WO2018106009A1 - Composition comprenant un extrait de feuille d'arbre d'érable ou des fractions de ce dernier destinée à prévenir ou à traiter des maladies oculaires inflammatoires - Google Patents

Composition comprenant un extrait de feuille d'arbre d'érable ou des fractions de ce dernier destinée à prévenir ou à traiter des maladies oculaires inflammatoires Download PDF

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WO2018106009A1
WO2018106009A1 PCT/KR2017/014224 KR2017014224W WO2018106009A1 WO 2018106009 A1 WO2018106009 A1 WO 2018106009A1 KR 2017014224 W KR2017014224 W KR 2017014224W WO 2018106009 A1 WO2018106009 A1 WO 2018106009A1
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fraction
maple leaf
extract
composition
eye
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PCT/KR2017/014224
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English (en)
Korean (ko)
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마진열
김연희
오태우
박은희
조원경
임남희
오유창
구민정
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한국한의학연구원
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/20—Aceraceae (Maple family)
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/03—Organic compounds
    • A23L29/035—Organic compounds containing oxygen as heteroatom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • 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
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9789—Magnoliopsida [dicotyledons]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q1/00—Make-up preparations; Body powders; Preparations for removing make-up
    • A61Q1/02—Preparations containing skin colorants, e.g. pigments
    • A61Q1/10—Preparations containing skin colorants, e.g. pigments for eyes, e.g. eyeliner, mascara
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation or decoction

Definitions

  • the present invention provides a pharmaceutical composition for the prevention or treatment of inflammatory eye disease, including maple leaf extract or a fraction thereof; A method of treating said disease comprising administering said composition to an eye of a subject; Quasi-drug compositions; Eye cosmetic additive compositions; Health functional food composition; And feed compositions.
  • Inflammatory disease is a generic term that refers to inflammation as the primary lesion, and is known to be involved in numerous human diseases.
  • the list of specific diseases of inflammatory diseases shows that there are many types of inflammatory diseases such as acne, asthma, autoimmune diseases, periodic fever syndrome, colitis, pelvic inflammatory disease, rheumatoid arthritis and vasculitis.
  • Dry eye syndrome is not simply a lack of tears, but causes eye discomfort, decreased vision, and instability of the tear layer due to tears and inflammation of the eye surface (cornea and conjunctiva), causing damage to the eye surface.
  • inflammation plays an important role, such as invasion of inflammatory cells, increased immune activating molecule and adhesion molecule expression, Th1 and Th17 responses, apoptosis markers and abnormal changes in chemokines. have.
  • Inflammatory eye disease is a disease that occurs in the eye due to inflammation of the eye or its surrounding tissues among numerous types of inflammatory diseases.
  • studies on inflammatory eye disease have mainly been carried out to activate autologous T cells and B cells through them. It focuses on the immune response that occurs through the disease.
  • the disease includes dry eye, conjunctivitis, hyperemia, keratitis, and the like, all of which are diseases directly occurring in the eye due to inflammation in the eye or its surrounding tissues.
  • Dry eye syndrome is a common disease that occurs in 5.5 to 15% of adults worldwide. It is not just a lack of tears, but an eye discomfort due to tears and inflammation of the eye surface (cornea and conjunctiva). It is known to cause instability and damage the ocular surface. The disease is characterized by eye pain, irregular corneal surfaces, corneal ulcers, and decreased vision. The altered corneal permeability in chronic dry eye and dry keratitis has been very well known to cause inflammation, which is known to be induced by increased cytokine mediating inflammation in tears. In general, it is recommended to eat foods rich in potassium and anthocyanin for the treatment of dry eye. In addition, it is also highly recommended to eat fruits such as kale, kiwi, and apples. Some modalities may be used.
  • Conjunctivitis is an inflammatory condition of the conjunctiva caused by microorganisms such as bacteria, viruses, and fungi, and environmental factors such as pollen and chemical stimulation, and is the most common eye disease because the conjunctiva is exposed to the outside. It usually heals well, but in some cases it can be fatal, resulting in blindness due to tissue damage. Conjunctivitis is largely classified into infectious conjunctivitis and non-infectious conjunctivitis depending on the cause.
  • Hyperemia is a condition in which the conjunctiva's blood vessels expand and the whites of the eyes appear red. Inflammation of the eyes such as all types of conjunctivitis, keratitis, and iris phloemitis can cause redness, and if the eyelids do not provide enough protection for the eyes due to dry eye syndrome, the redness develops well, and the cornea can be worn even when contact lenses are worn for a long time. Many new blood vessels are created around the redness.
  • Keratitis accounts for more than 90% of corneal diseases. Defects in the outermost part of the eye, such as corneal epithelium, and cloudiness caused by inflammatory reactions to the corneal parenchyma can lead to decreased vision. With more than 50,000 keratitis occurring each year in the United States, keratitis is the most important disease that can cause blindness in the United States. If you have keratitis, you may have redness, foreign body, and pain, and you may be sensitive to light, tears, or blurry symptoms. Keratitis is also classified into infectious keratitis and non-infectious keratitis depending on the cause.
