[go: up one dir, main page]

WO2016056769A1 - Composition pharmaceutique pour la prévention ou le traitement de maladies inflammatoires, contenant, en tant que principe actif, de la cérulénine ou un dérivé de la cérulénine - Google Patents

Composition pharmaceutique pour la prévention ou le traitement de maladies inflammatoires, contenant, en tant que principe actif, de la cérulénine ou un dérivé de la cérulénine Download PDF

Info

Publication number
WO2016056769A1
WO2016056769A1 PCT/KR2015/009809 KR2015009809W WO2016056769A1 WO 2016056769 A1 WO2016056769 A1 WO 2016056769A1 KR 2015009809 W KR2015009809 W KR 2015009809W WO 2016056769 A1 WO2016056769 A1 WO 2016056769A1
Authority
WO
WIPO (PCT)
Prior art keywords
cerulenin
formula
cerulein
derivative
inflammation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2015/009809
Other languages
English (en)
Korean (ko)
Inventor
권혁무
최수연
이환희
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
UNIST Academy Industry Research Corp
Original Assignee
UNIST Academy Industry Research Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by UNIST Academy Industry Research Corp filed Critical UNIST Academy Industry Research Corp
Publication of WO2016056769A1 publication Critical patent/WO2016056769A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

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
    • A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
    • 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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine

Definitions

  • the present invention relates to the use of cerulenin, cerulenin derivatives or pharmaceutically acceptable salts thereof.
  • Inflammation is a localized immune response that minimizes damage and restores damaged areas when cells or tissues are damaged or destroyed by various factors such as harmful substances or organisms from outside. It is a useful defense mechanism to remove products produced by tissue damage. Several factors that cause inflammation include physical factors caused by trauma, burns, frostbite, radioactivity, chemical factors such as acids, and immunological factors caused by antibody reactions. It can also occur.
  • Inflammation normally acts to restore the normal structure and function by neutralizing or eliminating the onset factors and regenerating the upper tissues through the inflammatory response in vivo, but the degree of inflammation becomes more than a certain level or becomes chronic. This is a problem if you progress to the same disease state.
  • Enzymes involved in the inflammatory response are produced by immune cells, which travel through the blood vessels to the damaged area with the help of histamine, nitric oxide (NO) or prostaglandin E2 (PGE2). Initiate an inflammatory response.
  • Immune cells migrated to the damaged area were tumor necrosis factor- ⁇ (TNF- ⁇ ), interleukin-1 ⁇ (interleukin-1 ⁇ , IL-1 ⁇ ) or interleukin-6 (interleukin-6, IL-6).
  • TNF- ⁇ tumor necrosis factor- ⁇
  • interleukin-1 ⁇ interleukin-1 ⁇
  • IL-6 interleukin-6
  • Cytokines macrophage inflammatory proteins
  • MIP-1 macrophage inflammatory proteins
  • IL-8 interleukin-8
  • monocyte chemotactic protein-1 Chemokine (MCP-1), etc.
  • chemokine secrete chemokine (chemokine) to destroy direct external invasion or other immune cells to initiate an inflammatory response.
  • chemokine Induced nitric oxide synthase when exposed to pro-inflammatory interferon- ⁇ , lipoichoic acid, lipopolysaccharide (LPS), or various inflammatory cytokines synthase (iNOS) and cyclooxygenase-2 (COX-2) are expressed, resulting in excess production of NO and PGE2.
  • iNOS inflammatory initiation factors
  • COX-2 cytokines synthase
  • COX-2 cyclooxygenase-2
  • NF- ⁇ B activated nuclear factor- ⁇ B
  • Steroidal anti-inflammatory drugs used to treat chronic inflammatory diseases such as conventional acute or rheumatoid arthritis, cause side effects such as glaucoma, cataracts, hypertension, mood swings, weight gain, diabetes and osteoporosis. Therefore, there is a need for the development of a substance that can effectively inhibit inflammation with a component derived from a natural substance having little or no risk for such side effects or cytotoxicity.
  • Serulenin inhibits sterol biosynthesis by inhibiting HMG-CoA reductase activity, and inhibits the activity of fatty acid biosynthetic enzymes by forming covalent bonds with fatty acid biosynthesis by reacting with cysteine in the region responsible for condensation reaction It is known.
