WO2023074894A1 - Agent pour favoriser la régénération de cartilages - Google Patents

Agent pour favoriser la régénération de cartilages Download PDF

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WO2023074894A1
WO2023074894A1 PCT/JP2022/040711 JP2022040711W WO2023074894A1 WO 2023074894 A1 WO2023074894 A1 WO 2023074894A1 JP 2022040711 W JP2022040711 W JP 2022040711W WO 2023074894 A1 WO2023074894 A1 WO 2023074894A1
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cartilage
hydroxycitric acid
extract
hydroxycitric
garcinia
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PCT/JP2022/040711
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English (en)
Japanese (ja)
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善之 水品
公輔 田中
淳也 戸口田
啓之 吉富
永輝 金
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小林製薬株式会社
国立大学法人京都大学
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Publication of WO2023074894A1 publication Critical patent/WO2023074894A1/fr

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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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)
    • 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)
    • A61K36/38—Clusiaceae, Hypericaceae or Guttiferae (Hypericum or Mangosteen family), e.g. common St. Johnswort
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • the present invention relates to a cartilage regeneration promoting agent.
  • Glucosamine is one of the amino sugars that make up GAG. Glucosamine is contained in the cell walls of crustaceans such as shrimps and crabs, insects such as beetles, and fungi, and is one of monosaccharides widely present in nature as a constituent unit of chitin. In addition, its important role in vivo has been studied, such as its existence as a constituent sugar of mucopolysaccharides in vivo. Glucosamine is not only a component of cartilage and connective tissue, but is also reported to have an anti-inflammatory effect via neutrophils, and is reported as an effective component for arthritis (Patent Document 1).
  • glucosamine is actively added to foods, quasi-drugs, or pharmaceuticals for the purpose of treating or preventing cartilage disorders.
  • a composition for improving arthralgia containing collagen, methylsulfonylmethane, glucosamine, and chondroitin, wherein the composition contains collagen in an intake of 2000 mg or more per day, relieves symptoms of arthralgia such as arthritis.
  • glucosamine in the treatment or prevention of cartilage disorders has attracted attention, and various glucosamine-containing compositions have been studied, but the level of the effect is still insufficient. Therefore, the present inventors believed that a component having an effect of promoting cartilage regeneration would be expected to be more effective in treating or preventing cartilage disorders.
  • An object of the present invention is to provide a cartilage regeneration-promoting agent having an excellent cartilage regeneration-promoting action.
  • Section 1 A cartilage regeneration promoter containing hydroxycitric acid and/or a salt thereof.
  • Section 2. Item 2. The cartilage regeneration promoter according to Item 1, wherein the hydroxycitric acid is (-) hydroxycitric acid and/or (+) allo-hydroxycitric acid.
  • Item 3. Item 3. The cartilage regeneration promoter according to Item 1 or 2, wherein the hydroxycitric acid is a non-lactone body and/or a lactone body.
  • Section 4. Item 4. The cartilage regeneration promoting agent according to any one of Items 1 to 3, which is used for promoting cartilage synthesis.
  • Item 5. Item 5.
  • Item 6. Item 6. The cartilage regeneration promoter according to Item 5, wherein the plant extract is Garcinia extract.
  • Item 7. Item 6.
  • Item 8. The cartilage regeneration-promoting agent according to any one of Items 1 to 7, which is used for the treatment or prevention of cartilage disorders.
  • a chondrocyte differentiation promoting agent that promotes differentiation of undifferentiated cells into chondrocytes, containing hydroxycitric acid and/or a salt thereof.
  • Item 11. Item 11. The chondrocyte differentiation promoting agent according to Item 10, wherein the hydroxycitric acid is (-) hydroxycitric acid and/or (+) allo-hydroxycitric acid.
  • Item 12. Item 12. The chondrocyte differentiation promoting agent according to Item 10 or 11, wherein the hydroxycitric acid is a non-lactone body and/or a lactone body.
  • Item 13 Item 13.
  • Item 14. Item 14. The chondrocyte differentiation promoting agent according to Item 13, wherein the plant extract is Garcinia extract.
  • Item 15. Item 14. The chondrocyte differentiation promoting agent according to Item 13, wherein the plant extract is a hibiscus extract.
  • Item 17. A cartilage degradation inhibitor containing hydroxycitric acid and/or a salt thereof.
  • Item 19. An agent for relieving joint pain, discomfort and/or discomfort, containing hydroxycitric acid and/or a salt thereof.
  • Item 20. Use of hydroxycitric acid and/or a salt thereof for producing a cartilage regeneration promoting agent.
  • Item 21. Hydroxycitric acid and/or its salts are chondrocyte differentiation promoters that promote differentiation from undifferentiated cells to chondrocytes, cartilage degradation inhibitors, protective agents for maintaining cartilage thickness, or joint pain. , for the manufacture of an agent for relieving discomfort and/or discomfort.
  • a composition containing hydroxycitric acid and/or a salt thereof for promoting cartilage regeneration.
  • Item 23 Said use promotes chondrocyte differentiation to promote differentiation from undifferentiated cells to chondrocytes, inhibits cartilage degradation, protects to maintain cartilage thickness, or relieves joint pain, discomfort, and/or discomfort 23.
  • Item 24 A cartilage regeneration method, comprising administering an effective amount of hydroxycitric acid and/or a salt thereof to a subject in need of cartilage regeneration.
  • cartilage regeneration-promoting agent having excellent cartilage regeneration-promoting action is provided.
  • Fig. 2 shows the results of cartilage matrix production brought about by induction of differentiation into chondrocytes by hydroxycitric acids in two-dimensional culture of human iPS cell-derived mesenchymal stem cells.
  • Fig. 2 shows the results of chondrocyte proliferation brought about by induction of differentiation into chondrocytes by hydroxycitric acids in two-dimensional culture of human iPS cell-derived mesenchymal stem cells.
  • Fig. 2 shows the results of cartilage matrix production and chondrocyte proliferation brought about by induction of chondrocyte differentiation with various concentrations of hydroxycitric acid in two-dimensional culture of human iPS cell-derived mesenchymal stem cells.
  • FIG. 2 shows the results of chondrocyte differentiation induction by hydroxycitric acids in three-dimensional culture of human bone marrow-derived mesenchymal stem cells.
  • Fig. 2 shows the results of cartilage matrix production brought about by induction of differentiation into chondrocytes by a garcinia extract in two-dimensional culture of human iPS cell-derived mesenchymal stem cells.