  • drugs with ocular anti-inflammatory effects play an important role in medicine.
  • Specific examples include steroidal drugs or nonsteroidal drugs.
  • an unpreserved fluorometholone (FML), a steroidal drug, or cyclosporin A, a nonsteroidal drug is used as an agent for treating inflammatory eye disease.
  • FML fluorometholone
  • cyclosporin A a nonsteroidal drug
  • the steroidal drug for the treatment of inflammatory eye disease is known to have side effects such as increased intraocular pressure or the occurrence of cataracts or glaucoma when used for a long period of time. It is known that this leads to a decrease in white blood cells, thereby weakening its immunity.
  • inflammatory eye diseases are also rapidly increasing. Therefore, there is a demand for the development of safer and inflammatory eye disease treatments that can be used by various age groups.
  • maple Acer palmatum
  • maple Acer palmatum
  • the present inventors as a result of intensive efforts to develop a composition comprising a natural extract or a fraction thereof having a prophylactic or therapeutic effect of inflammatory eye disease, specifically, dry eye syndrome, conjunctivitis, hyperemia or keratitis and without side effects, maple leaf extract Or the fraction thereof has been confirmed to increase the viability of corneal epithelial cells and conjunctival epithelial cells in the osmotic stress environment, and to treat inflammatory eye disease through the inhibitory effect of the expression of inflammation-induced cytokines, to complete the present invention.
  • a natural extract or a fraction thereof having a prophylactic or therapeutic effect of inflammatory eye disease, specifically, dry eye syndrome, conjunctivitis, hyperemia or keratitis and without side effects
  • maple leaf extract Or the fraction thereof has been confirmed to increase the viability of corneal epithelial cells and conjunctival epithelial cells in the osmotic stress environment, and to treat inflammatory eye disease through the inhibitory effect of the expression
  • Another object of the present invention is to provide a method for preventing or treating inflammatory eye disease, comprising administering the composition to an eye of an individual.
  • Another object of the present invention is to provide a quasi-drug composition for the prevention or treatment of inflammatory eye diseases, including maple leaf extract or fractions thereof.
  • Still another object of the present invention is to provide an eye cosmetic additive composition for preventing or improving inflammatory eye disease including maple leaf extract or a fraction thereof.
  • Still another object of the present invention is to provide a nutraceutical composition for the prevention or improvement of inflammatory eye disease, including maple leaf extract or a fraction thereof.
  • Still another object of the present invention is to provide a feed composition for preventing or improving inflammatory eye disease, including a maple leaf extract or a fraction thereof.
  • Maple leaf extract or a fraction thereof according to the present invention is effective in the prevention, improvement or treatment of inflammatory eye diseases, specifically dry eye, conjunctivitis, hyperemia and keratitis.
  • Figure 1 shows the manufacturing process of the fraction according to an embodiment of the present invention.
  • Figure 2 is a graph showing the cell viability of human corneal epithelial cells according to the fraction of the maple leaf hydrothermal extract (KIOM-2015EW) and the maple leaf ethanol extract (KIOM-2015EE) according to an embodiment of the present invention
  • KIOM-2015EW Frac. BuOH N-butanol fraction of maple leaf hydrothermal extract, KIOM-2015EW Frac.H 2 O
  • water fraction of the maple leaf ethanol extract ** p ⁇ 0.01, *** p ⁇ 0.001 vs. control, the same below.
  • Figure 3 is a graph showing the cell viability of human conjunctival epithelial cells according to the fraction of the maple leaf hydrothermal extract (KIOM-2015EW) and the maple leaf ethanol extract (KIOM-2015EE) according to an embodiment of the present invention (KIOM-2015EW Frac. DCM) Dichloromethane fraction of maple leaf hydrothermal extract, KIOM-2015EW Frac.EtOA; ethyl acetate fraction of maple leaf hydrothermal extract, KIOM-2015EE Frac.Hexane; hexane fraction of maple leaf ethanol extract).
  • Figure 4 is a graph showing the inflammation-related cytokine expression inhibitory activity of n-butanol fraction (KIOM-2015EW Frac. BuOH) of maple leaf hydrothermal extract on human corneal epithelial cells according to an embodiment of the present invention (** p ⁇ 0.01 , *** p ⁇ 0.001 vs. control; #p ⁇ 0.05, ## p ⁇ 0.01, ### p ⁇ 0.001 vs. HOS.
  • FIG. 5 is a graph showing the inhibitory activity of inflammation-related cytokine expression of the water fraction (KIOM-2015EW Frac. H 2 O) of maple leaf hydrothermal extract on human corneal epithelial cells according to an embodiment of the present invention.
  • Figure 6 is a graph showing the inflammation-related cytokine expression of the n-butanol fraction (KIOM-2015EE Frac. BuOH) of the maple leaf ethanol extract on human corneal epithelial cells according to an embodiment of the present invention (** p ⁇ 0.01 , *** p ⁇ 0.001 vs. control; #p ⁇ 0.05, ## p ⁇ 0.01, ### p ⁇ 0.001 vs. HOS.
