WO2023017958A1 - Composition pour la prévention, le traitement ou le soulagement de l'arthrite, comprenant un extrait d'elaeocarpus sylvestris ou un mélange d'extrait d'elaeocarpus sylvestris et de sulfasalazine en tant que principe actif - Google Patents
Composition pour la prévention, le traitement ou le soulagement de l'arthrite, comprenant un extrait d'elaeocarpus sylvestris ou un mélange d'extrait d'elaeocarpus sylvestris et de sulfasalazine en tant que principe actif Download PDFInfo
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- WO2023017958A1 WO2023017958A1 PCT/KR2022/005931 KR2022005931W WO2023017958A1 WO 2023017958 A1 WO2023017958 A1 WO 2023017958A1 KR 2022005931 W KR2022005931 W KR 2022005931W WO 2023017958 A1 WO2023017958 A1 WO 2023017958A1
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- WIPO (PCT)
- Prior art keywords
- elaeocarpus sylvestris
- sylvestris extract
- sulfasalazine
- extract
- arthritis
- Prior art date
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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Definitions
- the present invention relates to a composition for preventing, treating, or alleviating arthritis, comprising an Elaeocarpus sylvestris extract or a mixture of an Elaeocarpus sylvestris extract and sulfasalazine as an active ingredient.
- Arthritis refers to an inflammatory change in joints, and as tenderness and swelling occur in joints by inflammation, the range of motion of the joint is reduced. Arthritis is broadly classified into degenerative arthritis and rheumatoid arthritis. Degenerative arthritis, in which cartilage disappears and joints are deformed and inflammatory changes appear as one gets older, is also called osteoarthritis, and the number of patients is increasing year by year due to the aging of modern society, and recently, the number of patients is also increasing among young people in their 20s and 30s.
- Rheumatoid arthritis is the most common disease among chronic inflammatory diseases, occurs mainly in the 40s, increases the incidence of heart disease, infection and cancer, and is a disease whose incidence is expected to increase further due to social effects according to aging and economic growth.
- Rheumatoid arthritis is a systemic disease that causes chronic inflammation of the synovial membrane and surrounding soft tissues that mainly surround the joints, and occurs in about 1% of the adult population, and the cause of the disease has not yet been clarified.
- the purpose of treating arthritis is to not only reduce joint pain and inflammation and prevent joint deformity, but also more fundamentally, clarify a mechanism of intracellular action that induces arthritis and control the mechanism.
- NSAIDs non-steroidal anti-inflammatory drugs
- examples of known therapeutic agents for arthritis to date include non-steroidal anti-inflammatory drugs (NSAIDs; aspirin, ibuprofen), gold compounds, penicillamine, steroidal hormonal agents, and the like.
- NSAIDs non-steroidal anti-inflammatory drugs
- gold compounds gold compounds
- penicillamine steroidal hormonal agents
- TNF tumor necrosis factor
- sulfasalazine As a non-steroidal anti-inflammatory drug, sulfasalazine is a drug used for inflammatory diseases, ulcerative enteritis, rheumatoid arthritis and the like. Recently, it has been reported that sulfasalazine has the potential to be used for the treatment of osteoarthritis by protecting the changes in chondrocytes, which are the cause of osteoarthritis and suppressing the expression of factors related to cartilage destruction in the joint membrane. Further, sulfasalazine is known to suppress the secretion of histamine by IgE stimulation from cultured mast cells derived from mouse bone marrow and rat peritoneal mast cells.
- the sulfasalazine has side effects such as nausea, vomiting, loss of appetite, rashes, headaches, liver disorders, leukopenia, poikilocyte, proteinuria, and diarrhea when administered at a high dose for a long period of time.
- Elaeocarpus sylvestris is an evergreen tree which belongs to the family Elaeocarpaceae , inhabits subtropical regions including Jeju Island of Korea, China and the southern part of Japan, is a resource with little known active ingredient contained therein and efficacy, and can be said to be a material with extremely high material distinction and research and development rarity.
- the present inventors have tried to develop a single extract of Elaeocarpus sylvestris or a mixture of an Elaeocarpus sylvestris extract and sulfasalazine as a functional material derived from a natural product for preventing, treating, or alleviating arthritis by analyzing various physiological activities using the single extract or the mixture.
- the present inventors confirmed that a single extract of Elaeocarpus sylvestris or a mixture of an Elaeocarpus sylvestris extract and sulfasalazine exhibits excellent anti-inflammatory effects and arthritis treatment effects compared to the case of treatment with sulfasalazine alone, thereby completing the present invention based on this.
- an object of the present invention is to provide a pharmaceutical composition for preventing or treating arthritis, comprising an Elaeocarpus sylvestris extract; or a mixture of an Elaeocarpus sylvestris extract, and sulfasalazine or a pharmaceutically acceptable salt thereof as an active ingredient.
- Another object of the present invention is to provide a food composition for preventing or alleviating arthritis, comprising an Elaeocarpus sylvestris extract; or a mixture of an Elaeocarpus sylvestris extract, and sulfasalazine or a sitologically acceptable salt thereof as an active ingredient.
- the present invention provides a pharmaceutical composition for preventing or treating arthritis, comprising an Elaeocarpus sylvestris extract; or a mixture of an Elaeocarpus sylvestris extract, and sulfasalazine or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention provides a food composition for preventing or alleviating arthritis, comprising an Elaeocarpus sylvestris extract; or a mixture of an Elaeocarpus sylvestris extract, and sulfasalazine or a sitologically acceptable salt thereof as an active ingredient.
- the arthritis may be rheumatoid arthritis or degenerative arthritis, but is not limited thereto.
- the Elaeocarpus sylvestris extract may be extracted with one solvent selected from the group consisting of water, a C 1 to C 4 lower alcohol, n-hexane, ethyl acetate, acetone, acetonitrile, n-butyl acetate, 1,3-butylene glycol, methylene chloride, and a mixed solvent thereof, but the solvent is not limited thereto.
- the mixture may be mixed such that the weight ratio of an Elaeocarpus sylvestris extract : sulfasalazine, a pharmaceutically acceptable salt thereof, or a sitologically acceptable salt thereof is 1 : 0.2 to 3, but the weight ratio is not limited thereto.
