Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—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 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
• • 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
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2121/00—Preparations for use in therapy

Definitions

• the present invention relates to a composition for promoting cartilage regeneration.
• the present invention also relates to a method for promoting cartilage regeneration and the like.
• Cartilage is a connective tissue composed of chondrocytes and a substrate surrounding them, and forms joints, skeletons, etc. in animals such as humans.
• Articular cartilage plays a role of thinly covering the surface of the bone of the joint and smoothing the movement of the joint, and when the cartilage decreases due to aging or the like, the joint function is impaired.
• Patent Document 1 contains glucosamine and at least one component selected from the group consisting of plant materials, amino acids, polyphenols, vitamins and minerals, etc. as an active ingredient. The thing is listed.
• Patent Document 1 protects cartilage by suppressing the destruction of articular chondrocytes. However, once chondrocytes are destroyed due to aging or the like, it is not possible to regenerate the decreased cartilage by suppressing the destruction of chondrocytes. In Patent Document 1, a substance effective for promoting cartilage regeneration has not been studied.
• flavonoids having a specific structure have an action of promoting differentiation into chondrocytes and are useful for promoting cartilage regeneration.
• Techniques that can promote the differentiation into chondrocytes are particularly useful techniques that can regenerate cartilage even after it has been destroyed and reduced.
• the present invention relates to the following cartilage regeneration promoting composition, cartilage regeneration promoting method, and the like.
• R 1 , R 2 , R 3 , R 4 and R 5 each independently represent a hydrogen atom or a hydroxyl group.
• R 6 represents a hydroxyl group or an alkoxy group having 1 to 2 carbon atoms.
• R 7 and R 8 are one of a hydrogen atom,. broken line the other is hydroxyl or C 1 -C 2 alkoxy group having a carbon may optionally bond is formed, that may not be formed Represent.
• [2] The composition for promoting cartilage regeneration according to the above [1], which promotes differentiation into chondrocytes.
• [3] The compositions for promoting cartilage regeneration according to the above [1] or [2], wherein R 1 and R 3 represent hydrogen atoms.
• R 5a represents a hydrogen atom or a hydroxyl group.
• R 6a represents a hydroxyl group or a methoxy group.
• One of R 7a and R 8a represents a hydrogen atom and the other represents a hydroxyl group or a methoxy group.
• the broken line indicates that the bond may or may not be formed.
• the flavonoids represented by the general formula (1) are at least one selected from the group consisting of quercetin, hesperetin, taxifolin, isorhamnetin, eriodictyol, luteolin and morin, according to the above [1] to [5].
• the composition for promoting cartilage regeneration according to any one.
• cartilage regeneration promoting composition that promotes cartilage regeneration. Further, according to the present invention, a method for promoting cartilage regeneration is provided.
• the composition for promoting cartilage regeneration of the present invention contains flavonoids represented by the following general formula (1) as an active ingredient.
• the cartilage is preferably articular cartilage.
• R 1 , R 2 , R 3 , R 4 and R 5 each independently represent a hydrogen atom or a hydroxyl group.
• R 6 represents a hydroxyl group or an alkoxy group having 1 to 2 carbon atoms.
• R 7 and R 8 are one of a hydrogen atom,. broken line the other is hydroxyl or C 1 -C 2 alkoxy group having a carbon may optionally bond is formed, that may not be formed Represent.
• the flavonoid represented by the general formula (1) may be one kind or two or more kinds. In the present specification, flavonoids represented by the general formula (1) are also simply referred to as flavonoids.
• R 1 and R 3 are preferably hydrogen atoms.
• R 2 and R 4 are preferably hydroxyl groups.
• R 5 is preferably a hydrogen atom or a hydroxyl group.
• the alkoxy group having 1 to 2 carbon atoms is a methoxy group or an ethoxy group, preferably a methoxy group.
• R 6 is preferably a hydroxyl group or a methoxy group.
• R 7 represents a hydrogen atom
• R 8 represents a hydroxyl group or an alkoxy group having 1 to 2 carbon atoms.
• R 8 represents a hydrogen atom
• R 7 represents a hydroxyl group or an alkoxy group having 1 to 2 carbon atoms.
• R 7 is preferably a hydrogen atom, a hydroxyl group or a methoxy group.
• R 8 is preferably a hydrogen atom or a hydroxyl group.
• the flavonoid represented by the general formula (1) the flavonoid represented by the following general formula (2) is preferable.