  • Figure 7 is a graph showing the inhibitory activity of inflammation-related cytokine expression of maple leaf ethanol extract water fraction (KIOM-2015EE Frac. H 2 O) for human corneal epithelial cells according to an embodiment of the present invention.
  • FIG. 8 is a diagram showing the antioxidant protein expression ability of the maple leaf extract and fractions for human corneal epithelial cells according to an embodiment of the present invention (1; control, 2; high osmotic stress-induced human corneal epithelial cells (HOS)) 3, n-butanol fraction treatment of maple leaf hydrothermal extract (50 ⁇ g / ml), 4; water fraction treatment of maple leaf hydrothermal extract (50 ⁇ g / ml), 5; butanol fraction treatment of maple leaf ethanol extract (50 ⁇ g / ml) 6; water fraction treatment of maple leaf ethanol extract (50 ⁇ g / ml), 7; positive control dry eye treatment FML treatment, 8; positive control dry eye treatment CsA treatment, 9; maple leaf hydrothermal extract treatment (100 ⁇ g / ml), 10; maple leaf ethanol extract treatment (100 ⁇ g / ml).
  • HOS high osmotic stress-induced human corneal epithelial cells
  • FIG. 9 is a graph showing the inflammation-related cytokine expression inhibitory activity of the n-butanol fraction of maple leaf hydrothermal extract on human conjunctival epithelial cells according to an embodiment of the present invention.
  • FIG. 10 is a graph showing the inflammation-related cytokine expression inhibiting ability of the water fraction of the maple leaf hydrothermal extract for human conjunctival epithelial cells according to an embodiment of the present invention.
  • FIG. 11 is a graph showing the inflammation-related cytokine expression inhibitory activity of the n-butanol fraction of the maple leaf ethanol extract on human conjunctival epithelial cells according to an embodiment of the present invention.
  • FIG. 12 is a graph showing the inflammation-related cytokine expression inhibitory ability of the water fraction of the maple ethanol extract for human conjunctival epithelial cells according to an embodiment of the present invention.
  • the present invention as one aspect to achieve the above object, provides a pharmaceutical composition for the prevention or treatment of inflammatory eye disease comprising a maple leaf extract or a fraction thereof.
  • the present invention also provides a prophylactic or therapeutic use of an inflammatory eye disease of maple leaf extract or a fraction thereof.
  • inflammatory eye disease may have various forms of eye diseases involving various pains depending on the location of inflammation, and may include itching, redness, edema, ulcers, and the like. More than half of patients with ocular disease account for inflammatory ocular disease, so drugs with ocular anti-inflammatory efficacy play an important role in the medical field.
  • Specific examples of inflammatory eye diseases according to the present invention may be dry eye, conjunctivitis, hyperemia and keratitis.
  • foliage leaves is maple ( Acer palmatum ) leaves.
  • the maple tree is a deciduous lumbered arbor tree, about 10 to 20m high, and refers to a plant having a circular shape.
  • extract refers to a liquid component obtained by immersing a desired substance in various solvents, and then extracted for a predetermined time at room temperature or warm state, and a resultant such as a solid component obtained by removing the solvent from the liquid component.
  • a resultant such as a solid component obtained by removing the solvent from the liquid component.
  • the method for obtaining the extract is not particularly limited as long as an extract having a prophylactic or therapeutic effect of inflammatory eye disease can be obtained, but specifically, the maple leaf, its dried product, processed products, etc.
  • the extract may be included in an amount of 0.01 to 100% by weight, more specifically 1 to 80% by weight, based on the total weight of the pharmaceutical composition.
  • the maple leaf extract of the present invention may be a hot water extract.
  • maple leaf extract of the present invention may be an ethanol extract.
  • the maple leaf extract may be prepared and used as a fraction thereof.
  • fraction refers to the result obtained by performing the fractionation to separate a specific component or a specific component group from a mixture comprising various various components.
  • the fractionation method for obtaining the fraction is not particularly limited, and may be performed according to a method commonly used in the art. Solvent fractionation by treatment of various solvents, ultrafiltration fractionation through passage of ultrafiltration membranes with constant molecular weight cut-off values, chromatographic chromatography (manufactured for separation according to size, charge, hydrophobicity or affinity) Chromatography), and combinations thereof.
  • the kind of solvent used to obtain the fraction in the present invention is not particularly limited, and any solvent known in the art may be used.
  • the fractionation solvent water, an organic solvent or a mixed solvent thereof may be used.
  • the organic solvent may be a C 1-4 alcohol, a polar solvent such as ethyl acetate or acetone, hexane or dichloromethane.
  • a nonpolar solvent or a mixed solvent thereof can be used.
  • water, alcohols having 1 to 4 carbon atoms or mixed solvents thereof may be used, and more specifically, ethanol may be used.
  • the fractions may each comprise 0.001 to 100% by weight, more specifically 0.1 to 80% by weight relative to the total weight of the pharmaceutical composition.
  • the fraction of the maple leaf extract may be a fraction of maple leaf hydrothermal extract or ethanol extract.