- the Elaeocarpus sylvestris extract may be an Elaeocarpus sylvestris leaf extract, but is not limited thereto.
- the composition may suppress the production of nitric oxide (NO), but is not limited thereto.
- the composition may suppress the expression of one or more selected from the group consisting of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor- ⁇ (TNF- ⁇ ), interleukin-1 ⁇ (IL-1 ⁇ ), and interleukin-6 (IL-6), but is not limited thereto.
- iNOS inducible nitric oxide synthase
- COX-2 cyclooxygenase-2
- TNF- ⁇ tumor necrosis factor- ⁇
- IL-1 ⁇ interleukin-1 ⁇
- IL-6 interleukin-6
- the composition may suppress the activity of an inhibitor of nuclear factor kappa B (I- ⁇ B) or nuclear factor (NF)- ⁇ B, but is not limited thereto.
- the composition may suppress the expression of macrophage inflammatory protein (MIP)-1 ⁇ or regulated on activation, normal T cell expressed and secreted (RANTES), but is not limited thereto.
- MIP macrophage inflammatory protein
- RANTES normal T cell expressed and secreted
- the composition may reduce an arthritis index or have foot edema inhibitory activity, but is not limited thereto.
- the composition may suppress the expression of aggrecan, but is not limited thereto.
- the present invention provides a method for alleviating or treating arthritis, the method comprising: administering a composition comprising an Elaeocarpus sylvestris extract; or a mixture of an Elaeocarpus sylvestris extract and one or more selected from the group consisting of sulfasalazine, a pharmaceutically acceptable salt thereof, and a sitologically acceptable salt thereof as an active ingredient to a subject in need thereof.
- the present invention provides a use of a composition comprising an Elaeocarpus sylvestris extract; or a mixture of an Elaeocarpus sylvestris extract and one or more selected from the group consisting of sulfasalazine, a pharmaceutically acceptable salt thereof, and a sitologically acceptable salt thereof as an active ingredient for preventing, alleviating, or treating arthritis.
- the present invention provides a use of an Elaeocarpus sylvestris extract; or a mixture of an Elaeocarpus sylvestris extract, and sulfasalazine or a pharmaceutically acceptable salt thereof for preparing a medicament for treating arthritis.
- the Elaeocarpus sylvestris extract according to the present invention suppresses the production of nitric oxide, suppresses inflammatory cytokines, suppresses the production of iNOS or COX-2, suppresses the activity of NF- ⁇ B or I ⁇ B ⁇ , suppresses aggrecan expression, reduces an arthritis index, or exhibits foot edema inhibitory activity, and in particular, it was confirmed that a mixture of an Elaeocarpus sylvestris extract and sulfasalazine had excellent effects of suppressing the production of nitric oxide, suppressing inflammatory cytokines, suppressing the production of iNOS or COX-2, suppressing the activity of NF- ⁇ B or I ⁇ B ⁇ , reducing an arthritis index, or suppressing foot edema compared to the case of treatment with sulfasalazine alone.
- the Elaeocarpus sylvestris extract or a mixture of the Elaeocarpus sylvestris extract and sulfasalazine is expected to be usefully used for the development of a safe and effective medical product, health functional food, or the like for treating arthritis with few side effects.
- FIG. 1a is a view confirming the cytotoxicity by treatment with the Elaeocarpus sylvestris extract according to an exemplary embodiment of the present invention.
- FIG. 1b is a view confirming the cytotoxicity by mixed treatment with the Elaeocarpus sylvestris extract and sulfasalazine according to an exemplary embodiment of the present invention.
- FIG. 2a is a view confirming an effect of suppressing the production of NO by treatment with the Elaeocarpus sylvestris extract according to an exemplary embodiment of the present invention.
- FIG. 2b is a view confirming an effect of suppressing the production of NO by mixed treatment with the Elaeocarpus sylvestris extract and sulfasalazine according to an exemplary embodiment of the present invention.
- FIG. 3 is a set of views confirming an effect of suppressing the mRNA expression of iNOS, COX-2 and inflammatory cytokines by treatment with the Elaeocarpus sylvestris extract or mixed treatment with the Elaeocarpus sylvestris extract and sulfasalazine according to an exemplary embodiment of the present invention.
- FIG. 4a is a set of views confirming an effect of suppressing the protein expression of iNOS, COX-2, and TNF- ⁇ by treatment with the Elaeocarpus sylvestris extract or mixed treatment with the Elaeocarpus sylvestris extract and sulfasalazine according to an exemplary embodiment of the present invention.
- FIG. 4b is a set of views confirming an effect of suppressing the activation of NF- ⁇ B (p65) and I ⁇ B ⁇ by treatment with the Elaeocarpus sylvestris extract or mixed treatment with the Elaeocarpus sylvestris extract and sulfasalazine according to an exemplary embodiment of the present invention.
- FIG. 5 is a set of views confirming the effects of a reduction in arthritis index (left view) and a suppression in foot edema (right view) by administration of an Elaeocarpus sylvestris extract or a mixture of the Elaeocarpus sylvestris extract and sulfasalazine in a collagen-induced rheumatoid arthritis animal model (CIA) according to an exemplary embodiment of the present invention.
- CIA collagen-induced rheumatoid arthritis animal model
- FIG. 6a is a set of views confirming an effect of suppressing the protein expression of TNF- ⁇ , IL-1 ⁇ , and IL-6 in blood by the administration of an Elaeocarpus sylvestris extract or a mixture of the Elaeocarpus sylvestris extract and sulfasalazine in the blood of the collagen-induced rheumatoid arthritis animal model (CIA) according to an exemplary embodiment of the present invention.
- CIA collagen-induced rheumatoid arthritis animal model
- FIG. 6b is a set of views confirming an effect of suppressing the mRNA expression of MIP-1 ⁇ and RANTES by the administration of an Elaeocarpus sylvestris extract or a mixture of the Elaeocarpus sylvestris extract and sulfasalazine in cartilage tissues of the collagen-induced rheumatoid arthritis animal model (CIA) according to an exemplary embodiment of the present invention.