• the flavonoid represented by the general formula (2) has R 1 and R 3 as a hydrogen atom, R 2 and R 4 as a hydroxyl group, R 6 as a hydroxyl group or a methoxy group, and R 7 and R.
• Reference numeral 8 is a compound in which one represents a hydrogen atom and the other represents a hydroxyl group or a methoxy group.
• R 5a represents a hydrogen atom or a hydroxyl group.
• R 6a represents a hydroxyl group or a methoxy group.
• One of R 7a and R 8a represents a hydrogen atom and the other represents a hydroxyl group or a methoxy group.
• the broken line indicates that the bond may or may not be formed.
• R 7a represents a hydrogen atom
• R 8a represents a hydroxyl group or a methoxy group.
• R 7a represents a hydroxyl group or a methoxy group.
• it is preferable that R 7a is a hydrogen atom, a hydroxyl group or a methoxy group
• R 8a is a hydrogen atom or a hydroxyl group.
• flavonoid represented by the general formula (1) hesperetin, quercetin, taxifolin, isorhamnetin, eriodictyol, luteolin, and morin are preferable. These flavonoids have a high cartilage regeneration promoting effect. These flavonoids are flavonoids represented by the general formula (2).
• the composition for promoting cartilage regeneration of the present invention preferably contains one or more of these flavonoids as an active ingredient.
• flavonoid represented by the general formula (1) hesperetin, quercetin, taxifolin, isorhamnetin, eriodictyol, and morin are more preferable.
• the origin of the flavonoid represented by the general formula (1) is not particularly limited. Since the flavonoid represented by the general formula (1) is contained in a plant, it can be extracted and prepared from the plant. For flavonoids, chemically synthesized products can also be used. In the present invention, a plant-derived raw material such as a plant extract containing a flavonoid represented by the general formula (1) may be contained in the composition as long as the effect of the present invention is exhibited.
• the flavonoid represented by the general formula (1) is a compound contained in natural products and foods and drinks and has eating experience. Therefore, from the viewpoint of safety, it is considered that the flavonoids have little problem in ingestion every day, for example. According to the present invention, it is possible to provide a composition for promoting cartilage regeneration containing a highly safe substance as an active ingredient.
• the weight of cartilage pellets formed increased.
• the synovial cells used in the examples contain mesenchymal stem cells, and the mesenchymal stem cells differentiate into chondrocytes to form cartilage pellets.
• the above increase in cartilage pellet weight means that the differentiation of mesenchymal stem cells into chondrocytes was promoted. Therefore, the flavonoid represented by the general formula (1) promotes the differentiation of mesenchymal stem cells into chondrocytes.
• mesenchymal stem cells present in the synovium and the surface layer of articular cartilage are said to easily differentiate into chondrocytes.
• the flavonoid represented by the general formula (1) is useful for promoting the differentiation of synovial-derived mesenchymal cells or mesenchymal stem cells present on the surface layer of articular cartilage into chondrocytes, for example.
• cartilage regeneration can be promoted. Therefore, the flavonoid represented by the general formula (1) is useful for promoting cartilage regeneration.
• the composition for promoting cartilage regeneration of the present invention can be used to promote differentiation into chondrocytes and promote cartilage regeneration. By promoting cartilage regeneration, it becomes possible to increase cartilage. Therefore, promoting cartilage regeneration is useful, for example, in preventing cartilage loss. In addition, by promoting cartilage regeneration, the decreased cartilage can be repaired.
• the composition for promoting cartilage regeneration of the present invention can also be used as a composition for promoting differentiation of mesenchymal stem cells into chondrocytes.
• the composition for promoting cartilage regeneration of the present invention can be applied to either therapeutic use (medical use) or non-therapeutic use (non-medical use).
• Non-therapeutic is a concept that does not include medical practice, ie human surgery, treatment or diagnosis.
• the composition for promoting cartilage regeneration of the present invention can be in the form of foods and drinks, pharmaceuticals, quasi-drugs, feeds and the like.
• the composition for promoting cartilage regeneration of the present invention may itself be a food or drink, a pharmaceutical product, a quasi-drug, a feed, etc. for promoting cartilage regeneration, and is a material or preparation used in combination with these. It may be.
• the composition for promoting cartilage regeneration of the present invention can be provided in the form of an agent as an example, but is not limited to this form.
• the agent can be provided as it is as a composition or as a composition containing the agent.
• the cartilage regeneration promoting composition of the present invention can also be referred to as a cartilage regeneration promoting agent.