  • dry eye syndrome refers to abnormal tear evaporation due to tear secretion or meibomian gland dysfunction or eyelid dysfunction due to inflammation of the tear glands and denervation of the cornea. It may be a disease caused by the dry eye, and it may be a corneal epithelial disorder caused by excessive dryness of the tear due to the dry eye, which may damage the tear gland, blockage of the tear tube, and tear formation. Increased tear evaporation due to ocular surface disorders such as decreased tear secretion, meibomian gland dysfunction, eyelid openness, low eyelid disease, vitamin A deficiency, topical medications and preservatives, contact lens wear and allergy And keratoconjunctival epithelial disorders.
  • the term “conjunctival” refers to a tissue that forms the surface of the eye and protects the eye from foreign substances, and is a tissue involved in the formation of the mucus layer of the tear and immune function.
  • the term “conjunctivitis” refers to an inflammatory disease occurring in the conjunctiva, which is a tissue surrounding the eye, and has typical epidemic conjunctivitis.
  • the conjunctivitis may be non-infectious conjunctivitis.
  • non-infectious conjunctivitis it is caused by an allergic reaction to foreign substances.
  • the conjunctivitis may be infectious conjunctivitis.
  • infectious conjunctivitis is caused by infection of various pathogens such as bacteria, viruses, and fungi, and may be, for example, epidemic conjunctivitis, acute hemorrhagic conjunctivitis (Apollo conjunctivitis), and bacterial conjunctivitis.
  • cornea refers to a structure that allows the eye to be protected from the outside, through the light, and refracted as a transparent film on the ocular surface at the center of the eye.
  • keratitis refers to a disease in which the inflammation of the cornea causes pain, decreased visual acuity, corneal clouding, and the like, and ocular hyperemia may occur as a representative symptom.
  • the keratitis may be non-infectious keratitis.
  • it may mean exposed keratitis caused by continuous exposure to external air, toxic keratitis caused by drugs, neurotrophic keratitis caused by corneal nerve damage, disorders caused by contact lenses, trauma, or allergic keratitis.
  • Non-infectious keratitis is difficult to treat with general treatment for infectious keratitis.
  • the keratitis may be infectious keratitis caused by bacteria, viruses, fungi (fungus).
  • hypoemia refers to a symptom in which the conjunctival blood vessels are expanded to open the whites of the eyes. Congestion due to conjunctivitis is most severe in the far side of the eye, and congestion due to inflammation of the cornea or iris is most severe in the eye conjunctiva. Inflammation of the eye, such as conjunctivitis and keratitis of all kinds, can cause hyperemia, and congestion can occur if tears do not provide enough protection for the eyes due to dry eye.
  • the maple leaf extract or fractions thereof in order to confirm the dry eye improvement effect of the maple leaf extract or fractions thereof, as a result of observing the cell protective effect on human corneal epithelial cells and human conjunctival epithelial cells, dry eye syndrome induced by osmotic stress It was confirmed that the treatment of maple leaf hot water and ethanol extract in the environment inhibits the toxicity of the cells and increases the viability.
  • the maple leaf extract or fractions thereof may be used for the prevention or treatment of inflammatory eye diseases including dry eye, conjunctivitis, hyperemia or keratitis (FIGS. 2 and 3).
  • prevention refers to any action that inhibits or delays the symptoms of inflammatory eye disease by administration of a composition comprising a maple leaf extract or a fraction thereof.
  • treatment may mean any action that improves or advantageously changes the symptoms of the disease by administration of a composition comprising a maple leaf extract or a fraction thereof.
  • the term “improvement” may mean any action that at least reduces the parameters associated with the condition being treated, for example, the extent of symptoms.
  • the composition may be to inhibit inflammation-related cytokines.
  • cytokines related to inflammation such as IL-6, TNF- ⁇ , IL-1 ⁇ , and the like are expressed, and the composition of the present invention may be to suppress the amount of expression thereof.
  • the fraction of the maple leaf hot water and ethanol extract is IL-6
  • the concentration of TNF- ⁇ and IL-1 ⁇ was confirmed to decrease in a concentration-dependent manner (FIGS. 4 to 7 and 9 to 12). Therefore, it was confirmed that the fraction of the extract can be usefully used for the improvement or treatment of inflammatory eye disease.
  • the term "pharmaceutical composition” means prepared for the purpose of preventing or treating a disease, and may be used in various forms, each formulated in accordance with conventional methods. For example, they may be formulated in oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and the like, and may be used in the form of external preparations and sterile injectable solutions.
  • the pharmaceutical composition may be an external topical formulation, and may be specifically formulated into any one selected from the group including eye ointments, eye drops, and sprays, but formulations used for administration to the eye in the art. Is not limited.
  • the pharmaceutical composition including the maple leaf extract or a fraction thereof may further include a pharmaceutically acceptable carrier.
  • the term "pharmaceutically acceptable carrier” may refer to a carrier or diluent that does not interfere with the biological activity and properties of the compound to be injected without stimulating the organism.
  • the kind of the carrier usable in the present invention is not particularly limited, and any carrier can be used as long as it is a conventionally used and pharmaceutically acceptable carrier in the art.
  • Non-limiting examples of the carrier include saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol and the like. These may be used alone or in combination of two or more thereof.
  • the carrier may include a non-naturally occuring carrier.