- CIA collagen-induced rheumatoid arthritis animal model
- FIG. 7 is a set of views confirming the changes in destruction degree of ankle joint sites by the administration of an Elaeocarpus sylvestris extract (CSE100) or a mixture (CSLZN) of the Elaeocarpus sylvestris extract and sulfasalazine in the collagen-induced rheumatoid arthritis animal model (CIA) according to an exemplary embodiment of the present invention by micro-CT photography images.
- CSE100 Elaeocarpus sylvestris extract
- CSLZN mixture
- FIG. 8a is a view confirming an effect of suppressing the IL-6 expression in blood by the administration of an Elaeocarpus sylvestris extract in a monosodium iodoacetate-induced degenerative arthritis animal model (MIA) according to an exemplary embodiment of the present invention.
- MIA monosodium iodoacetate-induced degenerative arthritis animal model
- FIG. 8b is a view confirming an effect of suppressing the TNF- ⁇ in blood by the administration of an Elaeocarpus sylvestris extract in a monosodium iodoacetate-induced degenerative arthritis animal model (MIA) according to an exemplary embodiment of the present invention.
- MIA monosodium iodoacetate-induced degenerative arthritis animal model
- FIG. 8c is a view confirming an effect of suppressing the aggrecan expression in blood by the administration of an Elaeocarpus sylvestris extract in a monosodium iodoacetate-induced degenerative arthritis animal model (MIA) according to an exemplary embodiment of the present invention.
- MIA monosodium iodoacetate-induced degenerative arthritis animal model
- the present invention provides a pharmaceutical composition for preventing or treating arthritis, comprising an Elaeocarpus sylvestris extract; or a mixture of an Elaeocarpus sylvestris extract, and sulfasalazine or a pharmaceutically acceptable salt thereof as an active ingredient.
- arthritis collectively refers to an inflammatory change in a joint caused by some causes, and according to an exemplary embodiment of the present invention, the arthritis may be rheumatoid arthritis or degenerative arthritis, but is not limited thereto.
- rheumatoid arthritis is an autoimmune disease that causes inflammation by attacking one's joints or a part of the body by the dysfunction of the immune system, and T cells play an important role together with the local release of inflammatory mediators and cytokines in the resulting destruction of joints.
- Rheumatoid arthritis is a systemic chronic inflammatory disease whose main symptoms are fatigue, a feeling of helplessness, pain, and the like, and which exhibits symptoms in which various joints such as fingers, hands, feet, wrists, ankles, and knees are painful or swollen and may cause abnormalities in various organs such as muscles, the skin, the lungs, and the eyes, and specifically affects the joints to cause irreversible proliferative synovitis, which progresses to articular cartilage destruction and joint ankylosis.
- the cause of rheumatoid arthritis has not yet been clarified, but autoimmune responses play an important role in the chronicity and progression of the disease.
- degenerative arthritis refers to a disease in which the articular cartilage covering the joint surface of the bone is worn to expose the bone under the cartilage, and the synovial membrane around the joint is inflamed to cause pain and deformation, is also called osteoarthritis, and is the most common joint disease.
- the Elaeocarpus sylvestris extract may be an extract of Elaeocarpus sylvestris leaves, stems, branches, roots, or a whole plant extract including all of them, and may be an Elaeocarpus sylvestris leaf extract according to an exemplary embodiment of the present invention, but is not limited thereto.
- Elaeocarpus sylvestris those which are directly cultivated, those which are commercially available, or the like can be used without limitation.
- the "extract" includes an extract solution obtained by the extraction treatment of the Elaeocarpus sylvestris , a diluted solution or concentrated solution of the extract solution, a dried product obtained by drying the extract solution, a crude purified product or purified product of the extract solution, or a mixture thereof and the like, an extract solution itself and an extract of all formulations which can be formed using an extraction solution.
- the Elaeocarpus sylvestris extract may be in the form of a dried product, but is not limited thereto.
- a method of extracting the Elaeocarpus sylvestris is not particularly limited, and the Elaeocarpus sylvestris may be extracted by a method typically used in the art.
- the extraction method include a hot water extraction method, an ultrasonic extraction method, a filtration method, a reflux extraction method, a supercritical extraction method, a subcritical extraction method, high temperature extraction, high pressure extraction and the like, and these may be performed either alone or in combination of two or more thereof.
- the type of extraction solvent used for extracting the Elaeocarpus sylvestris is not particularly limited, and the Elaeocarpus sylvestris may be extracted by a typical method known in the art of extracting an extract, that is, may be extracted using a typical solvent under typical temperature and pressure conditions.
- the Elaeocarpus sylvestris in the present invention may be extracted with one solvent selected from the group consisting of water, a C 1 to C 4 lower alcohol, n -hexane, ethyl acetate, acetone, acetonitrile, n-butyl acetate, 1,3-butylene glycol, methylene chloride, and a mixed solvent thereof, and may be extracted using ethanol as a solvent according to an exemplary embodiment of the present invention, but is not limited thereto.
- one solvent selected from the group consisting of water, a C 1 to C 4 lower alcohol, n -hexane, ethyl acetate, acetone, acetonitrile, n-butyl acetate, 1,3-butylene glycol, methylene chloride, and a mixed solvent thereof, and may be extracted using ethanol as a solvent according to an exemplary embodiment of the present invention, but is not limited thereto.
- the solvent for example, 10% to 100% ethanol, 10% to 90% ethanol, 10% to 80% ethanol, 10% to 70% ethanol, 10% to 60% ethanol, 10% to 50% ethanol, 20% to 90% ethanol, 20% to 80% ethanol, 20% to 70% ethanol, 20% to 60% ethanol, 20% to 50% ethanol, 30% to 90% ethanol, 30% to 80% ethanol, 30% to 70% ethanol, 30% to 60% ethanol, 30% to 50% ethanol, 40% to 90% ethanol, 40% to 80% ethanol, 40% to 70% ethanol, 40% to 60% ethanol, 40% to 50% ethanol, 45% to 55% ethanol, or 50% ethanol may be used, but the solvent is not limited thereto.
- the prepared extract can be filtered or the solvent can be removed by performing a concentration or drying process, or all of the filtration, concentration and drying can be performed.