  • Fig. 2 shows the results of chondrocyte proliferation brought about by induction of differentiation into chondrocytes by a garcinia extract in two-dimensional culture of human iPS cell-derived mesenchymal stem cells.
  • Fig. 2 shows the results of chondrocyte differentiation induction by Garcinia extract in three-dimensional culture of human bone marrow-derived mesenchymal stem cells.
  • Fig. 2 shows the results of chondrocyte differentiation induction by hydroxycitric acids, garcinia extract and hibiscus extract in three-dimensional culture of human bone marrow-derived mesenchymal stem cells.
  • Fig. 2 shows the results of cartilage matrix production brought about by induction of differentiation into chondrocytes by hydroxycitric acids and garcinia extract and hibiscus extract in three-dimensional culture of human bone marrow-derived mesenchymal stem cells.
  • Fig. 3 shows the results of chondrocyte proliferation induced by induction of differentiation into chondrocytes by hydroxycitric acids and garcinia extract and hibiscus extract in three-dimensional culture of human bone marrow-derived mesenchymal stem cells.
  • Fig. 2 shows changes in body weight of cartilage-damaged rats to which Garcinia extract was administered.
  • Fig. 2 shows photographs of the cartilage surface of the trochlea of the knee femur on the day of rat cartilage injury surgery and after administration of garcinia extract (16 days after surgery).
  • Fig. 2 shows a stained image (a) of a cross-sectional specimen crossing a drilled hole in knee cartilage of a cartilage-damaged rat to which a garcinia extract was administered, and a measurement result (b) of the depth of the drilled hole.
  • Fig. 3 shows the measurement results of cartilage synthesis marker (CPII) and cartilage degradation marker (C2C) levels in the blood of cartilage-damaged rats to which Garcinia extract was administered.
  • Fig. I cartilage synthesis marker
  • C2C cartilage degradation marker
  • FIG. 2 shows a stained image of a cross-sectional sample of cartilage of knee femur prepared from a rat knee osteoarthritis-induced model to which a garcinia extract was administered.
  • Fig. 2 shows a stained image of a cross-sectional sample of knee femoral cartilage prepared from a mouse knee joint cartilage degeneration model to which a garcinia extract was administered.
  • Fig. 2 shows the cartilage degeneration score of a mouse knee joint cartilage degeneration model to which a garcinia extract was administered.
  • Fig. 3 shows measurement results of cartilage synthesis marker (CPII) amount and cartilage degradation marker (C2C) amount in blood of mouse knee joint cartilage degeneration model to which garcinia extract was administered.
  • 1 shows the relationship between the cartilage degeneration score and blood cartilage synthesis marker (CPII) amount in a mouse knee joint cartilage degeneration model to which a garcinia extract was administered, and the human-equivalent dose of hydroxycitric acid.
  • the cartilage regeneration-promoting agent of the present invention contains hydroxycitric acid, derivatives thereof, and/or salts thereof (hereinafter also referred to as "hydroxycitric acids"). Hydroxycitric acids are known as ingredients that promote fat metabolism. In the agent for promoting cartilage regeneration of the present invention, hydroxycitric acids act as active ingredients for promoting cartilage regeneration.
  • Hydroxycitric acid is an ⁇ -hydroxy tribasic acid (1,2-dihydroxypropane-1,2,3-tricarboxylic acid) with two asymmetric centers and can be formed into two pairs of diastereoisomers or four forms two different isomers.
  • hydroxycitric acid includes (-) hydroxycitric acid, (+) hydroxycitric acid, (-) allo-hydroxycitric acid, and (+) allo-hydroxycitric acid. These isomers may be used singly or in combination of two or more. Among these isomers, (-) hydroxycitric acid and (+) allo-hydroxycitric acid are preferred from the viewpoint of obtaining a more favorable effect of promoting cartilage regeneration.
  • Hydroxycitric acid and its salts are specifically represented by the following general formulas (I) and (II).
  • non-lactone form or “free form”
  • lactone form A dehydrated condensed cyclized product of a free form
  • the compounds represented by formulas (I) and (II) are salts of hydroxycitric acid
  • M 1 , M 2 and M 3 in formula (I) and M 1 and M 2 in formula (II) are simultaneously It never becomes a hydrogen atom.
  • the salt of hydroxycitric acid is not particularly limited as long as it is pharmaceutically or cosmetically acceptable.
  • M 1 , M 2 and M 3 in the formula (I) and M in the formula (II) 1 and M2 each independently represent an alkali metal or alkaline earth metal, or an organic base.
  • alkali metals include potassium and sodium.
  • Alkaline earth metals include calcium.
  • Organic bases include monoethanolamine, diethanolamine, triethanolamine, aminomethylpropanol, and aminomethylpropanediol groups.
  • either one of a free form and a lactone form may be used as hydroxycitric acid and its salt, or both may be used in combination.
  • lactone bodies one may be selected and used, or two or more may be used in combination.
  • lactone forms are preferred from the viewpoint of obtaining a more excellent effect of promoting cartilage regeneration.
  • Hydroxycitric acid derivatives are derived from hydroxycitric acid as a base, with introduction of functional groups, oxidation, reduction, and atom replacement. More specific examples of hydroxycitric acid derivatives include hydroxycitric acid-2-octanoate, hydroxycitric acid-2-caprate, hydroxycitric acid-2-laurate, hydroxycitric acid-2-myristate, hydroxycitric acid- 2-palmitate, hydroxycitrate-2-stearate, hydroxycitrate-2-behenoate, hydroxycitrate-2-isopalmitate, hydroxycitrate-2-isostearate, hydroxycitrate-2-hexyldecanoate, hydroxycitric acid-2-linolate, hydroxycitric acid monomethyl ester-2-myristate, hydroxycitric acid monomethyl ester-2-palmitate, hydroxycitric acid monomethyl ester-2-stearate and the like.
  • Salts of hydroxycitric acid derivatives include alkali metal or alkaline earth metal salts or organic base salts of the above hydroxycitric acid derivatives.
  • hydroxycitric acids one of the four types of hydroxycitric acid, hydroxycitric acid salts, hydroxycitric acid derivatives, and hydroxycitric acid derivative salts may be used.
  • two or more may be used in combination, and from among the compounds included in each of the above hydroxycitric acid, hydroxycitric acid salts, hydroxycitric acid derivatives, and hydroxycitric acid derivative salts, one may be selected and used, or two or more compounds may be used in combination.