  • ком ⁇ онентs such as antioxidants, buffers and / or bacteriostatic agents may be added and used, and diluents, dispersants, surfactants, binders, lubricants, and the like may be additionally added to provide a solution such as an aqueous solution, a suspension, an emulsion, or the like. It may be formulated into a use formulation, pills, capsules, granules or tablets.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient such as starch, calcium carbonate, and the like in the above extracts and fractions thereof. , Sucrose or lactose, gelatin and the like are mixed. In addition to simple excipients, lubricants such as magnesium styrate and talc are also used.
  • Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • the non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
  • As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • the pharmaceutical composition of the present invention may include a pharmaceutically effective amount of maple leaf extract or a fraction thereof.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, generally in an amount of 0.001 to 1000 mg / kg, specifically 0.05 To 200 mg / kg, more specifically, the amount of 0.1 to 100 mg / kg can be administered once to several times a day.
  • the specific therapeutically effective amount for a particular patient is determined by the specific composition, including the type and extent of the reaction to be achieved, whether or not other agents are used in some cases, the age, weight, general health of the patient, It is desirable to apply differently depending on various factors and similar factors well known in the medical field, including sex and diet, time of administration, route of administration and rate of composition, duration of treatment, drugs used with or co-specific with the specific composition.
  • compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents and may be administered sequentially or simultaneously with conventional therapeutic agents. And single or multiple administrations. In consideration of all the above factors, it is important to administer an amount that can achieve the maximum effect in a minimum amount without causing side effects, and can be easily determined by those skilled in the art.
  • the term "administration” means introducing a pharmaceutical composition of the present invention to a patient in any suitable manner, wherein the maple leaf extract of the present invention or a fraction thereof is effective in the prevention or treatment of inflammatory eye disease.
  • the route of administration of the composition can be administered through the eye.
  • a method of treating inflammatory eye disease comprising administering the composition to an eye of an individual.
  • the inflammatory eye disease, administration and treatment is as described above.
  • the term "individual" may refer to an animal other than a human who has or is likely to develop an inflammatory eye disease.
  • the animal may be a mammal such as, but not limited to, a human, a cow, a horse, a sheep, a pig, a goat, a camel, a antelope, a dog, a cat, and the like, which require treatment of similar symptoms.
  • composition may be administered in single or multiple amounts in a pharmaceutically effective amount.
  • the route of administration of the pharmaceutical composition for preventing or treating inflammatory eye disease of the present invention may be administered via any general route as long as it can reach the target tissue.
  • the pharmaceutical composition of the present invention is not particularly limited, but as desired, instillation, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, transdermal patch administration, oral administration, intranasal administration, pulmonary administration, It may be administered through a route such as rectal administration, and specifically, may be administered through a route of eye drop administration.
  • a quasi-drug composition for the prevention or treatment of inflammatory eye disease comprising a maple leaf extract or a fraction thereof.
  • maple leaf, extract, fraction, inflammatory eye disease, prevention and treatment are as described above.
  • the term "quasi drug” refers to articles that are less active than drugs among those used for the purpose of diagnosing, treating, ameliorating, alleviating, treating, or preventing a disease of a human or animal.
  • Quasi-drugs except those used for the purpose of medicines, are textiles and rubber products used in the treatment or prevention of diseases of humans and animals, and have a slight or no direct action on the human body; This includes sterilizing and insecticides for preventing infectious diseases.
  • the kind or formulation of the quasi-drug composition of the present invention is not particularly limited, but may preferably be a disinfectant cleaner, a shower foam, a gagreen, a wet tissue, a detergent soap, a hand wash, a humidifier filler, a mask, an ointment, or a filter filler.
  • an eye cosmetic additive composition for the prevention or improvement of inflammatory eye disease comprising a maple leaf extract or a fraction thereof.
  • the additive may be included in eye cosmetic products to exhibit an effect on the prevention or improvement of the disease.
  • maple leaf, extract, fraction, inflammatory eye disease, prevention and improvement are as described above.
  • the composition may include eye cosmetic products, and the eye cosmetic products may be any one selected from the group comprising eyebrow pencil, eyeliner, eye shadow, mascara, and eye makeup remover. have.
  • a dietary supplement composition for preventing or improving inflammatory eye disease including a maple leaf extract or a fraction thereof.
  • maple leaf, extract, fraction, inflammatory eye disease, prevention and improvement are as described above.
  • the maple leaf extract or a fraction thereof may be added as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method.
  • the blending amount of the active ingredient can be suitably determined according to the purpose of use (prevention, health or therapeutic treatment), and the composition of the present invention is environmentally friendly and there is no problem in terms of stability, so there is no big limitation on the blending amount.
  • the health functional food composition of the present invention can be ingested on a daily basis, an improvement effect on inflammatory eye disease can be expected, and thus can be very useful for health promotion purposes.
  • the term "health functional food” of the present invention is the same term as a food for special health use (FOSHU), and foods having high medical effects and medical effects processed to efficiently exhibit bioregulatory functions in addition to nutritional supply. Means.
  • the term 'function' refers to obtaining a useful effect for health purposes such as controlling nutrients or physiological effects on the structure and function of the human body.