- a filter paper may be used or a vacuum filter may be used for filtration, a vacuum decompression concentrator or a vacuum rotary evaporator may be used for concentration, and a decompression drying, vacuum drying, boiling drying, spray drying, freeze-drying method, and the like may be used for drying, but are not limited thereto.
- One or more extractions may be performed, but it may not be economical to repeat the extraction 5 times or more because the amount of obtained active ingredient decreases significantly as the number of extractions is increased.
- the number of extractions is 1 to 5, and it is more preferred that the extractions are repeated 2 to 5 times, but the number of extractions is not limited thereto.
- sulfasalazine is 2-hydroxy-5-[[4-(2-pyridinylamino)sulfonyl]azo]benzoic acid, is a compound formed by azo-bonding sulfapyridine and 5-aminosalicylic acid (5-ASA), and has a structure of the following Chemical Formula 1.
- the sulfasalazine may be chemically synthesized by a method known in the art or a commercially available material may be used.
- a mixture of the Elaeocarpus sylvestris extract, and sulfasalazine or a pharmaceutically acceptable salt thereof or a sitologically acceptable salt thereof may be mixed such that a weight ratio of the Elaeocarpus sylvestris extract : sulfasalazine, a pharmaceutically acceptable salt thereof, or a sitologically acceptable salt thereof becomes 1 : 0.2 to 3, 1 : 0.2 to 2.5, 1 : 0.2 to 2, 1 : 0.2 to 1.5, 1 : 0.2 to 1, 1 : 0.2 to 0.7, 1 : 0.3 to 3, 1 : 0.3 to 2.5, 1 : 0.3 to 2, 1 : 0.3 to 1.5, 1 : 0.3 to 1, 1 : 0.3 to 0.7, 1 : 0.5 to 3, 1 : 0.5 to 2.5, 1 : 0.5 to 2, 1 : 0.5 to 1.5, 1 : 0.5 to 1, 1 : 0.7 to 1.5, 1 : 1.5 to 2.5, or 1 :
- the weight may be dry weight, but is not limited thereto.
- the "pharmaceutically acceptable salt” includes a salt derived from a pharmaceutically acceptable inorganic acid, organic acid, or base.
- a suitable acid examples include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, gluconic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like.
- An acid addition salt may be prepared by a typical method, for example, dissolving a compound in an excessive amount of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
- the acid addition salt may be prepared by heating the same molar amount of compound and an acid or alcohol in water, subsequently evaporating the mixture to dry the mixture, or suction-filtering the precipitated salt.
- a salt derived from a suitable base may include an alkali metal such as sodium and potassium, an alkaline earth metal such as magnesium, ammonium and the like.
- An alkali metal or alkaline earth metal salt may be obtained by, for example, dissolving the compound in an excessive amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering a non-soluble compound salt, evaporating the filtrate, and drying the resulting product.
- the content of the Elaeocarpus sylvestris extract; or the mixture of the Elaeocarpus sylvestris extract, and sulfasalazine or the pharmaceutically acceptable salt thereof in the composition of the present invention can be appropriately adjusted according to the symptoms of a disease, the degree of progression of symptoms, the condition of a patient and the like, and may be, for example, 0.0001 to 99.9 wt%, 0.001 to 99.9 wt%, 0.01 to 99.9 wt%, 0.001 to 90 wt%, 0.001 to 80 wt%, 0.001 to 70 wt%, 0.001 to 60 wt%, 0.001 to 50 wt%, 0.1 to 90 wt%, 0.1 to 80 wt%, 0.1 to 70 wt%, 0.1 to 60 wt%, 0.1 to 50 wt%, 1 to 90 wt%, 1 to 80 wt%, 1 to 70 wt%, 1
- the pharmaceutical composition according to the present invention may further include a suitable carrier, excipient, and diluent which are commonly used in the preparation of pharmaceutical compositions.
- the excipient may be, for example, one or more selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, an adsorbent, a humectant, a film-coating material, and a controlled release additive.
- the pharmaceutical composition according to the present invention may be used by being formulated, according to commonly used methods, into a form such as powders, granules, sustained-release-type granules, enteric granules, liquids, eye drops, elixirs, emulsions, suspensions, spirits, troches, aromatic water, lemonades, tablets, sustained-release-type tablets, enteric tablets, sublingual tablets, hard capsules, soft capsules, sustained-release-type capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, perfusates, or a preparation for external use, such as plasters, lotions, pastes, sprays, inhalants, patches, sterile injectable solutions, or aerosols.
- the preparation for external use may have a formulation such as creams, gels, patches, sprays, ointments, plasters, lotions, liniments, pastes, or cataplasmas.
- lactose As the carrier, the excipient, and the diluent that may be included in the pharmaceutical composition according to the present invention, lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil may be used.
- diluents or excipients such as fillers, thickeners, binders, wetting agents, disintegrants, and surfactants are used.
- excipients such as corn starch, potato starch, wheat starch, lactose, white sugar, glucose, fructose, D-mannitol, precipitated calcium carbonate, synthetic aluminum silicate, dibasic calcium phosphate, calcium sulfate, sodium chloride, sodium hydrogen carbonate, purified lanolin, microcrystalline cellulose, dextrin, sodium alginate, methyl cellulose, sodium carboxymethylcellulose, kaolin, urea, colloidal silica gel, hydroxypropyl starch, hydroxypropyl methylcellulose (HPMC), HPMC 1928, HPMC 2208, HPMC 2906, HPMC 2910, propylene glycol, casein, calcium lactate, and Primojel ® ; and binders such as gelatin, Arabic gum, ethanol, agar powder, cellulose acetate phthalate, carboxymethylcellulose, calcium carboxymethylcellulose, glucose, pur
- water dilute hydrochloric acid, dilute sulfuric acid, sodium citrate, monostearic acid sucrose, polyoxyethylene sorbitol fatty acid esters (twin esters), polyoxyethylene monoalkyl ethers, lanolin ethers, lanolin esters, acetic acid, hydrochloric acid, ammonia water, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethylcellulose, and sodium carboxymethylcellulose may be used.