  • hydroxycitric acids hydroxycitric acid salts are preferable, and alkali metal salts and alkaline earth metal salts of hydroxycitric acid are more preferable, from the viewpoint of obtaining a more excellent effect of promoting cartilage regeneration.
  • Alkaline earth metal salts of hydroxycitric acid are more preferred, and calcium salts of hydroxycitric acid are particularly preferred.
  • hydroxycitric acids may be obtained from natural products or chemically synthesized.
  • Natural products include Garcinia species belonging to the family Hypericum genus Fukugi (specific examples include Garcinia cambogia, Garcinia indica, Garcinia atroviridis, Garcinia mangostana ), Garcinia subelliptica, etc.), and plants such as Hibiscus (Hibiscus L.) of the family Malvaceae, preferably the genus Garcinia, more preferably Garcinia cambogia (Garcinia cambogia). cambogia). Plants may be those produced by cultivation or those collected from nature. The part of the plant to be used is not limited as long as it contains hydroxycitric acids, but the pericarp is preferred. Methods for obtaining hydroxycitric acids from plants are conventionally known.
  • the cartilage regeneration-promoting agent of the present invention may contain isolated and purified hydroxycitric acids from natural products, or may contain crudely purified hydroxycitric acids from natural products.
  • Examples of crudely purified products of hydroxycitric acids include processed products of plants, preferably processed products of pericarp.
  • Specific examples of processed plant products include dried plant products, pulverized plant products (including fresh and dried products), and plant extracts.
  • As the processed plant product one derived from a single plant may be used, or two or more different plant-derived products may be used in combination.
  • plant extracts are preferred.
  • Specific examples of plant extracts include non-concentrated extracts (not concentrated), soft extracts (liquid concentrates) and powdered extracts (dry extracts).
  • plant extracts from the viewpoint of obtaining a more excellent cartilage regeneration promoting effect, preferred are plant extracts, and more preferred are extracts obtained from the genus Garcinia (Garcinia extract) (especially Preferred are extracts obtained from Garcinia cambogia) and hibiscus extracts obtained from Malvaceae.
  • the plant extract may be a squeezed juice, a solvent extract, or a fraction containing hydroxycitric acids from the solvent extract.
  • the method for obtaining the plant extract is not particularly limited, it can be obtained, for example, as follows.
  • the plant extract is prepared, for example, in the raw state of the pericarp of a plant such as Garcinia species or the petals of hibiscus, or in the state of a dried product such as the pericarp of a plant such as Garcinia species or the petals of hibiscus. It can be prepared according to a conventional extraction method such as solvent extraction, supercritical extraction, etc., after being cut or pulverized in size or further as required.
  • extraction solvents include water (including hot water and hot water), organic solvents (lower alcohols having 1 to 4 carbon atoms such as methanol, ethanol, n-propanol, isopropanol, n-butanol; propylene glycol, 1,3-butylene, polyhydric alcohols such as glycol; ketones such as acetone; esters such as diethyl ether, dioxane, acetonitrile, ethyl acetate; xylene, benzene, chloroform, etc.), mixtures thereof, preferably water, lower alcohol and mixtures thereof, more preferably heated water such as warm water or hot water, and still more preferably hot water. These solvents may be used singly or in combination of two or more.
  • a plant extract containing alkali metal salt and/or alkaline earth metal salt for example, calcium hydroxycitrate
  • alkali metal salt and/or alkaline earth metal salt for example, calcium hydroxycitrate
  • the plant extract is added to alkali metals and / Or a method of converting hydroxycitric acid in the extract to a salt by treating with a basic compound of an alkaline earth metal.
  • the plant extract When the obtained plant extract (squeezed juice, solvent extract, fraction containing hydroxycitric acids of solvent extract, etc.) is included in the cartilage regeneration promoting agent, the plant extract is used as a non-concentrated extract that is not concentrated as it is. It may be in the form of a concentrated liquid soft extract, or it may be an extract powder obtained by further drying a non-concentrated extract or soft extract. Drying processes include spray-drying and freeze-drying.
  • the amount of hydroxycitric acids in 100% by weight of the dry weight of the crudely purified hydroxycitric acids is, for example, 10% by weight or more, preferably 30% by weight or more, more preferably 50% by weight or more, and still more preferably 55% by weight or more.
  • the upper limit of the amount of hydroxycitric acids in 100% by weight in terms of dry weight is not particularly limited, examples thereof include 80% by weight or less or 70% by weight or less.
  • the method for obtaining an isolated and purified product of hydroxycitric acids is not particularly limited, but includes a method of further purifying the fraction containing hydroxycitric acids from the above extract.
  • the purification treatment can be carried out according to a conventional method, as long as it is a method of isolating hydroxycitric acids to further increase the degree of purification. Examples thereof include separation treatment such as chromatography, recrystallization treatment, and the like.
  • the amount of hydroxycitric acid compounded in the agent for promoting cartilage regeneration of the present invention is not particularly limited, and is appropriately set according to the formulation form and application of the agent for promoting cartilage regeneration. is 60 to 90% by weight.
  • the hydroxycitric acids contained in the agent for promoting cartilage regeneration of the present invention have the effect of promoting cartilage synthesis, which has not been observed with glucosamine.
  • the hydroxycitric acids contained in the cartilage regeneration-promoting agent of the present invention are excellent in suppressing the degradation of cartilage. Therefore, the agent for promoting cartilage regeneration of the present invention can regenerate damaged (defective or degenerated) cartilage by both promoting cartilage synthesis and inhibiting cartilage differentiation.
  • the cartilage regeneration promoting agent of the present invention may or may not contain other ingredients in addition to hydroxycitric acids, as long as the effects of the present invention are not impaired, depending on the form of application. good too.
  • Such other components include, for example, physiologically active substances and additives.
  • the physiologically active substance preferably includes components effective for improving cartilage and joints.
  • Specific examples include collagen, type II collagen, non-denaturing active type 2 collagen, collagen peptide, methylsulfonylmethane (MSM ), glucosamine, glucosamine hydrochloride, N-acetylglucosamine, N-acetylglucosamine sulfate, chondroitin, chondroitin sulfate, galactosamine, N-acetylgalactosamine, glucuronic acid, uronic acid, proteoglycan, non-denatured proteoglycan, heparin, heparan sulfate, iduron acid, keratan sulfate, dermatan sulfate, S-adenosylmethionine, creatine, theanine, piperine, maslinic acid, 5-aminolevulinic acid phosphate, cat's claw, black ginger, bo
  • Additives include pharmaceutically or food acceptable excipients, disintegrants, diluents, lubricants, flavoring agents, coloring agents, sweetening agents, corrigents, suspending agents, wetting agents, and emulsifying agents. , dispersants, adjuvants, preservatives, buffers, binders, stabilizers, extenders, thickeners, pH adjusters, surfactants, coating agents, nutritional components, and the like. These additives may be used singly or in combination of two or more.