  • cerulenin also inhibits the biosynthesis of polyketides, such as leucomycin, methylsalicylic acid, candicidin, flavanone, and alternari, which have a polyketide biosynthesis pathway. All of them are known to inhibit biosynthesis by cerulenin.
  • the study of the industrialization is still insignificant, and the degree of the sebum production inhibitory effect of cerulein is disclosed in Korean Patent Publication No. 10-2007-0023730 related to "method generation and pore size reduction method".
  • cerulenin or cerulenin derivatives have excellent anti-inflammatory activity without side effects.
  • Patent Document 1 Republic of Korea Patent Publication No. 10-2007-0023730
  • compositions for the prevention or treatment of inflammatory diseases, and the use thereof comprising a natural substance-derived component as an active ingredient.
  • Another object of the present invention to provide a composition for improving inflammation, containing a natural substance-derived component as an active ingredient.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of inflammatory diseases, containing as cerulein, cerulenin derivatives or pharmaceutically acceptable salts thereof as an active ingredient.
  • the present invention provides a method for preventing or treating an inflammatory disease comprising administering to a mammal a cerulein, a cerulein derivative or a pharmaceutically acceptable salt thereof.
  • the present invention provides the use of cerulenin, cerulenin derivatives or pharmaceutically acceptable salts thereof for use in the manufacture of a medicament for the prevention or treatment of inflammatory diseases.
  • the present invention provides a food and cosmetic composition for improving inflammation containing cerulein, a cerulein derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • composition containing cerulenin, cerulenin derivatives or pharmaceutically acceptable salts thereof according to the present invention as an active ingredient is derived from natural products, and MTT analysis shows no possibility of side effects due to lack of cytotoxicity, thereby improving inflammatory diseases. It can be used very effectively for prevention, or treatment.
  • 1 is a graph confirming the inhibition of NO production of cerulenin and comparing with BAY11-7082, where the horizontal axis represents the treatment concentration of cerulenin or BAY11-7082, and the vertical axis represents the amount of NO produced.
  • FIG. 2 is a graph confirming the cytotoxicity of cerulein and compared with BAY11-7082, the horizontal axis of the graph means the treatment concentration of cerulenin or BAY11-7082, the vertical axis shows the cell viability (%) Indicates.
  • Figure 3 is a graph confirming that the cerulein inhibits the mRNA expression of inflammatory factors iNOS, COX-2, TNF ⁇ , IL-6, MCP-1 and IL-1, Con on the horizontal axis of the graphs treated LPS Lng 100ng / ml represents the group which treated LPS with 100ng / ml.
  • the vertical axis represents the degree of mRNA expression relative to CypA mRNA expression of each inflammation-related factor.
  • Figure 4 is an electrophoresis picture confirming that the cerulein inhibits protein expression of inflammation-related factors iNOS and COX-2, the number above the figure is the concentration of LPS (ng / ml), the left is specific to each protein A protein whose expression was confirmed using a primary antibody of interest is shown.
  • FIG. 5 is a graph confirming the inhibition of NF- ⁇ B transcriptional activity of cerulenin, wherein the horizontal axis of the graph shows the treatment and concentration of LPS, the vertical axis of the NF- ⁇ B reporter activity (renilla) value of The degree of transcriptional activity of NF- ⁇ B corrected by the ratio is shown.
  • FIG. 6 is a graph confirming that cerulein inhibits the increase in serum TNF- ⁇ concentration caused by LPS administered to mice, wherein the horizontal axis shows whether cerulein and LPS are administered, and the vertical axis shows serum concentration of TNF- ⁇ ( ng / ml).
  • FIG. 7 is a graph confirming the inhibition of NO production of cerulenin derivative C75 and comparing it with cerulenin, wherein the horizontal axis of the graph represents the treatment concentration of the samples, and the vertical axis represents the amount of NO production.
  • FIG. 9 is a graph confirming that the cerulein derivative C75 inhibits mRNA expression of inflammation-related factors and compared with cerulein, wherein the horizontal axis of the graph shows the treatment and concentration of LPS, and the vertical axis shows the CypA of each inflammation-related factor. The degree of mRNA expression relative to mRNA expression is shown.