- a white sugar solution other sugars or sweeteners, and the like may be used, and as necessary, a fragrance, a colorant, a preservative, a stabilizer, a suspending agent, an emulsifier, a viscous agent, or the like may be used.
- purified water may be used, and as necessary, an emulsifier, a preservative, a stabilizer, a fragrance, or the like may be used.
- suspending agents such as acacia, tragacanth, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropyl methylcellulose (HPMC), HPMC 1828, HPMC 2906, HPMC 2910, and the like may be used, and as necessary, a surfactant, a preservative, a stabilizer, a colorant, and a fragrance may be used.
- Injections according to the present invention may include: solvents such as distilled water for injection, a 0.9% sodium chloride solution, Ringer's solution, a dextrose solution, a dextrose+sodium chloride solution, PEG, lactated Ringer's solution, ethanol, propylene glycol, non-volatile oil-sesame oil, cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate; cosolvents such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, the Tween series, amide nicotinate, hexamine, and dimethylacetamide; buffers such as weak acids and salts thereof (acetic acid and sodium acetate), weak bases and salts thereof (ammonia and ammonium acetate), organic compounds, proteins, albumin
- bases such as cacao butter, lanolin, Witepsol, polyethylene glycol, glycerogelatin, methylcellulose, carboxymethylcellulose, a mixture of stearic acid and oleic acid, Subanal, cottonseed oil, peanut oil, palm oil, cacao butter + cholesterol, lecithin, lanette wax, glycerol monostearate, Tween or span, imhausen, monolan(propylene glycol monostearate), glycerin, Adeps solidus, buytyrum Tego-G, cebes Pharma 16, hexalide base 95, cotomar, Hydrokote SP, S-70-XXA, S-70-XX75(S-70-XX95), Hydrokote 25, Hydrokote 711, idropostal, massa estrarium (A, AS, B, C, D, E, I, T), masa-MF, masupol, masupol-15, neo
- Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations are formulated by mixing the composition with at least one excipient, e.g., starch, calcium carbonate, sucrose, lactose, gelatin, and the like.
- excipients e.g., starch, calcium carbonate, sucrose, lactose, gelatin, and the like.
- lubricants such as magnesium stearate and talc are also used.
- liquid preparations for oral administration include suspensions, liquids for internal use, emulsions, syrups, and the like, and these liquid preparations may include, in addition to simple commonly used diluents, such as water and liquid paraffin, various types of excipients, for example, a wetting agent, a sweetener, a fragrance, a preservative, and the like.
- Preparations for parenteral administration include an aqueous sterile solution, a non-aqueous solvent, a suspension, an emulsion, a freeze-dried preparation, and a suppository.
- the non-aqueous solvent and the suspension include propylene glycol, polyethylene glycol, a vegetable oil such as olive oil, and an injectable ester such as ethyl oleate.
- the pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount.
- the pharmaceutically effective amount refers to an amount sufficient to treat diseases at a reasonable benefit/risk ratio applicable to medical treatment, and an effective dosage level may be determined according to factors including types of diseases of patients, the severity of disease, the activity of drugs, sensitivity to drugs, administration time, administration route, excretion rate, treatment period, and simultaneously used drugs, and factors well known in other medical fields.
- composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with therapeutic agents in the related art, and may be administered in a single dose or multiple doses. It is important to administer the composition in a minimum amount that can obtain the maximum effect without any side effects, in consideration of all the aforementioned factors, and this may be easily determined by those of ordinary skill in the art.
- the pharmaceutical composition of the present invention may be administered to a subject via various routes. All administration methods can be predicted, and the pharmaceutical composition may be administered via, for example, oral administration, subcutaneous injection, intraperitoneal injection, intravenous injection, intramuscular injection, intrathecal (space around the spinal cord) injection, sublingual administration, administration via the buccal mucosa, intrarectal insertion, intravaginal insertion, ocular administration, intra-aural administration, intranasal administration, inhalation, spraying via the mouth or nose, transdermal administration, percutaneous administration, or the like.
- the pharmaceutical composition of the present invention is determined depending on the type of a drug, which is an active ingredient, along with various related factors such as a disease to be treated, administration route, the age, gender, and body weight of a patient, and the severity of diseases.
- the present invention provides a method for alleviating or treating arthritis, the method comprising: administering a composition comprising an Elaeocarpus sylvestris extract; or a mixture of an Elaeocarpus sylvestris extract and one or more selected from the group consisting of sulfasalazine, a pharmaceutically acceptable salt thereof, and a sitologically acceptable salt thereof as an active ingredient to a subject in need thereof.
- the present invention provides a use of a composition comprising an Elaeocarpus sylvestris extract; or a mixture of an Elaeocarpus sylvestris extract and one or more selected from the group consisting of sulfasalazine, a pharmaceutically acceptable salt thereof, and a sitologically acceptable salt thereof as an active ingredient for preventing, alleviating, or treating arthritis.
- the present invention provides a use of an Elaeocarpus sylvestris extract; or a mixture of an Elaeocarpus sylvestris extract, and sulfasalazine or a pharmaceutically acceptable salt thereof for preparing a medicament for treating arthritis.
- prevention refers to all actions that suppress or delay the onset of arthritis
- treatment refers to all actions that ameliorate or beneficially change arthritis and the resulting metabolic abnormalities by administration of the pharmaceutical composition according to the present invention
- adjuviation refers to all actions that reduce arthritis and associated parameters, for example, the severity of symptoms, by administration of the pharmaceutical composition according to the present invention.
- the "subject” refers to a subject in need of treatment of a disease, and more specifically, refers to a mammal such as a human or a non-human primate, a mouse, a rat, a dog, a cat, a horse, and a cow.
- administration refers to the provision of a predetermined composition of the present invention to a subject in need by any suitable method.
- the present invention provides a food composition for preventing or alleviating arthritis, comprising an Elaeocarpus sylvestris extract; or a mixture of an Elaeocarpus sylvestris extract, and sulfasalazine or a sitologically acceptable salt thereof as an active ingredient.
- the "sitologically acceptable salt” includes a salt derived from a sitologically acceptable organic acid, inorganic acid, or base.
