporation of resveratrol into the aforesaid composition results in significantly excellent prophylactic and therapeutic effects on atopic dermatitis.
Claims
[I] A composition for prevention and/or treatment of atopic dermatitis, comprising hyaluronic add and/or a hyaluronic acid salt.
[2] The composition according to claim 1, wherein the hyaluronic acid salt is selected from the group consisting of sodium hyaluronate, potassium hya- luronate, ammonium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, cobalt hyaluronate, and any combination thereof.
[3] The composition according to claim 2, wherein the hyaluronic acid salt is sodium hyaluronate.
[4] The composition according to claim 1, wherein the hyaluronic acid and/or the hyaluronic add salt has a molecular weight of 2x10 5 Da or higher.
[5] The composition according to claim 1, wherein the hyaluronic add and/or the hyaluronic add salt has a content of 0.5% by weight or higher, based on the total weight of the composition.
[6] The composition according to claim 1, further comprising resveratrol.
[7] The composition according to claim 6, wherein the resveratrol is trans-res- veratrol (trans-3,5,4'-trihyiroxystilbene).
[8] The composition according to claim 6, wherein the resveratrol has a purity of more than 90%.
[9] The composition according to claim 6, wherein the content of resveratrol is in the range of 0.01 to 50% by weight, based on the total weight of the composition.
[10] The composition according to any one of claims 1 to 9, wherein the composition is a pharmaceutical composition comprising a pharmaceutically arceptable carrier or vehicle.
[I I] The composition according to any one of claims 1 to 9, wherein the composition is a cosmetic composition comprising a cosmetically acceptable carrier or vehicle.
[12] The composition according to claim 11, wherein the cosmetic composition is formulated into a gel type.
[13] The composition according to claim 11, wherein the cosmetic composition is formulated into a cream type.
[14] The composition according to claim 11, wherein the cosmetic composition is formulated into an ointment type.
[15] A pharmaceutical preparation for prevention and treatment of atopic dermatitis, comprising the composition of claim 1 as an active ingredient, and one or more pharmaceutically acceptable carriers or vehicles.
[16] The preparation according to claim 15, wherein the preparation is a parenteral or oral preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007800410606A CN101534842B (en) | 2006-12-13 | 2007-12-12 | Composition comprising hyaluronic acid and/or its salts for treatment of atopic dermatitis |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2006-0127123 | 2006-12-13 | ||
| KR1020060127123A KR100927579B1 (en) | 2006-12-13 | 2006-12-13 | Composition Comprising Hyalruronic Acid and/or their Salt for Treatment of Atopic Dermatitis |
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| Publication Number | Publication Date |
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| WO2008072905A1 true WO2008072905A1 (en) | 2008-06-19 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/KR2007/006486 WO2008072905A1 (en) | 2006-12-13 | 2007-12-12 | Composition comprising hyaluronic acid and/or its salts for treatment of atopic dermatitis |
Country Status (3)
| Country | Link |
|---|---|
| KR (1) | KR100927579B1 (en) |
| CN (1) | CN101534842B (en) |
| WO (1) | WO2008072905A1 (en) |
Cited By (8)
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| WO2008094910A2 (en) * | 2007-01-30 | 2008-08-07 | Cypress Pharmaceutical, Inc. | Hyaluronate compositions |
| WO2010104281A2 (en) * | 2009-03-11 | 2010-09-16 | 주식회사 엘지생명과학 | Composition for improving atopic skin diseases |
| WO2012116391A1 (en) * | 2011-02-09 | 2012-09-07 | Lien Wendy | Cosmetic or pharmaceutical formulation |
| WO2016193791A1 (en) * | 2015-06-05 | 2016-12-08 | Caudalie Ip Limited | Process for stimulating hyaluronic acid synthesis |
| FR3036956A1 (en) * | 2015-06-05 | 2016-12-09 | Caudalie Ip Ltd | METHOD FOR STIMULATING THE SYNTHESIS OF HYALURONIC ACID |