  • FIG. 10 is a graph confirming that cerulein increases the survival rate of animals in the sepsis animal model, the horizontal axis of the graph shows the time course after galactosamine N and LPS administration for sepsis induction, the vertical axis of the animal Survival rate.
  • the present invention provides a composition for preventing or treating inflammatory diseases containing cerulenin, cerulenin derivatives or pharmaceutically acceptable salts thereof as an active ingredient.
  • cerulenin or cerulenin derivatives may be represented by the following Chemical Formula 1 or 2, respectively:
  • the cerulenin (C 12 H 17 NO 3 ;
  • the molecular weight of (2R, 3S) -3-[(4E, 7E) -nona-4,7-dienoyl] oxirane-2-carboxamide) is 223.2 (g / mol).
  • cerulenin is cephalosporium carulens ( Cephalosporium) caerulens ) or may be prepared by methods known in the art.
  • the molecular weight of the cerulein derivative C75 (C 14 H 22 O 4 ; 4-Methylene-2-octyl-5-oxotetrahydrofuran-3-carboxylic acid) is 254.32 (g / mol).
  • Serulenin or a cerulenin derivative, an active ingredient of the composition according to the present invention can be used for the prevention and treatment of inflammatory diseases by inhibiting the transcriptional activity of NF- ⁇ B, the production of nitric oxide and the expression of inflammation-related factors.
  • the inflammation-related factors include inducible nitric oxide synthases (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), monocytes
  • iNOS inducible nitric oxide synthases
  • COX-2 cyclooxygenase-2
  • IL-6 interleukin-6
  • monocytes In the group consisting of chemotactic protein-1 (MCP-1), interleukin-1 ⁇ (IL-1 ⁇ ) and tumor necrosis factor- ⁇ (TNF- ⁇ ) Can be selected.
  • MCP-1 chemotactic protein-1
  • IL-1 ⁇ interleukin-1 ⁇
  • TNF- ⁇ tumor necrosis factor- ⁇
  • composition according to the invention shows a concentration dependent NO production inhibitory activity without toxicity.
  • each composition containing 1, 5, 10 and 2 ⁇ M of cerulein was found to inhibit the production of NO without toxicity (Examples 1-2, FIGS. 1 and 2).
  • composition according to the present invention exhibits expression inhibitory activity of iNOS, COX-2, TNF- ⁇ , IL-6, MCP-1 ⁇ and IL-1 ⁇ .
  • mRNA expression of iNOS, COX-2, TNF- ⁇ , IL-6, MCP-1 and IL-1 ⁇ induced by LPS in the experimental group treated with 10 ⁇ M of cerulein is It was confirmed to be significantly suppressed (Examples 1-3, see FIG. 3).
  • composition according to the present invention shows the expression inhibitory activity of iNOS and COX-2. Specifically, according to one embodiment of the present invention, it was confirmed that protein expression of iNOS and COX-2 induced by LPS is significantly suppressed in the experimental group treated with 10 ⁇ M of cerulein (Examples 1-4 and FIG. 4). Reference).
  • composition according to the present invention exhibits NF- ⁇ B transcriptional activity inhibitory activity. Specifically, according to one embodiment of the present invention, it was confirmed that the NF- ⁇ B transcriptional activity induced by LPS is significantly inhibited in the experimental group treated with 10 ⁇ M of cerulein (see Example 1-5, FIG. 5).
  • composition according to the present invention exhibits TNF- ⁇ blood concentration inhibitory activity. Specifically, according to one embodiment of the present invention, it was confirmed that cerulenin significantly inhibits the secretion of TNF- ⁇ by LPS (see Examples 1-6 and FIG. 6).
  • composition according to the invention shows a concentration dependent NO production inhibitory activity without toxicity.
  • 1, 5 and 10 ⁇ M of cerulein derivative C75 was found to inhibit the production of NO by LPS without toxicity (see Example 2, FIGS. 7 and 8).
  • composition according to the present invention shows the mRNA expression inhibitory activity of iNOS, COX-2 and IL-6. Specifically, according to one embodiment of the present invention, it was confirmed that mRNA expression of iNOS, COX-2 and IL-6 induced by LPS is significantly suppressed in the experimental group treated with 10 ⁇ M of cerulein derivative C75 (Example 2, see FIG. 9).