- food refers to a natural product or processed product containing one or more nutrients, preferably refers to a state in which the food can be directly eaten after undergoing some processing steps, and means including all health functional foods, beverages, food additives, beverage additives and the like as a typical meaning.
- the food composition may be a health functional food composition, but is not limited thereto.
- the "health functional food” is the same term as a food for special health use (FoSHU), refers to a food with high pharmaceutical and medical effects, which is processed such that a bioregulatory function is efficiently exhibited in addition to nutritional supply, and may be prepared into a tablet, capsule, pill, granule, powder, liquid, flake, paste, syrup, gel, jelly, bar or film formulation.
- “functional” means that useful effects for health purposes such as regulating nutrients and physiological actions are obtained for the structure and function of the human body.
- the Elaeocarpus sylvestris extract of the present invention or the Elaeocarpus sylvestris extract, and sulfasalazine or a sitologically acceptable salt thereof are used as food additives, the same may be added as it is, or may be used with other foods or food components, and may be appropriately used by a typical method.
- the amount of active ingredient mixed may be suitably determined according to the purpose of use (prevention, health or therapeutic treatment).
- the Elaeocarpus sylvestris extract of the present invention may be added in an amount of 15 wt% or less, or 10 wt% or less based on the raw material.
- the amount may be equal to or less than the above range, and the effective ingredient may be used in an amount equal to or more than the above range due to no problem in terms of safety.
- the type of food is not particularly limited.
- Examples of food to which the material may be added include meats, sausage, bread, chocolate, candies, snacks, confectioneries, pizza, instant noodles, other noodles, gums, dairy products including ice creams, various soups, beverages, tea, drinks, alcoholic beverages, vitamin complexes, and the like, and include all health functional foods in a typical sense.
- the health beverage composition according to the present invention may contain various flavors or natural carbohydrates, and the like as additional ingredients as in a typical beverage.
- the above-described natural carbohydrates may be monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
- a sweetener it is possible to use a natural sweetener such as thaumatin and stevia extract, a synthetic sweetener such as saccharin and aspartame, and the like.
- the proportion of the natural carbohydrates is generally about 0.01 to 0.20 g, or about 0.04 to 0.10 g per 100 ml of the composition of the present invention.
- the composition of the present invention may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like.
- the composition of the present invention may contain flesh for preparing natural fruit juice, fruit juice drinks, and vegetable drinks. These ingredients may be used either alone or in combinations thereof. The proportion of these additives is not significantly important, but is generally selected within a range of 0.01 to 0.20 part by weight per 100 parts by weight of the composition of the present invention.
- Korean Elaeocarpus sylvestris leaves from the Jeju Island area were purchased, dried and chopped, and then 100 kg of Elaeocarpus sylvestris leaves were extracted with 2,000 L of 50% ethanol at 60°C for 16 hours, filtered and concentrated, and then dried to extract 28 kg (yield 28%) of an Elaeocarpus sylvestris extract.
- a RAW264.7 macrophage cell line was cultured in a Dulbecco's modified Eagle's medium (DMEM, WelGENE) supplemented with 10% fetal bovine serum (FBS, WelGENE) and 1% penicillin/streptomycin (P/S, WelGENE) under conditions of 37°C and 5% CO 2 .
- DMEM Dulbecco's modified Eagle's medium
- FBS fetal bovine serum
- P/S penicillin/streptomycin
- Example 1 To confirm whether the Elaeocarpus sylvestris extract produced in Example 1 has a therapeutic effect on rheumatoid arthritis and degenerative arthritis in vivo , 7-week-old DBA/1J male mice and 6-week-old male SD rats were purchased. All animals were bred in a pathogen-free environment and were allowed to freely ingest sterilized standard animal feed and water.
- an emulsion was produced by uniformly mixing isolated and quantified bovine type II collagen (Central Lab, South Korea) by a method known in the art with an equal amount of complete Freund's adjuvant (Sigma-Aldrich), 50 ⁇ L of the emulsion was intradermally injected at a site 2 to 3 cm away from the base of the mouse's tail, and then an incomplete Freund's adjuvant (Sigma-Aldrich) was additionally inoculated by the same method 2 weeks later to produce collagen-induced arthritis (CIA) mice.
- complete Freund's adjuvant Sigma-Aldrich
- NC Normal control
- CSLZN Collagen-induced rheumatoid arthritis control treated with sulfasalazine
- CSE Collagen-induced rheumatoid arthritis model test group treated with sulfasalazine + Elaeocarpus sylvestris extract
- CE Collagen-induced rheumatoid arthritis model test group treated with Elaeocarpus sylvestris extract
- MIA monosodium iodoacetate-induced degenerative arthritis
- a blood degenerative arthritis index was measured by administering the Elaeocarpus sylvestris extract prepared in Example 1 to the MIA rats thus produced at a dose of 100 mg/kg.
- RAW264.7 cells which are mouse macrophages
- Elaeocarpus sylvestris extract an Elaeocarpus sylvestris extract.
- RAW264.7 cells were inoculated into 96 well-plates at a concentration of 1 ⁇ 10 4 cells/well. Then, the cells were cultured in a 37°C and 5% CO 2 incubator for 24 hours and treated with the Elaeocarpus sylvestris extract at each concentration (3.125, 6.25, 12.5, 25, 50, and 100 ⁇ g/mL) for 24 hours, and then 10 ⁇ L of a 5 mg/mL MTT solution was added thereto, and the cells were cultured for 2 hours.
- the medium supernatant was removed, the residue was dissolved by adding 100 ⁇ L of DMSO thereto, and then the cytotoxicity of the Elaeocarpus sylvestris extract was measured by measuring absorbance at 540 nm.
- RAW264.7 cells were inoculated into 96 well-plates at a concentration of 1 ⁇ 10 4 cells/well. Then, the cells were cultured in a 37°C and 5% CO 2 incubator for 24 hours and pre-treated with the Elaeocarpus sylvestris extract at each concentration (3.125, 6.25, 12.5, 25, 50, and 100 ⁇ g/mL) for 2 hours, and then treated with LPS at a concentration of 1 ⁇ g/mL for 24 hours.