  • the health functional food of the present invention can be prepared by a method commonly used in the art, and the preparation can be prepared by adding raw materials and ingredients commonly added in the art.
  • the formulation of the health functional food can also be prepared without limitation as long as the formulation is recognized as a food.
  • the health functional food composition of the present invention can be prepared in various forms of formulations, unlike the general medicine has the advantage that there is no side effect that can occur when taking long-term use of the drug as a raw material, and excellent portability
  • the health functional food of the present invention can be ingested as an adjuvant to enhance the improvement effect of inflammatory eye disease.
  • the health functional food refers to foods having active health maintenance or promotion effect as compared to general foods, and health supplement food means foods for health supplement purposes.
  • health supplement food means foods for health supplement purposes.
  • nutraceutical, health food, dietary supplement are used.
  • the health functional food is a food prepared by adding the compound of the present invention to food materials such as beverages, teas, spices, gums, confections, or the like, encapsulated, powdered, suspensions, etc.
  • food materials such as beverages, teas, spices, gums, confections, or the like, encapsulated, powdered, suspensions, etc.
  • the health functional food composition may further include a physiologically acceptable carrier, and the type of carrier is not particularly limited and may be used as long as it is commonly used in the art.
  • the health functional food composition may include additional ingredients that are commonly used in food compositions to improve the smell, taste, time and the like.
  • additional ingredients that are commonly used in food compositions to improve the smell, taste, time and the like.
  • it may include vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid, and the like.
  • minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn) and copper (Cu);
  • amino acids such as lysine, tryptophan, cysteine, valine and the like.
  • the health functional food composition is a preservative (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetic acid, etc.), fungicides (bleaching powder and highly bleaching powder, sodium hypochlorite, etc.), antioxidants (butylhydroxyanisol (BHA), Butylhydroxytoluene (BHT), etc.), colorant (such as tar pigment), coloring agent (sodium nitrite, sodium nitrite, etc.), bleach (sodium sulfite), seasoning (such as MSG glutamate), sweetener (ducin, cyclate , Saccharin, sodium, etc.), fragrances (vanillin, lactones, etc.), swelling agents (alum, D-potassium hydrogen titanate, etc.), reinforcing agents, emulsifiers, thickeners (pigments), coatings, gum herbicides, foam inhibitors, solvents, modifiers, etc. May contain food additives.
  • the additive may be selected according to the type
  • An example of the health functional food composition of the present invention can be used as a health beverage composition, in which case it may contain various flavors or natural carbohydrates as additional ingredients, such as conventional drinks.
  • the above-mentioned natural carbohydrates include monosaccharides such as glucose and fructose; Disaccharides such as maltose and sucrose; Polysaccharides such as dextrin, cyclodextrin; Sugar alcohols such as xylitol, sorbitol, and erythritol.
  • Sweeteners include natural sweeteners such as taumartin, stevia extract; Synthetic sweeteners such as saccharin and aspartame;
  • the ratio of the natural carbohydrate may be generally about 0.01 to 0.04 g, specifically about 0.02 to 0.03 g per 100 mL of the health beverage composition of the present invention.
  • the health beverage composition includes various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid, salts of pectic acid, alginic acid, salts of alginic acid, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, Alcohol or carbonation agent and the like.
  • Others may contain fruit flesh for the production of natural fruit juices, fruit juice drinks, or vegetable drinks. These components can be used independently or in combination.
  • the ratio of such additives is not critical, but is generally selected from 0.01 to 0.1 parts by weight per 100 parts by weight of the health beverage composition of the present invention.
  • the present invention also provides a feed composition for the prevention or improvement of inflammatory eye disease, including the maple leaf extract or a fraction thereof.
  • the content of the maple leaf extract in the feed composition for the prevention or improvement of inflammatory eye disease may be appropriately selected according to the species, age, weight, and breeding conditions of the feed livestock, and 0.01 to 95% by weight based on the total weight of the feed composition. May be a ratio of 0.1 to 80% by weight.
  • the feed composition may include a feed additive.
  • the feed additive of the present invention corresponds to a feed supplement in the Feed Control Act.
  • feed may refer to any natural or artificial diet, one meal, or the like or a component of the one meal for the animal to eat, ingest, and digest.
  • the kind of the feed is not particularly limited, and may be used a feed commonly used in the art.
  • Non-limiting examples of the feed may include plant feeds such as cereals, fruits, food processing by-products, algae, fibres, pharmaceutical by-products, oils, starches, gourds or grain by-products; And animal feeds such as proteins, minerals, fats and oils, minerals, fats and oils, single cell proteins, zooplankton or foods. These may be used alone or in combination of two or more thereof.
  • the feed additive may additionally contain a carrier that is acceptable to the unit animal.
  • the feed additive may be added as it is, or a known carrier, stabilizer, or the like. If necessary, various nutrients such as vitamins, amino acids, minerals, antioxidants, and other additives may be added. Powders, granules, pellets, suspensions and the like may be in a suitable state.
  • the unit animal may be supplied alone or mixed with feed.