  • composition according to the invention increases the survival of sepsis animal models. Specifically, according to one embodiment of the present invention, the survival rate for sepsis induced by galactosamine N and LPS in the experimental group treated with cerulein at 15, 30 or 60 mg / kg is significantly increased. (Example 3, see FIG. 10).
  • the inflammatory disease may be a chronic inflammatory disease, an acute inflammatory disease or other inflammation-related diseases, but is not limited thereto.
  • the chronic inflammatory disease may be rheumatoid arthritis, arteriosclerosis, diabetes, osteoporosis, Alzheimer's disease, Parkinson's disease, lupus or multiple sclerosis.
  • the acute inflammatory disease may be a rejection of sepsis, shock or organ transplantation.
  • the other inflammation-related diseases may be ophthalmic diseases, bronchitis, dermatitis, allergy, systemic lupus erythematosus, retinitis, gastritis, hepatitis, enteritis, pancreatitis or nephritis.
  • the dermatitis or allergy may be hypersensitivity, allergic rhinitis, asthma, allergic conjunctivitis, allergic dermatitis, atopic dermatitis, contact dermatitis, urticaria, insect allergy, food allergy or drug allergy.
  • the present invention also provides pharmaceutically acceptable salts of cerulenin or cerulenin derivatives represented by Formula 1 or 2.
  • Pharmaceutically acceptable salts are of low toxicity to humans and should not adversely affect the biological activity and physicochemical properties of the parent compound.
  • Pharmaceutically acceptable salts include pharmaceutically usable free acids and acid addition salts of base compounds of formula (1), alkali metal salts (such as sodium salts) and alkaline earth metal salts (such as calcium salts), organic bases and carboxylic acids of formula (1).
  • Organic base addition salts, amino acid addition salts and the like are possible.
  • Preferred salt forms of the compounds according to the invention include salts with inorganic or organic acids.
  • the inorganic acid may be used hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid and the like.
  • Organic acids include acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, Oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid and the like can be used.
  • Organic bases that can be used for the preparation of organic base addition salts are tris (hydroxymethyl) methylamine, dicyclohexylamine and the like.
  • Amino acids that can be used to prepare amino acid addition bases are natural amino acids such as alanine, glycine and the like.
  • Such salts can be prepared by conventional methods.
  • the compound of Formula 1 or 2 may be prepared by dissolving in a solvent which may be mixed with water such as methanol, ethanol, acetone, 1,4-dioxane, and then crystallizing after adding a free acid or free base. .
  • the compounds according to the invention may have an asymmetric carbon center so that they may exist as R or S isomers, racemic compounds, individual enantiomers or mixtures, individual diastereomers or mixtures, All stereoisomers and mixtures are included within the scope of the present invention.
  • hydrates or solvates may be prepared by known methods, and are preferably nontoxic and water soluble, and are hydrates or solvates having 1 to 5 molecules of water or alcoholic solvents (especially ethanol, etc.) bound together. It is preferable.
  • composition according to the present invention has an anti-inflammatory effect, and may further contain one or more substances known to have an anti-inflammatory effect on the composition of the present invention.
  • the known material may be a COX-2 inhibitor or a nitrogen monoxide (NO) inhibitor, but is not limited thereto.
  • composition according to the invention may further contain one or more pharmaceutically acceptable additives selected from the group consisting of excipients, lubricants, wetting agents, sweeteners, fragrances and preservatives.
  • compositions according to the invention can each be formulated and used according to conventional methods.
  • methods known in the art may be employed and formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
  • the method of administering the composition according to the present invention can be easily selected according to the dosage form, and can be administered orally or parenterally.
  • it may be used through intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, nasal, epidural and oral routes, but is not limited thereto.
  • Solid preparations for oral administration may be, but are not limited to, tablets, pills, soft or hard capsules, pills, powders or granules.
  • the form for parenteral administration may be in the form of creams, lotions, ointments, warnings, solutions, patches or injections, but is not limited thereto.
  • the dosage of the composition according to the present invention may vary depending on the age, sex, weight, degree of disease, and route of administration of the patient, but is generally in an amount of 5 to 500 mg / kg, preferably 100 to 250 mg / kg. The amount may be administered once to three times daily. However, the dosage does not limit the scope of the invention in any aspect.