  • the form and properties of the cartilage regeneration-promoting agent of the present invention are not particularly limited as long as it contains the hydroxycitric acids described above.
  • the dosage form of the agent for promoting cartilage regeneration of the present invention includes both oral and parenteral dosage forms. Therefore, the agent for promoting cartilage regeneration of the present invention is prepared as an oral preparation, an injection, a drip, a nasal drop, a percutaneous absorbable preparation (external preparation), and the like. Since the cartilage regeneration-promoting agent of the present invention is used for the purpose of cartilage regeneration, it is preferably an oral preparation that can be easily administered (taken) on a daily and/or continuous basis.
  • the properties of the cartilage regeneration promoting agent of the present invention may be liquid or solid.
  • liquids include liquids, beverages, emulsions, suspensions, spirits, syrups, elixirs, soft extracts, etc.
  • solids include tablets, pills, Powders, fine granules, granules, tablets, capsules (including hard capsules and soft capsules), lozenges, chewables, dry extracts and the like.
  • the agent for promoting cartilage regeneration of the present invention is in a solid form, it may be in a sustained or sustained release dosage form, or may be mixed with water or the like at the time of administration (ingestion).
  • the agent for promoting cartilage regeneration of the present invention is used as general food and drink, food with health claims (including food for specified health use, food with nutrient function claims, food with functional claims, supplements, etc.), food for the sick, pharmaceuticals, and quasi-drugs. It can also be used as an additive to foods, pharmaceuticals, quasi-drugs, and the like. In particular, from the viewpoint of casual ingestion on a daily and/or continuous basis, it can be used as a supplement containing hydroxycitric acids, or a supplement containing a plant extract containing hydroxycitric acids, preferably a supplement containing garcinia extract. preferable.
  • the method for manufacturing the cartilage regeneration-promoting agent of the present invention uses the above-mentioned hydroxycitric acids and other ingredients that are blended as necessary, according to various forms and properties, and the purpose of use. Normal formulation procedures may be followed.
  • the agent for promoting cartilage regeneration of the present invention promotes cartilage regeneration by administration (ingestion).
  • Regeneration of cartilage refers to the process of synthesizing cartilage, i.e., differentiating undifferentiated cells into chondrocytes, proliferating them, and synthesizing the cartilage matrix, thereby replacing defective or degenerated cartilage tissue with normal cartilage tissue (hyraline tissue).
  • Cartilage normal cartilage tissue to reconstruct.
  • the promotion of cartilage regeneration refers to promoting the regeneration of cartilage, suppressing further degradation of cartilage tissue, and promoting reconstruction of cartilage tissue.
  • the cartilage regeneration-promoting agent of the present invention suppresses and/or regenerates the wear and tear of cartilage, enhances the ability to form cartilage, and cartilage components (specifically, cartilage matrix) for subjects requiring cartilage regeneration. ) and/or can be used for the purpose of maintaining the state of healthy cartilage.
  • More specific examples of the above object of the cartilage regeneration promoting agent of the present invention are when walking (particularly when walking long distances in a certain period of time), when going up and down stairs, and when putting on and taking off socks.
  • knee flexion and extension i.e. smoothness of knee motion
  • flexibility i.e., flexibility
  • mobility i.e., mobility
  • help i.e., support
  • Targets requiring cartilage regeneration are preferably mammals, more specifically, humans; pets such as dogs and cats; and domesticated animals such as horses and cows.
  • Hydroxycitric acids which are the active ingredients of the agent for promoting cartilage regeneration of the present invention, have not only the effect of promoting cartilage synthesis but also the effect of suppressing cartilage degradation.
  • One aspect of the preferred application of is application for the purpose of treatment of cartilage damage to a subject having cartilage damage (an example of a subject requiring cartilage regeneration ability).
  • Treatment of cartilage disorders includes not only cure but also reduction of cartilage disorders.
  • Cartilage disorders are not particularly limited as long as they are pathological conditions caused by loss or degeneration of cartilage, and include osteoarthritis, traumatic cartilage injury, and arthritis due to various causes.
  • the target cartilage site is not particularly limited, but includes various joint sites in the body, such as knee joints, hip joints, elbow joints, shoulder joints, wrist joints, ankle joints, and temporomandibular joints.
  • hydroxycitric acids which are active ingredients of the agent for promoting cartilage regeneration of the present invention, have excellent cartilage synthesis-promoting action and cartilage degradation-inhibiting action.
  • One aspect of preferred application of the regeneration promoter includes application for the purpose of preventing cartilage damage to subjects at risk of cartilage damage (examples of subjects requiring cartilage regeneration ability).
  • Subjects at risk of cartilage damage include elderly people at risk of osteoarthritis, which is often seen in humans over the age of 50, especially over the age of 65, and sports enthusiasts at risk of cartilage damage, which is seen in sports injuries.
  • Home or professional athletes other people who overuse their joints on a daily basis, or those who experience the natural wear and tear of cartilage with age, preferably with the natural wear and tear of cartilage with age.
  • the cartilage regeneration-promoting agent of the present invention exerts an effect of suppressing degradation of cartilage tissue and promoting reconstruction.
  • it can be used for the purpose of maintaining the thickness of the knee cartilage that has become thinner with age, and alleviating knee pain, discomfort, and/or discomfort in daily life.
  • Hydroxycitric acids which are the active ingredients of the agent for promoting cartilage regeneration of the present invention, also have the effect of differentiating undifferentiated cells into chondrocytes.
  • one aspect of the preferred application of the agent for promoting cartilage regeneration of the present invention is a subject having severe cartilage damage in which a defect in the cartilage itself (that is, cartilage deficiency) is observed (cartilage For the purpose of treatment to regenerate the cartilage itself for a subject that requires regenerative power.
  • Treatment of severe cartilage disorders includes not only cure but also reduction of cartilage disorders. Specific examples of severe cartilage disorders include traumatic cartilage defects caused by sports or traffic accidents.