  • the extracted maple leaf extract was filtered using a standard test sieve (sieve) (150 ⁇ m, Retsch, Han, Germany) and concentrated to dryness in a freeze dryer.
  • the freeze-dried maple leaf extract powder 50 mg was dissolved in 1 ml of distilled water, filtered through a 0.22 ⁇ m disk filter, and stored at ⁇ 20 ° C. until use.
  • KIOM-2015EW maple leaf hydrothermal extract
  • a solvent fraction using an organic solvent was performed to separate components in the extract according to polarity. That is, 4 g of KIOM-2015EW extract was suspended in 80 mL of water, and then 80 mL of hexane (Hexane) was added to obtain a component eluted three times with hexane (hexane fraction; Hexane Fr.).
  • the cells were grown in a growth medium and stabilized, and then the cells were treated with a fraction of maple leaf hydrothermal extract and maple leaf ethanol extract and cultured for 24 hours. Then, add 100 ⁇ l of MTT (3- (4,5-Dimethylthiazol-2-yl) -2,5-Diphenyltetrazolium Bromide) at a concentration of 5 mg / ml for 2 hours, remove supernatant, and then remove DMSO ( 100 ul of dimethyl sulfoxide) was added to dissolve the precipitate, and the viability of the cells was measured at an absorbance of 570 nm.
  • MTT 3- (4,5-Dimethylthiazol-2-yl) -2,5-Diphenyltetrazolium Bromide
  • the fraction of the maple leaf hot water or ethanol extract of the present invention was able to confirm the cell viability of human corneal epithelial cells and human conjunctival epithelial cells in the same environment as dry eye syndrome induced by osmotic stress.
  • Example 2 Maple Leaf Extract on Human Corneal Epithelial Cells Fraction Inhibitory Effect of Inflammation-related Cytokines
  • human corneal epithelial cells are grown in a growth medium and stabilized, followed by adding 450 mOsM of DMEM / F-12 medium to osmotic stress (HOS) to the same environment as dry eye caused by osmotic stress. Human corneal epithelial cells were exposed.
  • HOS osmotic stress
  • the n-butanol (n-BuOH) fraction of KIOM-2015EW of Preparation Example 2-1 in consideration of the cytotoxicity of each fraction to the cells at a concentration of 25, 50 and 100 ⁇ g / ml, water (H 2 O) Fractions were treated at concentrations of 50, 100 and 150 ⁇ g / ml and incubated for 24 hours, and the supernatant of the cell culture was recovered. Thereafter, Human IL-6 ELISA kit II (eBioscience catalog No. 88-7066), Human TNF ELISA kit II (eBioscience catalog No. 88-7346), and Human IL-1 ⁇ ELISA kit II (eBioscience catalog No. 88-7261) The amount of expression of IL-6, TNF- ⁇ , and IL-1 ⁇ included in the cell culture was measured using.
  • Example 2-2 Maple Leaf Ethanol Extract Fraction Confirmation of Inhibitory Effect of Inflammatory Cytokines
  • IL-6, TNF- ⁇ and IL-1 ⁇ after the KIOM-2015EE fraction prepared in Preparation Example 2-2 was treated in the same manner as in Example 2-1. Expression level was measured.
  • n-butanol and water fractions fractionated from KIOM-2015EW and KION-2015EE of the present invention are TNF- ⁇ , IL-1 ⁇ and IL in human corneal epithelial cells induced with the same environment as dry eye syndrome.
  • the cells were treated with osmotic stress at the same time concentrations of 50 ⁇ g / ml and n-butanol fractions of KIOM-2015EW and KIOM-2015EE at 100 ⁇ g / ml, KIOM-2015EW 100 ⁇ g / ml and KIOM-2015EE 100 ⁇ g / ml was treated. At this time, it was incubated for 24 hours using CsA 5 ⁇ g / ml and FML 10 ⁇ g / ml used as a treatment for dry eye as a positive control group.
  • the expression level of the protein related to antioxidant in the cells was confirmed by Western blot analysis. After incubation of the cells three times with 1 ⁇ PBS, using lysis buffer (50 mM HEPES, pH 7.4, 150 mM NaCl, 1% deoxycholate, 1 mM EDTA, 1 mM PMSF, 1 ⁇ g / ml aprotinin) Dissolved. Then, the supernatant was recovered to quantify the protein present in each sample, and 30 ⁇ g of protein was mixed with 4 ⁇ sample buffer to mix 12% SDS-polyacrylamide gel (1.5 M Trisma base, 10% SDS, 30% acrylamide, 10%). ammonium persulfate, TEMED).
  • lysis buffer 50 mM HEPES, pH 7.4, 150 mM NaCl, 1% deoxycholate, 1 mM EDTA, 1 mM PMSF, 1 ⁇ g / ml aprotinin
  • the electrophoresed gel-like proteins were transferred to NC membranes, and each membrane was blocked by reaction for 1 hour at room temperature with 5% skim milk to prevent nonspecific binding with antibodies.