  • the present invention provides a method for preventing or treating an inflammatory disease, comprising administering to a mammal a cerulein, a cerulein derivative or a pharmaceutically acceptable salt thereof.
  • the present invention also provides the use of a cerulenin, a cerulenin derivative or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the prevention or treatment of an inflammatory disease.
  • cerulenin and cerulenin derivatives may be represented by Formula 1 or 2, and the cerulein, cerulenin derivatives or pharmaceutically acceptable salts thereof are as described above.
  • Inflammatory diseases according to the present invention may be chronic inflammatory diseases, acute inflammatory diseases or other inflammation-related diseases, specific examples of inflammatory diseases are as described above.
  • the present invention provides a food composition for improving inflammation containing cerulenin, a cerulein derivative or a pharmaceutically acceptable salt thereof.
  • cerulenin or cerulenin derivatives may be represented by Formula 1 or 2, respectively.
  • Food composition for improving inflammation of the present invention is a compound represented by the formula (1) or 2 of the present invention, or a pharmaceutically acceptable salt thereof in an amount of 0.1 to 100% by weight, preferably 20 to 80% by weight of the total composition Include.
  • the food composition for improving inflammation of the present invention may be in the form of powder, granules, tablets, capsules or beverages, and may further include other natural or synthetic substances for health function and additives for commercialization.
  • the health beverage of the present invention may contain 0.1 to 50 g, preferably 1 to 10 g of the compound represented by Formula 1 or 2, or a pharmaceutically acceptable salt thereof, based on 100 ml.
  • the liquid component except for containing the compound as an essential ingredient in the indicated ratio, and various flavors or natural carbohydrates, etc. may be added as additional ingredients, as in general beverages.
  • natural carbohydrates include monosaccharides such as glucose, fructose and other disaccharides such as maltose and sucrose polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and Sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents such as, tauumatin, stevia extract (e.g., Rebaudioside A, glycyrazine, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
  • the ratio of the natural carbohydrate is generally about 1-20 g, preferably about 5-12 g per 100 mg of the compound of the present invention.
  • the food composition for improving inflammation of the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors such as flavoring agents, colorants and neutralizing agents (such as cheese and chocolate), pectic acid and salts thereof.
  • Alginic acid and salts thereof organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like.
  • Others may contain pulp for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These components can be used independently or in combination.
  • Inflammation-improving foods to which the compound represented by Formula 1 or 2 of the present invention, or a pharmaceutically acceptable salt thereof may be added for example, various foods, beverages, gums, vitamin complexes, health supplements, etc. There is this.
  • the present invention provides a cosmetic composition for improving inflammation containing cerulenin, cerulenin derivatives or pharmaceutically acceptable salts thereof.
  • cerulenin or cerulenin derivatives may be represented by Formula 1 or 2, respectively.
  • the cosmetic composition of the present invention can be applied directly to the skin for the purpose of improving inflammation.
  • the cosmetic composition may be formulated into a cosmetic formulation commonly prepared in the art.
  • the cosmetic composition is formulated, for example, in solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, veins, surfactant-containing cleansing, oils, powder foundations, emulsion foundations, wax foundations and sprays, and the like.
  • the present invention is not limited thereto. More specifically, it may be formulated in the form of a flexible lotion, nutrition lotion, nutrition cream, massage cream, essence, eye cream, cleansing cream, cleansing foam, cleansing water, pack, spray or powder.
  • the formulation of the cosmetic composition of the present invention is a paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide and mixtures thereof It may include a carrier component selected from the group consisting of.
  • the formulation of the cosmetic composition of the present invention is a powder or a spray
  • it may include a carrier component selected from the group consisting of lactose, talc, silica, aluminum hydroxide, calcium silicate, polyamide powder and mixtures thereof, in particular spray
  • a carrier component selected from the group consisting of lactose, talc, silica, aluminum hydroxide, calcium silicate, polyamide powder and mixtures thereof, in particular spray
  • chlorofluorohydrocarbon it may further include propane / butane or dimethyl ether.
  • the formulation of the cosmetic composition of the present invention is a solution or emulsion
  • it may include a carrier component selected from the group consisting of solvents, solvating agents, emulsions and mixtures thereof.
  • solvents include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylglycol oil, glycerol aliphatic esters, polyethylene glycols, sorbitan fatty acid esters, mixtures thereof, and the like.