  • the dose of the agent for promoting cartilage regeneration of the present invention is, for example, 0.1 g/day/60 kg or more, preferably 0.2 g/day/60 kg or more, more preferably 0.2 g/day/60 kg or more, in terms of hydroxycitric acid equivalent, as a dose to humans.
  • the upper limit of the dose is not particularly limited, for example, 18 g/day/60 kg or less, preferably 10 g/day/60 kg or less, more preferably 2 g/day/60 kg or less, further preferably 1.5 g/day/60 kg or less, More preferably 1.2 g/day/60 kg or less, still more preferably 0.9 g/day/60 kg or less, and particularly preferably 0.7 g/day/60 kg or less.
  • the dosage for humans is 0.16 g/day/60 kg or more, preferably 0.3 g/day/60 kg or more, preferably 0.3 g/day/60 kg or more.
  • the upper limit of the dose is not particularly limited, but is, for example, 30 g/day/60 kg or less, preferably 17 g/day/60 kg or less, more preferably 3.3 g/day/60 kg or less, still more preferably 2.5 g/day/60 kg. Below, more preferably 2 g/day/60 kg or less, still more preferably 1.5 g/day/60 kg or less, and particularly preferably 1.2 g/day/60 kg or less.
  • the method of administration (ingestion) of the agent for promoting cartilage regeneration of the present invention is not particularly limited. ⁇ 3 doses can be given orally.
  • chondrocyte differentiation promoting agent cartilage degradation inhibitor, protective agent for maintaining cartilage thickness, and joint pain, discomfort, and/or discomfort alleviating agent
  • hydroxycitric acid, its derivatives, and salts thereof have an action of promoting the differentiation of undifferentiated cells into chondrocytes, an action of promoting cartilage synthesis, and an action of inhibiting cartilage degradation, so they are chondrocyte differentiation promoters, cartilage degradation inhibitors, and maintain cartilage thickness. It is also useful as an active ingredient in a protective agent for joint pain, discomfort, and/or discomfort.
  • the present invention provides chondrocyte differentiation promoting agents, cartilage degradation inhibitors, protective agents for maintaining cartilage thickness, and joints containing hydroxycitric acid, derivatives thereof, and/or salts thereof. Also provided are pain, discomfort, and/or discomfort relievers.
  • Hydroxycitric acid as an active ingredient in chondrocyte differentiation promoters, cartilage degradation inhibitors, protective agents for maintaining cartilage thickness, and joint pain, discomfort, and/or discomfort relief agents, Details of derivatives and/or salts thereof, details of other components whether or not they are contained, formulation forms, manufacturing methods, uses, and dosages are the same as those described in "1. Cartilage regeneration promoter" above.
  • chondrocyte differentiation promoting agents can also be used in vitro for the purpose of promoting chondrocyte differentiation by direct exposure to undifferentiated cells.
  • concentration of the chondrocyte differentiation promoting agent when exposed to undifferentiated cells is not particularly limited. 0.3 mM, more preferably 0.1-0.32 mM, still more preferably 0.15-0.25 mM, even more preferably 0.18-0.22 mM.
  • Test Example 1 Chondrocyte differentiation-inducing activity, cartilage matrix production activity, and chondrocyte proliferation activity of hydroxycitric acids (in vitro) 1.
  • Primary screening method/cultured cells PLoS ONE, (US), 2014, 9(12), e112291.
  • Mesenchymal stem cells were induced via neural crest cells from the cells, and an equal amount of cell cryoprotectant CP-1 (manufactured by Kyokuto Pharmaceutical Co., Ltd.) was added and cryopreserved.
  • chondrocyte differentiation induction medium (-) hydroxycitric acid (HCA, free form) (manufactured by ChromaDex, Inc.); K) (manufactured by Sigma-Aldrich) or (-) hydroxycitrate-3 calcium (HCA-Ca) (manufactured by Sigma-Aldrich); - lactone or garcinia acid) (Sigma-Aldrich) was added to a final concentration of 60 ⁇ g/mL.
  • HCA hydroxycitric acid
  • K manufactured by Sigma-Aldrich
  • HCA-Ca hydroxycitrate-3 calcium
  • Sigma-Aldrich hydroxycitrate-3 calcium
  • - lactone or garcinia acid (Sigma-Aldrich) was added to a final concentration of 60 ⁇ g/mL.
  • BMP-7 manufactured by R&D Systems
  • an osteogenic factor was added to the control group.
  • the cells were fixed with 4% paraformaldehyde/phosphate buffer (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.). After fixation, staining was performed for 1 hour with an alcian blue solution (manufactured by Muto Kagaku), and the dye was eluted using a 6M guanidine hydrochloride solution (manufactured by Tokyo Kasei Kogyo). The eluate was transferred to a 96-well plate, and the OD value at 620 nm of each well was measured using a microplate reader to measure the amount of matrix produced by the differentiation-induced chondrocytes. Specifically, when the average OD value in the control group was set to 1, the average OD value in each group was derived as the cartilage matrix production ratio.
  • Fig. 1A shows the results of cartilage matrix production brought about by induction of differentiation into chondrocytes in two-dimensional culture of human iPS cell-derived mesenchymal stem cells.
  • 200 ⁇ M ( ⁇ ) hydroxycitric acid (HCA-free form) improved the cartilage matrix production ratio (1.25 times or more as compared to the control) compared to the control without the material.
  • 200 ⁇ M ( ⁇ ) hydroxycitric acid (HCA, free body) induced differentiation of human iPS cell-derived mesenchymal stem cells into chondrocytes that produce cartilage matrix. ing.
  • the potassium salt and calcium salt of 200 ⁇ M (-) hydroxycitric acid improved the cartilage matrix production ratio by 1.05 and 1.08 times, respectively, as compared with the free form.
  • the hydroxycitric acid salt has higher chondrocyte differentiation-inducing activity and cartilage matrix-producing activity than the free body (HCA).
  • the lactone body (HCA-lactone) also showed a higher cartilage matrix production ratio than the free body, indicating higher chondrocyte differentiation-inducing activity and cartilage matrix production activity.
  • HCA hydroxycitric acid
  • K manufactured by Sigma-Aldrich
  • HCA-Ca hydroxycitrate-3 calcium
  • - lactone or garcinia acid was added to a final concentration of 60 ⁇ g/mL.
  • 10 ng/mL of BMP-7 manufactured by R&D Systems
  • osteogenic factor was added to the positive control group. Neither the test substance nor the osteogenic factor was added to the control group.