• the composition for promoting cartilage regeneration of the present invention may be either an oral composition or a parenteral composition, but is preferably an oral composition. Examples of the oral composition include foods and drinks, oral medicines, quasi-drugs, and feeds, preferably foods and drinks or oral medicines, and more preferably foods and drinks.
• the composition for promoting cartilage regeneration of the present invention may contain any additive and any component in addition to the flavonoids as long as the effects of the present invention are not impaired.
• additives and ingredients can be selected according to the form of the composition and the like, and generally those that can be used for foods and drinks, pharmaceuticals, quasi-drugs, feeds and the like can be used.
• the composition for promoting cartilage regeneration is a food or drink, a pharmaceutical product, a quasi-drug, a feed or the like
• the production method thereof is not particularly limited and can be produced by a general method.
• the flavonoids are mixed with ingredients that can be used in the food or drink (for example, food materials, food additives used as needed, etc.).
• Various foods and drinks can be used.
• Foods and drinks are not particularly limited, and examples thereof include general foods and drinks, health foods, health drinks, foods with functional claims, foods for specified health use, foods and drinks for the sick, and the like.
• the above-mentioned health foods, foods with functional claims, foods for specified health use, etc. shall be in various forms such as fine granules, tablets, granules, powders, capsules, chewables, syrups, liquids, liquid foods, etc. Can be done.
• composition for promoting cartilage regeneration of the present invention is used as a pharmaceutical product or a quasi-drug
• a pharmacologically acceptable carrier for example, an additive added as necessary, or the like is added to the flavonoid.
• It can be a drug of various dosage forms or a quasi drug.
• Such carriers, additives and the like may be pharmacologically acceptable as long as they can be used in pharmaceutical products or quasi-drugs, for example, excipients, binders, disintegrants, lubricants, etc.
• antioxidants, colorants and the like can be mentioned.
• Examples of the administration (ingestion) form of the drug or quasi-drug include oral or parenteral (transdermal, transmucosal, intestinal, injection, etc.) administration forms.
• composition for promoting cartilage regeneration of the present invention is a drug or a quasi drug
• it is preferably an oral drug or a quasi drug.
• Dosage forms for oral administration include liquids, tablets, powders, fine granules, granules, sugar-coated tablets, capsules, suspensions, emulsions, chewables and the like.
• Dosage forms for parenteral administration include injections, infusions, patches and the like.
• the drug may be a non-human animal drug.
• the flavonoids may be added to the feed.
• the feed also contains feed additives.
• the feed include livestock feed used for cattle, pigs, chickens, sheep, horses and the like; small animal feed used for rabbits, rats, mice and the like; pet food used for dogs, cats, small birds and the like.
• the content of the flavonoid represented by the general formula (1) contained in the composition for promoting cartilage regeneration of the present invention is not particularly limited and can be set according to its form and the like.
• the content of flavonoids represented by the general formula (1) in the composition for promoting cartilage regeneration of the present invention is, for example, preferably 0.0001% by weight or more, more preferably 0.001% by weight or more in the composition. Further, 90% by weight or less is preferable, and 50% by weight or less is more preferable.
• the content of the flavonoid represented by the general formula (1) is preferably 0.0001 to 90% by weight, more preferably 0.001 to 50% by weight in the cartilage regeneration promoting composition.
• the above-mentioned content is the total content of the above-mentioned flavonoids when two or more kinds are contained.
• the administration route of the composition for promoting cartilage regeneration of the present invention is not particularly limited, and the composition can be ingested or administered by an appropriate method according to its form.
• the cartilage regeneration promoting composition is preferably taken orally (orally administered).
• the dose (which can also be referred to as the intake amount) of the composition for promoting cartilage regeneration of the present invention is not particularly limited as long as it has an effect of promoting differentiation into chondrocytes and an effect of promoting cartilage regeneration.
• the administration form, the administration method and the like may be appropriately set.
• the dose of flavonoid represented by the general formula (1) is 60 kg in body weight per day, preferably 0.1 mg or more. It is more preferably 1 mg or more, preferably 8000 mg or less, and more preferably 4000 mg or less. In one embodiment, the dose of flavonoids for humans (adults) is 60 kg body weight per day, preferably 0.1 to 8000 mg, more preferably 1 to 4000 mg. It is preferable to ingest or administer the above amount once or more a day, for example, once to several times a day (for example, 2 to 3 times).
• the above amounts of flavonoids be orally ingested or administered to humans.