  • solvents selected from the group consisting of solvents, solvating agents, emulsions and mixtures thereof.
  • examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylglycol oil, glycerol
  • the formulation of the cosmetic composition of the present invention is a suspension
  • a liquid diluent such as water, ethanol or propylene glycol
  • suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystal Carrier cellulose, aluminum metahydroxy, bentonite, agar, tragacanth and mixtures thereof.
  • the formulation of the cosmetic composition of the present invention is a surfactant-containing cleansing, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide ether
  • a carrier component selected from the group consisting of sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives, ethoxylated glycerol fatty acid esters, and mixtures thereof.
  • the "carrier component" in the cosmetic composition of the present invention is a compound or composition already known and used that may be included in a cosmetic preparation, and is a component that is not toxic, unstable, or irritating beyond contact with the human body.
  • the cosmetic composition of the present invention may further include an adjuvant selected from the group consisting of antioxidants, stabilizers, solubilizers, humectants, pigments, perfumes, sunscreens, colorants, surfactants, and combinations thereof.
  • the adjuvant is not limited to use as long as the adjuvant commonly used in the preparation of the cosmetic composition.
  • Dulbecco's modified Eagles medium (DMEM), Fetal bovine serum (FBS) and penicillin / streptomycin are from Hyclone (Thermo Scientific Inc., Germany), SYBR green from Roche (Switzerland), Dual The luciferase reporter system and the Griess reagent system were purchased from promega (USA) and the TNF- ⁇ ELISA kit was purchased from the R & D system (USA).
  • anti-iNOS polyclonal antibody was purchased from BD bioscience (USA)
  • anti-COX2 polyclonal antibody was Cell Signaling (USA)
  • anti-HSC70 monoclonal antibody was purchased from Rockland (USA).
  • Cerulenin, BAY11-7082, MTT and the remaining reagents were purchased from Sigma Aldrich Co. (USA).
  • macrophage line RAW264.7 purchased from ATCC and peritoneal macrophages isolated from mice.
  • RAW264.7 and peritoneal macrophages were treated at 37 ° C., 5% CO 2 , using glucose high glucose DMEM with 10% FBS and penicillin (100 U / ml) / streptomycin (100 ⁇ g / ml). Cultured in the incubator.
  • C57 / BL6 mouse species were used to determine the anti-inflammatory activity of cerulenin in animal models.
  • the diet used solid feed and mice and diet were purchased from Hyochang Science (Korea).
  • the breeding of the experimental animals was carried out under a temperature condition of 20 °C to 24 °C, humidity conditions of 60% to 70% and day and night lighting conditions of 12 hours cycle, water and diet was to be ingested freely.
  • the anti-inflammatory activity of cerulenin was measured by measuring mRNA expression, protein expression, transcriptional activity and NO production of factors related to the inflammatory response using the cells, mice, reagents and devices. Experimental results for identifying anti-inflammatory activity were expressed as mean ⁇ S.D., and in relation to statistical significance, defined as * (p ⁇ 0.05), the p ⁇ 0.05 was considered to be statistically significant.
  • Example 1-2 Inhibition of NO and production of NO
  • RAW264.7 cells a mouse macrophage line
  • RAW264.7 cells a mouse macrophage line
  • LPS LPS was treated at 100 ng / ml as an inflammatory derivative and incubated for 16 hours.
  • Grease reagent was added to the culture to quantify NO content. Specifically, 50 ⁇ l of the cultured cell culture solution and 50 ⁇ l of the grease reagent were mixed and reacted at room temperature for about 5 minutes, and then the absorbance was measured at 540 nm using a microplate reader (Tecan). After obtaining a standard curve using 0.1M nitrite standard solution, the NO concentration of the cell culture solution was calculated. The calculated NO value is shown in FIG. 1.
  • MTT 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide
  • Example 1-3 Inhibition of mRNA expression of inflammation-related factors
  • peritoneal macrophages 1 ml of 3% thioglycollate was intraperitoneally administered to male mice (C57 / BL6) weighing 20 g to 25 g, and 4 days after administration, The macrophages were obtained.