  • chondrocyte differentiation induction medium prepared in 10% Cell Counting Kit-8 (manufactured by Dojin Kagaku Kenkyusho) was added and cultured for 1 hour. After that, the OD value at 450 nm of each well of this 96-well plate was measured with a microplate reader to measure the number of proliferation-induced chondrocytes. Specifically, when the average OD value in the control group was set to 1, the average OD value in each group was derived as the chondrocyte proliferation ratio.
  • Fig. 1B shows the results of chondrocyte proliferation brought about by induction of differentiation into chondrocytes in two-dimensional culture of human iPS cell-derived mesenchymal stem cells.
  • FIG. 1B the same tendency as in FIG. 1A was observed.
  • 200 ⁇ M (-) hydroxycitric acid (HCA-free form) improved the chondrocyte proliferation rate compared to no material (control).
  • This also indicates that 200 ⁇ M ( ⁇ ) hydroxycitric acid (HCA, free body) induced the differentiation of human iPS cell-derived mesenchymal stem cells into chondrocytes prior to chondrocyte proliferation.
  • the potassium salt and calcium salt of 200 ⁇ M (-) hydroxycitric acid were found to have an effect of improving the chondrocyte proliferation ratio superior to that of the free form, and among them, the calcium salt showed an even more excellent effect of improving the chondrocyte proliferation ratio. was accepted.
  • the hydroxycitric acid salt has higher chondrocyte differentiation-inducing activity and chondrocyte proliferation activity than the free form (HCA).
  • the lactone body (HCA-lactone) also showed higher chondrocyte proliferation activity than the free body, indicating that the chondrocyte proliferation activity was higher.
  • Chondrocyte proliferation activity was also observed when hydroxycitric acid-2-palmitate was used in place of hydroxycitric acid and its salts.
  • cartilage matrix production ratio and chondrocyte proliferation ratio were observed at 0.1 to 0.4 mM, preferably 0.1 to 0.3 mM, particularly preferably 0.2 mM. . That is, the concentration of hydroxycitric acid at which chondrocyte differentiation-inducing activity, cartilage matrix-producing activity, and chondrocyte-proliferating activity is expressed is 0.1 to 0.4 mM, preferably 0.1 to 0.3 mM, and particularly preferably. was shown to be 0.2 mM (53 ⁇ g/ml).
  • Fig. 2 shows the morphology and red area ratio of differentiated chondrocytes obtained by three-dimensional culture of human bone marrow-derived mesenchymal stem cells.
  • 100 ⁇ M HCA- which is the lactone form of (-) hydroxycitric acid
  • lactone proteoglycan staining with safranin O was observed, and differentiated chondrocytes were observed, as compared with no material (control).
  • hydroxycitric acid and its salts have excellent chondrocyte differentiation-inducing activity.
  • hydroxycitric acid derivatives were also found to have chondrocyte differentiation-inducing activity.
  • Test Example 2 Chondrocyte differentiation-inducing activity, cartilage matrix production activity, and chondrocyte proliferation activity of Garcinia extract (in vitro) (Preparation of Garcinia extract)
  • the pericarp of Garcinia cambogia was dried and extracted with hot water by adding 10 times the amount of water and eggshell calcium. After filtering the resulting extract, it was concentrated under reduced pressure using a rotary evaporator, and the obtained concentrate was further spray-dried. The dried extract was pulverized to obtain powdered Garcinia extract.
  • This garcinia extract (garcinia cambogia extract) was used in all test examples below.
  • the hydroxycitric acid ((-) hydroxycitric acid) contained in the pericarp of Garcinia cambogia is contained in the form of a calcium salt due to the use of eggshell calcium at the time of extraction.
  • the content of active ingredients in this garcinia extract is 60% by weight in terms of hydroxycitric acid.
  • FIG. 3A shows the results of cartilage matrix production brought about by induction of differentiation into chondrocytes in two-dimensional culture of human iPS cell-derived mesenchymal stem cells.
  • the positive controls 10 ng/mL BMP7 and 60 ⁇ g/mL Garcinia extract, improved the cartilage matrix production ratio (specifically, 1.25-fold or more than the control) compared to the no material (control). This also indicates that prior to cartilage matrix production, 10 ng/mL BMP7 and 60 ⁇ g/mL Garcinia extract induced differentiation of human iPS cell-derived mesenchymal stem cells into chondrocytes that produce cartilage matrix.
  • HCA-Ca calcium hydroxycitrate
  • FIG. 3A calcium hydroxycitrate (HCA-Ca) was used as a test substance at the same concentration (specifically, 60 ⁇ g/mL), and cartilage matrix production accompanying chondrocyte differentiation induction was measured in the same manner as described above. The results obtained are also shown.
  • Garcinia extract and hydroxycitric acid at the same concentration were found to have a lower cartilage matrix production ratio than HCA/Ca, although Garcinia extract had a lower amount of hydroxycitric acid (p ⁇ 0 .01) was improving. In other words, it was shown that Garcinia extract enhances the activity of inducing differentiation into chondrocytes and the activity of producing cartilage matrix more than HCA ⁇ Ca.
  • FIG. 3B shows the results of chondrocyte proliferation brought about by induction of differentiation into chondrocytes by Garcinia extract in two-dimensional culture of human iPS cell-derived mesenchymal stem cells.
  • the positive control 10 ng / mL BMP7 and 60 ⁇ g / mL Garcinia extract improved the chondrocyte proliferation ratio compared to no material (control). It has been shown.
  • FIG. 3B shows the results of measuring the number of chondrocytes in the same manner as described above using garcinia extract or calcium hydroxycitrate (HCA/Ca) as test substances at the same concentration (specifically 60 ⁇ g/mL). are also shown. Garcinia extract and hydroxycitric acid at the same concentration were found to have a lower chondrocyte proliferation ratio than HCA/Ca, although Garcinia extract had a smaller amount of hydroxycitric acid (p ⁇ 0 .05) was improving. In other words, it was shown that Garcinia extract enhances chondrocyte differentiation-inducing activity and chondrocyte proliferation activity more than HCA ⁇ Ca.
  • chondrocyte differentiation was induced by three-dimensional culture of human bone marrow-derived mesenchymal stem cells in the same manner as in Test Example 1, except that Garcinia extract was added as a test substance at a concentration of 30 ⁇ g/mL. Observation of cell morphology and derivation of red area ratio were performed.