  • Antioxidant primary antibodies were reacted overnight at 4 ° C. (GPX-1; Anti-Glutathione Peroxidase 1 antibody (Abcam, ab26604), SOD-1; Cu / Zn SOD polyclonal antibody (Enzo, ADI-SOD-100) , After washing three times with TBS containing 0.05% Tween, and reacted with the secondary antibody anti-IgG conjugated HRP for 1 hour at room temperature, washed three times with TBS containing 0.05% Tween and then ECL solution The amount of protein expression was detected using.
  • Example 4 human On conjunctival epithelial cells For maple leaf extract Fraction Inhibitory Effect of Inflammation-related Cytokines
  • Example 4-1 Confirmation of Inhibitory Effect of Inflammatory Cytokines on Fractions of Maple Leaf Hydrothermal Extracts
  • Inflammation-related cytokines are overexpressed when dry eye syndrome is induced, and the representative inflammation-induced cytokines are investigated to confirm the anti-inflammatory effects of the hot water extract fraction of maple leaf on human conjunctival epithelial cells in the same environment as ocular dryness induced by osmotic stress. Protein expression levels of IL-6, TNF- ⁇ and IL-1 ⁇ were analyzed. As a positive control, 5 ⁇ g / mL of CsA and 10 ⁇ g / mL of FML used as a dry eye treatment were used.
  • the specific experimental method is the same as that of the human corneal epithelial cell of Example 2-1.
  • Example 4-2 Maple Leaf Ethanol Extract Fraction Confirmation of Inhibitory Effect of Inflammatory Cytokines
  • Example 2-2 After treating the KIOM-2015EE fraction prepared in Preparation Example 2-2 in the same manner as in Example 2-1, the IL-6, TNF- ⁇ and IL-1 ⁇ Expression level was measured.
  • the fractions of KIOM-2015EW and KIOM-2015EE of the present invention are characterized in that the IL-6, TNF- ⁇ and IL-1 ⁇ proteins in human conjunctival epithelial cells Since inflammation is improved by reducing expression, it has been confirmed that it can be usefully used for the improvement and treatment of dry eye syndrome.

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Abstract

La présente invention concerne : une composition pharmaceutique comprenant un extrait de feuille d'arbre d'érable ou des fractions de ce dernier destinée à prévenir ou à traiter des maladies oculaires inflammatoires; un procédé destiné à traiter les maladies comportant une étape d'administration de la composition dans l'œil d'un sujet; une composition de quasi-médicament; une composition destinée à un additif de maquillage de l'œil; une composition alimentaire de santé fonctionnelle; et une composition d'aliment pour animaux.
PCT/KR2017/014224 2016-12-07 2017-12-06 Composition comprenant un extrait de feuille d'arbre d'érable ou des fractions de ce dernier destinée à prévenir ou à traiter des maladies oculaires inflammatoires WO2018106009A1 (fr)

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WO2019013518A2 (fr) * 2017-07-10 2019-01-17 한국한의학연구원 Composition comprenant un extrait de feuille d'érable pour l'hypotonie oculaire
KR102085566B1 (ko) * 2018-07-10 2020-03-06 한국 한의학 연구원 맥문동 추출물 또는 이의 분획물을 유효성분으로 포함하는 안구건조증의 예방, 개선 또는 치료용 조성물

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JP2003113068A (ja) * 2001-08-02 2003-04-18 Maruzen Pharmaceut Co Ltd 皮膚化粧料
US20100068297A1 (en) * 2006-12-06 2010-03-18 Nature Therapeutics Limited Antimicrobial Composition
JP2010070487A (ja) * 2008-09-18 2010-04-02 Fancl Corp Ｍｉｆ分泌抑制剤
KR101089779B1 (ko) * 2011-04-29 2011-12-07 주식회사 청진바이오텍 정제봉독, 단풍나무 추출물 및 작살나무 추출물을 유효성분으로 포함하는 기능성 천연 화장료 조성물
KR101662720B1 (ko) * 2015-07-08 2016-10-07 한국 한의학 연구원 각막질환 또는 결막질환의 치료용 조성물
KR101762797B1 (ko) * 2016-04-20 2017-07-31 한국 한의학 연구원 단풍나무 잎 추출물을 포함하는 안구건조증의 예방 또는 치료용 조성물

Patent Citations (6)

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Publication number Priority date Publication date Assignee Title
JP2003113068A (ja) * 2001-08-02 2003-04-18 Maruzen Pharmaceut Co Ltd 皮膚化粧料
US20100068297A1 (en) * 2006-12-06 2010-03-18 Nature Therapeutics Limited Antimicrobial Composition
JP2010070487A (ja) * 2008-09-18 2010-04-02 Fancl Corp Ｍｉｆ分泌抑制剤
KR101089779B1 (ko) * 2011-04-29 2011-12-07 주식회사 청진바이오텍 정제봉독, 단풍나무 추출물 및 작살나무 추출물을 유효성분으로 포함하는 기능성 천연 화장료 조성물
KR101662720B1 (ko) * 2015-07-08 2016-10-07 한국 한의학 연구원 각막질환 또는 결막질환의 치료용 조성물
KR101762797B1 (ko) * 2016-04-20 2017-07-31 한국 한의학 연구원 단풍나무 잎 추출물을 포함하는 안구건조증의 예방 또는 치료용 조성물

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