  • the obtained peritoneal macrophages were incubated in DMEM medium for 24 hours, and cultured for 24 hours by dispensing 200 ⁇ 10 4 cells / well in 6-well plates. Thereafter, cerulein was pretreated at 10 ⁇ M for 1 hour, treated with LPS (100 ng / ml) for 1 hour to confirm expression of TNF- ⁇ , and incubated for 6 hours for other cytokines. After the LPS treatment, RNA was isolated from each cell.
  • RNA isolation of the RNA was carried out in the following manner.
  • the cultured cells were washed twice with 1 ml PBS, lysed with 500 ⁇ l of trizol reagent (Life technologies), and then 100 ⁇ l of chloroform was added and vortexed. After incubation at room temperature for 10 minutes, the mixture was centrifuged at 13,000 rpm for 15 minutes to obtain 400 ⁇ l supernatant, and incubated with 500 ⁇ l of isopropanol for 10 minutes at room temperature. Thereafter, pellets were obtained by centrifugation for 15 minutes at 13,000 rpm. The obtained pellet was washed with 1 ml of 75% ethanol and dried at room temperature to separate RNA.
  • the isolated RNA is 0.1% DEPC (Diethyl pyrocarbonate) It was dissolved in 20 ⁇ l to 30 ⁇ l of solution and used for cDNA synthesis. 4 g of the isolated RNA was aliquoted to synthesize cDNA using M-MLV reverse transcriptase (promega), and real-time PCR analysis was performed to measure mRNA content of inflammatory factors.
  • DEPC Diethyl pyrocarbonate
  • the mRNA expression level of the inflammation-related factors is shown in FIG. 3, and the mRNA expression level is corrected and expressed as a ratio with respect to the amount of the control group CypA mRNA.
  • Example 1-4 Inhibition of protein expression of inflammation-related factors
  • Protein separation was carried out in the following manner. First, the cultured cells were washed twice with 1 ml PBS, and then PBS was removed and 0.01 M Tris-HCl (pH 7.4), 0.15 M NaCl, 0.001 M EDTA, 0.001 M EGTA, 1% Triton X-100, 200 ⁇ l of RIPA buffer containing 0.002M PMSF (phenylmethanesulfonyl fluoride) and a protease inhibitor were added, vortexed, placed on ice for 30 minutes, and centrifuged for 10 minutes at 13,000 rpm. Then, the supernatant was obtained, and the protein content was quantified using BCA reagent (pierce biotechnology).
  • Tris-HCl pH 7.4
  • RIPA buffer containing 0.002M PMSF phenylmethanesulfonyl fluoride
  • a protease inhibitor were added, vortexed, placed on ice for 30 minutes, and centrifuged
  • the quantitated protein samples were dispensed in equal amounts, mixed with 5 ⁇ SDS sample buffer, boiled at 95 for 5 minutes, and then subjected to SDS-PAGE using a 7% gel.
  • the protein of the electrophoresis was transferred to the nitrocellulose membrane, and pretreated with 5% skim milk for 1 hour at room temperature to inhibit nonspecific antibody binding. Thereafter, anti-iNOS polyclonal antibody, anti-COX-2 polyclonal antibody and anti-HSC70 monoclonal antibody were added to 5% skim milk to react with the membrane for 4 to 24 hours depending on the type of antibody. After the reaction, the mixture was washed three times with PBST for 10 minutes, and reacted with a secondary antibody at room temperature for 1 hour. Then, the membrane was washed three times with PBST for 10 minutes, and then reacted with ECL western blotting detection reagent (GE healthcare) to confirm the expression level of each protein with LAS2000 (GE healthcare).
  • iNOS and COX-2 were not expressed in the control group not treated with LPS, but expression was increased when LPS was treated with 100ng / ml or 1000ng / ml.
  • the protein expression of iNOS and COX-2 increased by the LPS is significantly inhibited by cerulenin.
  • cerulenin has been shown to have excellent anti-inflammatory activity.
  • Example 1-5 Inhibition of transcriptional activity of NF- ⁇ B
  • the RAW264.7 cells were transfected with NF- ⁇ B reporter vector and Renilla vector using lipofectamine 2000 (life technologies) to 40 ⁇ in a 24-well plate with high glucose DMEM medium. Aliquots were made to 10 4 cells / well. After 6 hours of incubation, the medium was replaced and incubated for another 16 hours. After the incubation, cerulein or BAY11-7082 was added at 10 ⁇ M, and after 1 hour, LPS was treated with 100ng / ml for 8 hours and 100 ⁇ l of lysis buffer was added.