• the composition for promoting cartilage regeneration can be used for ingesting or administering the above amount of flavonoids per day per 60 kg of body weight.
• the above dose is the total amount of flavonoids when two or more flavonoids are used.
• the composition for promoting cartilage regeneration of the present invention is preferably continuously ingested or administered.
• the flavonoids are expected to have a higher cartilage regeneration promoting effect by being continuously ingested or administered.
• the composition for promoting cartilage regeneration of the present invention is useful for preventing or ameliorating symptoms or diseases that can be expected to be prevented or ameliorated by promoting cartilage regeneration.
• a symptom or disease include a symptom or disease caused by a decrease in cartilage, and examples thereof include cartilage defect, cartilage damage, and osteoarthritis (osteoarthritis of the knee, etc.).
• prevention of a symptom or disease means preventing the onset of the symptom or disease, delaying the onset of the symptom or disease, reducing the incidence of the symptom or disease, or risking the development of the symptom or disease. Including mitigation and so on. Improvement of a symptom or disease includes recovering the subject from the symptom or disease, alleviating the symptom or disease, aggravating the symptom or delaying or preventing the progression of the disease, and the like.
• the subject to ingest or administer the composition for promoting cartilage regeneration of the present invention (which can also be referred to as an administration subject) is not particularly limited. It is preferably a human or non-human mammal, more preferably a human.
• the administration target includes a subject who needs or desires promotion of cartilage regeneration.
• the composition for promoting cartilage regeneration of the present invention can also be used for healthy subjects, for example, for the purpose of preventing symptoms or diseases that can be expected to be prevented or improved by promoting cartilage regeneration.
• the composition for promoting cartilage regeneration of the present invention may be labeled with a function exerted by promoting cartilage regeneration. Even if the composition for promoting cartilage regeneration of the present invention is labeled with one or more functions such as "maintenance of cartilage amount", “suppression of cartilage wear” and “suppression of cartilage degeneration”. Good.
• the composition for promoting cartilage regeneration of the present invention is preferably a food or drink with the above indication.
• the above display may be a display to the effect that it is used to obtain the above function.
• the composition for promoting cartilage regeneration of the present invention can be used as a reagent for culturing chondrocytes and the like.
• the cartilage regeneration promoting composition of the present invention may be a cultured cartilage regeneration promoting composition.
• mesenchymal stem cells are cultured in a medium containing flavonoids represented by the general formula (1)
• the differentiation of the cells into chondrocytes can be promoted.
• the amount of flavonoids represented by the general formula (1) in the medium is preferably 0.1 to 100 ⁇ M, more preferably 1. It is preferable to use an amount of up to 50 ⁇ M.
• the present invention also includes the following methods and uses.
• a method for promoting cartilage regeneration in which flavonoids represented by the above general formula (1) are administered.
• the methods and uses may be therapeutic or non-therapeutic methods or uses.
• the flavonoid represented by the general formula (1) is administered (ingested) to a subject, the differentiation of mesenchymal stem cells into chondrocytes can be promoted, and cartilage regeneration can be promoted. Promotion of cartilage regeneration is useful for preventing or ameliorating the above-mentioned cartilage deficiency, cartilage damage, osteoarthritis (osteoarthritis, etc.) and other symptoms or diseases.
• flavonoids and preferred embodiments thereof are the same as those of the above-mentioned composition for promoting cartilage regeneration of the present invention.
• One flavonoid represented by the general formula (1) may be used, or two or more flavonoids may be used.
• the flavonoid represented by the general formula (1) is administered (ingested) to the subject at least once a day, for example, once to several times a day (for example, 2 to 3 times). Is preferable.
• the above use is preferably in humans or non-human mammals, more preferably in humans.
• flavonoids represented by the general formula (1) in an amount (which can also be called an effective amount) that promotes cartilage regeneration may be used.
• the preferred dose of flavonoids, the subject of administration, and the like are the same as those of the above-mentioned composition for promoting cartilage regeneration of the present invention.
• the flavonoid represented by the general formula (1) may be administered as it is, or may be administered as a composition containing the flavonoid.
• the above-mentioned composition for promoting cartilage regeneration of the present invention may be used.
• flavonoids are preferably administered orally (ingested).
• the flavonoid represented by the general formula (1) can be used for producing foods and drinks, pharmaceuticals, quasi-drugs, feeds and the like used for promoting cartilage regeneration.
• the present invention also includes the use of flavonoids represented by the general formula (1) for producing a composition for promoting cartilage regeneration.