| WO2019202015A1 (en) * | 2018-04-18 | 2019-10-24 | i.com medical GmbH | High molecular weight hyaluronic acid for enhancing epithelial survival and reconstitution of body surfaces |
| DE102022202547A1 (en) | 2021-12-09 | 2023-06-15 | Beiersdorf Aktiengesellschaft | Topically applicable preparation to improve the condition of the skin |
| WO2023104843A1 (en) | 2021-12-09 | 2023-06-15 | Beiersdorf Ag | Topical preparation for enhancing skin condition |
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| EP2545925B1 (en) | 2011-07-12 | 2018-02-14 | Holy Stone Healthcare Co.,Ltd. | Compositions comprising hyaluronic acid for treating and preventing mucosa related diseases |
| TWI446915B (en) * | 2011-07-12 | 2014-08-01 | Holy Stone Healthcare Co Ltd | Composition for use in treating and preventing mucosa related disease |
| CA2896038C (en) | 2015-07-03 | 2022-08-09 | Glycobiosciences Inc. | Polymer matrix compositions comprising a high concentration of bio-fermented sodium hyaluronate and uses thereof |
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| CN109045279B (en) * | 2018-09-10 | 2020-01-21 | 因之彩生物科技（武汉）有限公司 | External composition, application thereof and external therapeutic agent |
| KR102289551B1 (en) * | 2019-07-17 | 2021-08-13 | 주식회사 제이투케이바이오 | A skin-care agent containing hyaluronic acid complex |
| CN110237091A (en) * | 2019-07-27 | 2019-09-17 | 海南希睿达生物技术有限公司 | A kind of hyaluronic acid maintenance biomembrane can be used for children |
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| JPH10287550A (en) * | 1997-04-10 | 1998-10-27 | Nippon Rideia Oririi Kyokai | Preparation for external use for skin |
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| WO2008094910A3 (en) * | 2007-01-30 | 2008-11-27 | Cypress Pharmaceutical Inc | Hyaluronate compositions |
| WO2008094910A2 (en) * | 2007-01-30 | 2008-08-07 | Cypress Pharmaceutical, Inc. | Hyaluronate compositions |
| US8466128B2 (en) | 2007-01-30 | 2013-06-18 | Cypress Pharmaceuticals, Inc. | Hyaluronate compositions |
| US9937134B2 (en) | 2007-01-30 | 2018-04-10 | Cypress Pharmaceuticals, Inc. | Hyaluronate compositions |
| WO2010104281A2 (en) * | 2009-03-11 | 2010-09-16 | 주식회사 엘지생명과학 | Composition for improving atopic skin diseases |
| WO2010104281A3 (en) * | 2009-03-11 | 2010-12-23 | 주식회사 엘지생명과학 | Composition for improving atopic skin diseases |
| WO2012116391A1 (en) * | 2011-02-09 | 2012-09-07 | Lien Wendy | Cosmetic or pharmaceutical formulation |
| GB2502029B (en) * | 2011-02-09 | 2018-02-21 | Forward Scout Entpr Pty Ltd | Cosmetic or pharmaceutical formulation comprising hyaluronate crosspolymer and one or more of; azelaic acid, or derivative, and natural oils |
| US9931289B2 (en) | 2011-02-09 | 2018-04-03 | Forward Scout Enterprises Pty Ltd | Cosmetic or pharmaceutical formulation |
| GB2502029A (en) * | 2011-02-09 | 2013-11-13 | Wendy Lien | Cosmetic or pharmaceutical formulation |
| WO2016193791A1 (en) * | 2015-06-05 | 2016-12-08 | Caudalie Ip Limited | Process for stimulating hyaluronic acid synthesis |
| FR3036956A1 (en) * | 2015-06-05 | 2016-12-09 | Caudalie Ip Ltd | METHOD FOR STIMULATING THE SYNTHESIS OF HYALURONIC ACID |
| US10470987B2 (en) | 2015-06-05 | 2019-11-12 | Tomcat International Limited | Process for stimulating hyaluronic acid synthesis |
| WO2019202015A1 (en) * | 2018-04-18 | 2019-10-24 | i.com medical GmbH | High molecular weight hyaluronic acid for enhancing epithelial survival and reconstitution of body surfaces |
| JP2021522189A (en) * | 2018-04-18 | 2021-08-30 | アイ．コム メディカル ゲーエムベーハー | High molecular weight hyaluronic acid to enhance epithelial survival and body surface reconstruction |
| DE102022202547A1 (en) | 2021-12-09 | 2023-06-15 | Beiersdorf Aktiengesellschaft | Topically applicable preparation to improve the condition of the skin |
| WO2023104843A1 (en) | 2021-12-09 | 2023-06-15 | Beiersdorf Ag | Topical preparation for enhancing skin condition |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101534842A (en) | 2009-09-16 |
| KR20080054627A (en) | 2008-06-18 |
| CN101534842B (en) | 2013-07-03 |
| KR100927579B1 (en) | 2009-11-23 |
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