  • Fig. 3C shows the morphology and red area ratio of chondrocytes obtained by three-dimensional culture of human bone marrow-derived mesenchymal stem cells using garcinia extract or calcium hydroxycitrate (HCA/Ca).
  • HCA/Ca calcium hydroxycitrate
  • Test Example 3 Chondrocyte differentiation-inducing activity, cartilage matrix production activity, and chondrocyte proliferation activity (in vitro) by various hydroxycitric acids and plant extracts
  • Garcinia extract The Garcinia extract prepared in Test Example 2 was used.
  • chondrocyte differentiation was induced in all HCAs of (+) form, (-) form, free form and lactone form, as well as garcinia extract and hibiscus extract.
  • Test Example 4 Rat knee joint cartilage regeneration test with garcinia extract (in vivo) A garcinia extract was administered to articular cartilage of the femoral trochlea of rats after drilling (cartilage damage), and cartilage regeneration was examined.
  • test target Ten 8-week-old female SD rats (Japan SLC) were prepared, and after acclimatization for one week, a 1.0 mm diameter drill was drilled on the cartilage surface of the femoral trochlea of the left knee joint using a microdrill. Surgery was performed to create one hole and one drilled hole of 1.5 mm diameter.
  • Test schedule and test method Water was administered to 5 rats in the control group, and 2000 mg/kg/day of the garcinia extract used in Test Example 1 was administered to 5 rats in the test group (this dose is converted to the human equivalent dose of garcinia extract). (60 kg per human using a divisor of 6.2 for rats, which is 19.4 g/day) once daily orally. Rats were weighed on days 0 (the day of surgery), 4 and 16 days. 16 days after the start of administration, all the rats were dissected, and after photographing the surface of the left knee articular cartilage, which was the surgical site, the femur was excised.
  • specimens were prepared. The prepared specimen was subjected to HE staining, Alcian blue staining and Safranin O staining.
  • blood was collected from rats at the time of dissection, serum was prepared, and then quantified using a commercially available cartilage degradation marker C2C and a cartilage synthesis marker CPII kit (IBEX).
  • FIG. 5 shows changes in body weight of rats. As shown in FIG. 5, weight gain was observed in rats administered water and rats administered garcinia extract for 16 days. Garcinia extract is known to have a fat-burning effect and a diet (weight loss) effect, but under the conditions of this test example, no significant difference was observed in body weight change between water-administered rats and Garcinia extract-administered rats. .
  • FIG. 6 shows photographs of the operated part of the cartilage surface of the femoral trochlea on the day of the operation (Day 0) and 16 days after the operation (Day 16).
  • locations indicated by arrows indicate locations where drill holes are drilled.
  • the upper hole is a drilled hole with a diameter of 1.5 mm
  • the lower hole is a drilled hole with a diameter of 1.0 mm.
  • FIG. 7(a) A stained image of the cross-sectional specimen is shown in FIG. 7(a).
  • locations indicated by arrows indicate locations where drilled holes are made.
  • the defect was filled in both the water-administered rat and the garcinia extract-administered rat, but in the garcinia extract-administered rat, the surface layer was covered with cartilage tissue, and the formation of hyaline cartilage was confirmed.
  • the cell nucleus in HE staining, the cell nucleus is visible as a small dark purple dot, and in the garcinia extract-administered rat, a dot indicating the cell nucleus was observed on the surface layer of the filled drill hole. It was confirmed that it existed.
  • the tissue formed in the surface layer of the rats administered the garcinia extract was stained blue with alcian blue and red with safranin O, so it was determined to be cartilage tissue composed of differentiated and proliferated chondrocytes.
  • no staining indicating cartilage tissue was observed at the drilled portion.
  • Fig. 7(b) shows the results of measuring the remaining depth of the drilled hole. As shown in FIG. 7(b), the average value of 5 water-administered rats was 105 ⁇ m, whereas the average value of 5 Garcinia extract-administered rats was 32 ⁇ m (p ⁇ 0.01). significant difference).
  • FIG. 8 shows the measurement results of the blood cartilage synthesis marker (CPII) level and the cartilage degradation marker (C2C) level.
  • CPII blood cartilage synthesis marker
  • C2C cartilage degradation marker
  • Test Example 5 Onset prevention test for rat osteoarthritis-induced model with garcinia extract (in vivo) Cartilage regeneration was investigated by administering garcinia extract or glucosamine to a rat model in which articular cartilage degeneration due to joint instability was induced by amputation of the medial collateral ligament of the knee joint.
  • test target 14 8-week-old female SD rats (Japan SLC) were prepared, and after acclimatization for one week, the inside of the left knee joint was incised, Nagoya Gakuin University Review, (Japan), 2018, 6, p1-9 According to ., an operation (OA operation) was performed to cut the medial collateral ligament.
  • Test schedule and test method Two rats were administered water without administration (control); six rats were administered 258 mg/kg/day of the garcinia extract used in Test Example 1 (this dose was the same as that of the garcinia extract Converted to a human equivalent dose (using a divisor of 6.2 for rats and 60 kg per human), it is 2.5 g / day), once a day from the day after OA surgery, daily oral administration and 6 other rats were orally administered glucosamine at 258 mg/kg/day once daily. Twenty-eight days after the start of administration, the rats were dissected, the left femur was extracted, and tissue sample analysis was performed.
  • garcinia extract is more effective than glucosamine in suppressing cartilage degeneration due to joint instability. This result indicates that the cartilage degradation inhibitory action of the garcinia extract, together with the cartilage synthesis-promoting action, is considered to have maintained articular cartilage.
  • Test Example 6 Cartilage regeneration test (in vivo) for accelerated mouse knee cartilage degeneration model with Garcinia extract Cartilage regeneration was examined when the same doses of hydroxycitric acid (HCA) and Garcinia extract were administered to a mouse model of accelerated knee cartilage degeneration.
  • HCA hydroxycitric acid
  • mice were forced to walk for 2 weeks to promote degeneration of knee articular cartilage. In this way, we constructed an animal experimental model without surgery, which is similar to cartilage degeneration associated with aging in humans, that is, knee cartilage wear and tear.
  • cartilage degeneration score was smaller in the administration of hydroxycitric acid and the garcinia extract than in the administration of water, indicating cartilage tissue regeneration.
  • the score of cartilage degeneration with garcinia extract administration was significantly smaller than that with hydroxycitric acid administration (p ⁇ 0.05), indicating even better cartilage tissue regeneration.