- RAW264.7 cells the mRNA expression of iNOS, COX-2, and inflammatory cytokines by the treatment with the Elaeocarpus sylvestris extract and sulfasalazine was confirmed.
- RAW264.7 cells were first inoculated into 6 well-plates at 2 ⁇ 10 5 cells/well, cultured in a 37°C and 5% CO 2 incubator for 24 hours, and pre-treated with sulfasalazine (50 ⁇ g/mL) and the Elaeocarpus sylvestris extract (25, 50, and 100 ⁇ g/mL) for 2 hours.
- the cells were treated with LPS at a concentration of 1 ⁇ g/mL for 24 hours, and then after 24 hours, the cells were washed with PBS, and then isolated according to the manufacturer's instructions using TRIzol (Invitrogen, USA). After the isolated total RNA was synthesized into cDNA using a cDNA synthesis kit (Takara, Japan), the expression of iNOS, COX-2, and inflammatory cytokines was measured using real-time PCR. The sequences of primers used for real time PCR are shown in the following Table 2.
- RAW264.7 cells were treated with the Elaeocarpus sylvestris extract and sulfasalazine at the same concentrations as in Experimental Example 3, and then treated with LPS (1 ⁇ g/mL) for 30 minutes or 24 hours, proteins were extracted using a RIPA buffer (Thermo Scientific, USA), and equal amounts of proteins (25 ⁇ g) were separated by electrophoresis on a SDS-PAGE gel and electroblotted on a nitrocellulose membrane. Then, a membrane was blocked with 5% skim milk and then cultured with other antibodies, and proteins were detected using the antibodies according to the manufacturer's instructions for the chemiluminescent ECL assay kit.
- the protein expression of iNOS, COX-2, and TNF- ⁇ was increased by LPS treatment, and Elaeocarpus sylvestris -alone extract treatment and mixed treatment with an Elaeocarpus sylvestris extract and sulfasalazine reduced the protein expression of iNOS, COX-2, and TNF- ⁇ and exhibited better suppressive efficacy than a sulfasalazine treatment group.
- NF- ⁇ B (p65) and I ⁇ B ⁇ which are upstream transcription factors of iNOS, COX-2, and TNF- ⁇
- p-NF- ⁇ B (p65), p-I ⁇ B ⁇ ) of NF- ⁇ B (p65) and I ⁇ B ⁇ was increased by LPS treatment, and the activation of NF- ⁇ B and I ⁇ B ⁇ was suppressed by Elaeocarpus sylvestris -alone extract treatment and mixed treatment of an Elaeocarpus sylvestris extract and sulfasalazine.
- An Elaeocarpus sylvestris extract or a mixture of the Elaeocarpus sylvestris extract and sulfasalazine was orally administered to the CIA mice produced in Example 3 at various concentrations shown in Table 1 once a day for 4 weeks. Furthermore, the experiment was also performed on mice (normal) in which arthritis was not induced as negative control mice.
- the degree of joint swelling was measured by measuring foot edema using a plethysmometer (BioSurpulus, USA) and was shown as an average for each group.
- mice After oral administration of an Elaeocarpus sylvestris alone extract or a mixture of the Elaeocarpus sylvestris extract and sulfasalazine for 4 weeks, mice were sacrificed and a joint structure analysis was performed on blood and cartilage tissue samples. The presence or absence and degree of arthritis were evaluated by the presence or absence of edema in the forepaws and hindpaws of mice in each group and their volume.
- mice After oral administration of an Elaeocarpus sylvestris alone extract or a mixture of the Elaeocarpus sylvestris extract and sulfasalazine for 4 weeks, mice were sacrificed and an inflammatory marker analysis was performed on blood and cartilage tissue samples.
- TNF- ⁇ , IL-1 ⁇ , and IL-6 were significantly highly exhibited in a rheumatoid arthritis model (CIA) and decreased in the Elaeocarpus sylvestris extract-alone administration group and the Elaeocarpus sylvestris extract and sulfasalazine-mixed administration group.
- CIA rheumatoid arthritis model
- mRNA was extracted from mouse cartilage tissue by the method of Experimental Example 3, synthesized into cDNA, and then the gene expression level was measured by real-time PCR.
- the primers used in the experiment are shown in the following Table 4.
- mice for which the experiment was completed were sacrificed to remove the skin and muscle around the ankle joint and femur of the mouse and were fixed in formalin for 24 hours. And then, the mice were photographed using a micro-CT apparatus.
- the Elaeocarpus sylvestris extract was orally administered at 100 mg/kg to the MIA-induced degenerative arthritis rats produced in Example 3 once a day for 8 weeks, and the experiment was also performed on rats (CON) in which arthritis was not induced as a negative control.
- FIGS. 8a to 8c the protein expression of IL-6 (FIG. 8a), TNF- ⁇ (FIG. 8b), and aggrecan (Fig. 8c) in blood was highly exhibited in the degenerative arthritis model (MIA), and it was confirmed that the protein expression was reduced in the Elaeocarpus sylvestris extract administration group.
- MIA degenerative arthritis model
- the expression of inflammatory cytokines in blood was suppressed by the administration of the Elaeocarpus sylvestris extract of the present invention, and the Elaeocarpus sylvestris extract had an effect of suppressing degenerative arthritis by suppressing the expression of aggrecan which is a proteoglycan specific to cartilage tissue.
- the Elaeocarpus sylvestris extract according to the present invention and a mixture of the Elaeocarpus sylvestris extract and sulfasalazine have excellent effects of suppressing the production of nitric oxide, suppressing inflammatory cytokines, suppressing the production of iNOS or COX-2, suppressing the activity of NF- ⁇ B or I ⁇ B ⁇ , reducing an arthritis index, or suppressing foot edema, and have few side effects, and thus it is expected that the Elaeocarpus sylvestris extract or a mixture of the Elaeocarpus sylvestris extract and sulfasalazine can be usefully used for the development of a safe and effective medical product, health functional food, or the like for treating arthritis.