• HFLS Human synovial cells
• a 150 mm culture dish manufactured by Toyobo Co., Ltd.
• the above-mentioned human synovial cells were cultured in the following medium.
• ⁇ -MEM manufactured by Nacalai Tesque Co., Ltd.
• 10% fetal bovine serum manufactured by Sigma-Aldrich
• Antibiotic-Antimycotic Mixed Stock Solution manufactured by Nacalai Tesque, Inc.
• the grown human synovial cells were exfoliated with Accutase (manufactured by Funakoshi Co., Ltd.), and a medium containing 20 ⁇ 10 4 cells cells was placed in a 15 mL tube made of polypropylene and centrifuged at 1,000 ⁇ rpm for 5 minutes.
• the medium containing the test compound was exchanged once every two or three days.
• test compound was dissolved in dimethyl sulfoxide (DMSO) (manufactured by Nacalai Tesque, Inc., final concentration 0.1%) in a medium so as to have a final concentration of 50 ⁇ M.
• DMSO dimethyl sulfoxide
• Taxifolin manufactured by Sigma-Aldrich
• hesperetin manufactured by Funakoshi Co., Ltd.
• the following medium was used for culturing the above cartilage pellets.
• the control was cultured by adding DMSO containing no test compound to the following medium (DMSO had a final concentration of 0.1%).
• DMEM high-glucose manufactured by Thermo Fisher Scientific
• 50 ⁇ g / mL L-Ascorbic acid 2-phosphate sesquimagnesium salt hydrate manufactured by Sigma-Aldrich
• 40 ⁇ g / mL L-Proline manufactured by Sigma-Aldrich
• 100 ⁇ g / mL Sodium pyruvate manufactured by Sigma-Aldrich
• Premix manufactured by Corning
• 10 ng / mL transforming growth factor ⁇ 3 manufactured by Sigma-Aldrich
• 100nM dexamethasone manufactured by Sigma-Aldrich
• the relative value with the weight of the control cartilage pellet as 100% is shown in Table 1 as the rate of increase (%).
• the rate of increase (%) obtained from the cartilage pellet weight a significant difference from the control was tested using the Student's t-test test, and 5% or less was considered significant.
• the results of the significance test are shown in Table 1. Taxifolin and hesperetin confirmed a significant increase in cartilage pellet weight compared to controls.
• Example 2 Except that quercetin (manufactured by Nacalai Tesque Co., Ltd.), isorhamnetin (manufactured by Funakoshi Co., Ltd.) or eriodictyol (manufactured by Funakoshi Co., Ltd.) was used as the test compound, and the final concentration of the test compound in the medium was set to 5 ⁇ M.
• Quercetin, isorhamnetin, and eriodictyol were found to increase cartilage pellet weight by more than 130%. Quercetin, isorhamnetin and eriodictyol were found to have a significant increase in cartilage pellet weight compared to controls.
• Example 3 The test was carried out in the same manner as in Example 1 except that luteolin (manufactured by Funakoshi Co., Ltd.) or morin (manufactured by Nacalai Tesque Co., Ltd.) was used as the test compound and the final concentration of the test compound in the medium was 5 ⁇ M. It was.
• Synovial cells include mesenchymal stem cells, and the mesenchymal stem cells differentiate into chondrocytes.
• the increase in cartilage pellet weight by the addition of the test compound in Examples 1 to 3 as compared with the control means that the test compound promoted the differentiation of mesenchymal stem cells into chondrocytes.
• test compounds used in Examples 1 to 3 are flavonoids represented by the above general formula (1), and the compounds used in Comparative Example 1 are polyphenols having a structure different from that of the general formula (1).
• the test compounds used in Examples 1 to 3 had a stronger effect of promoting the differentiation of mesenchymal stem cells into chondrocytes than the compounds of Comparative Example 1. From the above, it was shown that the flavonoid represented by the general formula (1) has an excellent effect of promoting differentiation into chondrocytes.

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• 2020
  • 2020-07-21 CA CA3147400A patent/CA3147400A1/en active Pending
  • 2020-07-21 PH PH1/2022/550260A patent/PH12022550260A1/en unknown
  • 2020-07-21 EP EP20849263.7A patent/EP4008401A4/en not_active Withdrawn
  • 2020-07-21 CN CN202080055516.XA patent/CN114206330A/zh active Pending
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  • 2020-07-21 WO PCT/JP2020/028306 patent/WO2021024801A1/ja not_active Ceased
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