  • both the administration of hydroxycitric acid and the administration of garcinia extract confirmed an increase in the amount of cartilage synthesis markers and a decrease in cartilage degradation markers.
  • administration of the garcinia extract resulted in a further increase in cartilage synthesis marker level and a further decrease in cartilage degradation marker level compared to administration of hydroxycitric acid.
  • the garcinia extract was found to have stronger cartilage synthesizing action and cartilage degradation inhibitory action than the hydroxycitric acid, although the garcinia extract was less than the hydroxycitric acid.
  • Test Example 7 Hydroxycitric Acid Dose Dependence of Cartilage Regeneration in Mouse Knee Cartilage Degeneration Accelerated Model by Garcinia Extract (in vivo) Test examples, except that the dose of garcinia extract (hydroxycitric acid content is 60% by weight) was 0 mg/kg/day, 103 mg/kg/day, 206 mg/kg/day, or 512 mg/kg/day A cartilage regeneration test was performed on a mouse knee cartilage degeneration accelerated model in the same manner as in 6, and a cartilage degeneration score was derived and a cartilage synthesis marker (CPII) in blood was measured.
  • CPII cartilage synthesis marker
  • the doses of 0 mg/kg/day, 103 mg/kg/day, 206 mg/kg/day, and 512 mg/kg/day of the garcinia extract administered to the mice in this test example were converted to 0 mg/day in terms of hydroxycitric acid. /kg/day, 62 mg/kg/day, 124 mg/kg/day, and 307 mg/kg/day. These doses are 0 g/day, 0.5 g/day, 1 g/day and 2.5 g/day and converted to human equivalent doses of hydroxycitric acid (60 kg per human using a divisor of 12.3 for mice) of 0 g/day, 0.3 g/day, and 0 g/day, respectively. .6 g/day and 1.5 g/day.
  • FIG. 13 shows the relationship between the cartilage degeneration score and blood cartilage synthesis marker (CPII) concentration and the human-equivalent dose of hydroxycitric acid.
  • CPII blood cartilage synthesis marker
  • the relationship between the dose of hydroxycitric acid and the degree of cartilage synthesis effect and cartilage tissue regeneration effect shows that the concentration of hydroxycitric acid exposed to the cells shown in FIG. A similar trend was observed in relation to Specifically, from the results of FIG. 13, the preferred human equivalent dose of hydroxycitric acid of Garcinia extract for cartilage synthesis and cartilage regeneration is 0.3 g to 1.5 g/day, especially 0.3 g to 1.5 g/day. The highest cartilage synthesizing effect and cartilage tissue regeneration effect were observed at 6 g/day.

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Abstract

L'objectif de la présente invention est de fournir un nouveau composant ayant un effet qui favorise la régénération des cartilages. Cet agent pour favoriser la régénération des cartilages contenant de l'acide hydroxycitrique et/ou un sel de celui-ci est en mesure de favoriser la régénération des cartilages.
PCT/JP2022/040711 2021-11-01 2022-10-31 Agent pour favoriser la régénération de cartilages WO2023074894A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060025483A1 (en) * 2004-07-29 2006-02-02 Clouatre Dallas L (-)-Hydroxycitric acid for protection against soft tissue and arterial calcification
JP2007522090A (ja) * 2003-07-02 2007-08-09 グリュコン テクノロジーズ グループ エルエルシー 制御された炎症のための（−）−ヒドロキシクエン酸
EP1889615A2 (fr) * 2006-08-04 2008-02-20 Rottapharm S.p.A. Formulations pour l'administration orale avec un effet de promotion de la santé sur les articulations osseuses et les muscles squelettiques
JP2014129252A (ja) * 2012-12-28 2014-07-10 Nof Corp 皮膚機能改善剤
JP2016193844A (ja) * 2015-03-31 2016-11-17 株式会社東洋新薬 オシダ科植物含有組成物
US20180065992A1 (en) * 2016-09-08 2018-03-08 Glykon Technologies Group, Llc Monomeric bimetal hydroxycitric acid compounds and methods of making and using the same
US20190211007A1 (en) * 2014-07-29 2019-07-11 Shenzhen Hightide Biopharmaceutical, Ltd. Berberine salts, ursodeoxycholic salts and combinations, methods of preparation and application thereof

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007522090A (ja) * 2003-07-02 2007-08-09 グリュコン テクノロジーズ グループ エルエルシー 制御された炎症のための（−）−ヒドロキシクエン酸
US20060025483A1 (en) * 2004-07-29 2006-02-02 Clouatre Dallas L (-)-Hydroxycitric acid for protection against soft tissue and arterial calcification
EP1889615A2 (fr) * 2006-08-04 2008-02-20 Rottapharm S.p.A. Formulations pour l'administration orale avec un effet de promotion de la santé sur les articulations osseuses et les muscles squelettiques
JP2014129252A (ja) * 2012-12-28 2014-07-10 Nof Corp 皮膚機能改善剤
US20190211007A1 (en) * 2014-07-29 2019-07-11 Shenzhen Hightide Biopharmaceutical, Ltd. Berberine salts, ursodeoxycholic salts and combinations, methods of preparation and application thereof
JP2016193844A (ja) * 2015-03-31 2016-11-17 株式会社東洋新薬 オシダ科植物含有組成物
US20180065992A1 (en) * 2016-09-08 2018-03-08 Glykon Technologies Group, Llc Monomeric bimetal hydroxycitric acid compounds and methods of making and using the same

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEN LIANG-YU, LOTZ MARTIN, TERKELTAUB ROBERT, LIU-BRYAN RU: "Modulation of matrix metabolism by ATP-citrate lyase in articular chondrocytes", JOURNAL OF BIOLOGICAL CHEMISTRY, AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY, US, vol. 293, no. 31, 1 August 2018 (2018-08-01), US , pages 12259 - 12270, XP093061561, ISSN: 0021-9258, DOI: 10.1074/jbc.RA118.002261 *
PEAL A., D'ALTILIO M., SIMMS C., ALVEY M., GUPTA R. C., GOAD J. T., CANERDY T. D., BAGCHI M., BAGCHI D.: "Therapeutic efficacy and safety of undenatured type-II collagen (UC-II) alone or in combination with (?)-hydroxycitric acid and chromemate in arthritic dogs", JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS, vol. 30, no. 3, 1 June 2007 (2007-06-01), GB , pages 275 - 278, XP093061567, ISSN: 0140-7783, DOI: 10.1111/j.1365-2885.2007.00844.x *

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