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Abstract
La présente invention concerne une composition pour prévenir, traiter ou soulager l'arthrite, comprenant un extrait d'Elaeocarpus sylvestris ou un mélange d'un extrait d'Elaeocarpus sylvestris et de sulfasalazine comme principe actif, et l'extrait d'Elaeocarpus sylvestris selon la présente invention supprime la production d'oxyde nitrique, supprime les cytokines inflammatoires, supprime la production d'iNOS ou de COX-2, supprime l'activité de NF-κB ou d'IκBα, supprime l'expression de l'aggrécane, réduit un indice d'arthrite, ou présente une activité inhibitrice de l'œdème à la patte, et en particulier, il a été confirmé qu'un mélange d'un extrait d'Elaeocarpus sylvestris et de sulfasalazine avait d'excellents effets de suppression de la production d'oxyde nitrique, de suppression des cytokines inflammatoires, de suppression de la production d'iNOS ou de COX-2, de suppression de l'activité de NF-κB ou d'IκBα, de réduction d'un indice d'arthrite, ou de suppression de l'œdème à la patte par rapport au cas du traitement avec la sulfasalazine seule. Ainsi, l'extrait d'Elaeocarpus sylvestris ou un mélange de l'extrait d'Elaeocarpus sylvestris et de sulfasalazine devrait être utilisé utilement pour la mise au point d'un produit médical, d'un aliment fonctionnel de santé ou analogue sûr et efficace pour traiter l'arthrite avec peu d'effets secondaires.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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KR10-2021-0105993 | 2021-08-11 | ||
KR1020210105993A KR20230024004A (ko) | 2021-08-11 | 2021-08-11 | 담팔수 추출물 또는 담팔수 추출물과 설파살라진의 혼합물을 유효성분으로 포함하는 관절염 예방, 치료, 또는 개선용 조성물 |
Publications (1)
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WO2023017958A1 true WO2023017958A1 (fr) | 2023-02-16 |
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PCT/KR2022/005931 WO2023017958A1 (fr) | 2021-08-11 | 2022-04-26 | Composition pour la prévention, le traitement ou le soulagement de l'arthrite, comprenant un extrait d'elaeocarpus sylvestris ou un mélange d'extrait d'elaeocarpus sylvestris et de sulfasalazine en tant que principe actif |
Country Status (2)
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KR (1) | KR20230024004A (fr) |
WO (1) | WO2023017958A1 (fr) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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KR101834872B1 (ko) * | 2016-09-09 | 2018-04-13 | 주식회사 제넨셀 | 담팔수 추출물 또는 이의 분획물을 유효 성분으로 포함하는 알파 계열 허피스 바이러스 감염증의 예방 또는 치료용 약제학적 조성물 |
KR20190036298A (ko) * | 2017-09-27 | 2019-04-04 | 충북대학교 산학협력단 | 상록성 목본식물 추출물을 포함하는 염증성 피부질환 개선용 조성물 |
EP3488868A1 (fr) * | 2017-11-23 | 2019-05-29 | medac Gesellschaft für klinische Spezialpräparate mbH | Composition pharmaceutique pour administration orale contenant de la sulfasalazine et/ou un sel organique de sulfasalazine, procédé de production et utilisation |
KR20190123384A (ko) * | 2018-04-24 | 2019-11-01 | 경북대학교 산학협력단 | 엘래오카푸신을 유효성분으로 포함하는 비만세포 유래 알레르기 질환의 예방 또는 치료용 약학적 조성물 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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KR101895950B1 (ko) | 2015-12-18 | 2018-09-06 | (주)한국비엠아이 | 골관절염 치료를 위한 친수화된 설파살라진 및 히알루론산을 포함하는 조성물 및 이의제조방법 |
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2021
- 2021-08-11 KR KR1020210105993A patent/KR20230024004A/ko not_active Application Discontinuation
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2022
- 2022-04-26 WO PCT/KR2022/005931 patent/WO2023017958A1/fr active Application Filing
Patent Citations (4)
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KR101834872B1 (ko) * | 2016-09-09 | 2018-04-13 | 주식회사 제넨셀 | 담팔수 추출물 또는 이의 분획물을 유효 성분으로 포함하는 알파 계열 허피스 바이러스 감염증의 예방 또는 치료용 약제학적 조성물 |
KR20190036298A (ko) * | 2017-09-27 | 2019-04-04 | 충북대학교 산학협력단 | 상록성 목본식물 추출물을 포함하는 염증성 피부질환 개선용 조성물 |
EP3488868A1 (fr) * | 2017-11-23 | 2019-05-29 | medac Gesellschaft für klinische Spezialpräparate mbH | Composition pharmaceutique pour administration orale contenant de la sulfasalazine et/ou un sel organique de sulfasalazine, procédé de production et utilisation |
KR20190123384A (ko) * | 2018-04-24 | 2019-11-01 | 경북대학교 산학협력단 | 엘래오카푸신을 유효성분으로 포함하는 비만세포 유래 알레르기 질환의 예방 또는 치료용 약학적 조성물 |
Non-Patent Citations (3)
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ANONYMOUS: "Therapeutic agent for degenerative arthritis", MEDI:GATE NEWS, 28 April 2021 (2021-04-28), XP093034669, Retrieved from the Internet <URL:https://medigatenews.com/news/925727256> [retrieved on 20230324] * |
NEGI MANORMA, BAEK HYUN-JIN, PARK DAE WON, SO RINA, KWON JEONG EUN, JEON HYELIN, JEONG YONG JOON, PARK JAE-HYUN, KIM INHYE, KIM TA: "Elaeocarpus sylvestris extract (ESE) inhibits inflammatory mediators and increases the efficacy of sulfasalazine in rheumatoid arthritis", PHYTOMEDICINE PLUS, vol. 2, no. 1, 1 February 2022 (2022-02-01), pages 100207, XP093034670, ISSN: 2667-0313, DOI: 10.1016/j.phyplu.2021.100207 * |
R. L. LAKEY, CAWSTON T. E.: "Sulfasalazine blocks the release of proteoglycan and collagen from cytokine stimulated cartilage and down-regulates metalloproteinases", RHEUMATOLOGY, OXFORD UNIVERSITY PRESS, LONDON, GB, vol. 48, no. 10, 1 January 2009 (2009-01-01), GB , pages 1208 - 1212, XP055495727, ISSN: 1462-0324, DOI: 10.1093/rheumatology/kep236 * |
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