  • lipofectamine 2000 life technologies
  • the degree of NF- ⁇ B transcriptional activity was measured using a dual-luciferase reporter system (promega), and the results are shown in FIG. 5. At this time, the degree of NF- ⁇ B transcriptional activity was expressed by adjusting the ratio of the Renilla value which is a control of each sample.
  • Example 1-6 Decreased Plasma Levels of TNF- ⁇ Induced by LPS in Mice
  • mice 8 weeks-old C57 / BL6 male mice each administered nothing, a group administered with cerulein 60 mg / kg intraperitoneally, a group administered with LPS 50 mg / kg, and cerulein 60 mg / kg 1 hour after the administration of LPS 50mg / kg divided into the group was administered to the experiment.
  • One hour after the administration of LPS 200 ⁇ l of blood was obtained from the mice, and serum was separated by centrifugation at 13,000 rpm for 3 minutes with a BD microtainer. After diluting the separated serum 50-fold, serum TNF- ⁇ concentration was measured using a TNF- ⁇ ELISA kit (R & D system).
  • Example 1-2 the inhibition of NO production was confirmed by treating C75 and cerulein with 1, 5, and 10 ⁇ M in RAW264.7 cells in the same manner as in Example 1-2 above, and the result was confirmed in FIG. 7 by cytotoxicity. The results are shown in FIG. In addition, in the same manner as in Example 1-3, C75 and cerulein was confirmed in the inhibition of mRNA expression of inflammation-related factors induced by LPS is shown in Figure 9 shown.
  • cerulein has a therapeutic effect of an inflammatory disease in an animal model.
  • the following experiment was performed by treating cerulein with a sepsis mouse model.
  • mice with a body weight of about 25 g of 8-week-old C57 / BL6 mice were conducted in one group.
  • cerulein dissolved in 40% DMSO solution 1 hour before induction of sepsis was administered to each group of mice intraperitoneally at concentrations of 15, 30 and 60 mg / kg, respectively, and only 40% DMSO solution was administered to mice as a control.
  • galactosamine N and LPS were dissolved in PBS at a concentration of 700 mg / kg and 150 ⁇ g / kg, respectively, and intraperitoneally administered to induce sepsis.
  • Survival measurement was calculated by checking every hour after induction of sepsis.
  • the group of mice administered with cerulein at a concentration of 30 mg / kg had a sharp survival rate from 6 hours after induction of sepsis, and the group of mice administered with a concentration of 15 mg / kg with cerulein after 8 hours. After 12 hours, the survival rate was about 10% for the 15 mg / kg group and about 25% for the 30 mg / kg group.
  • the cerulein 60 mg / kg administration group showed a sharp decrease in survival rate of about 60% after 7 hours of induction of sepsis, but after about 12% after about 12 hours, the survival rate was about 40%.
  • the survival rate decreased to 20% after 7 hours of induction of sepsis, and decreased to 10% after 12 hours.
  • the cerulein of the present invention which inhibits the expression and activity of inflammatory factors, has an effect of preventing and treating sepsis by increasing the survival rate in sepsis-generating animal models, and the cerulein derivatives showing the same activity also have the same effect. It can be seen that there is.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Dermatology (AREA)
  • Birds (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)

Abstract

La présente invention concerne une composition anti-inflammatoire contenant, en tant que principe actif, de la cérulénine, un dérivé de la cérulénine, ou un sel pharmaceutiquement acceptable de ceux-ci. La cérulénine ou un dérivé de la cérulénine de la présente invention présentent d'excellents effets en terme de prévention, traitement et soulagement de maladies inflammatoires, et ainsi peuvent être appliqués à une composition destinée à prévenir ou traiter des maladies inflammatoires et à un matériau destiné à des produits alimentaires ou cosmétiques apparentés.
PCT/KR2015/009809 2014-10-06 2015-09-18 Composition pharmaceutique pour la prévention ou le traitement de maladies inflammatoires, contenant, en tant que principe actif, de la cérulénine ou un dérivé de la cérulénine Ceased WO2016056769A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2014-0134560 2014-10-06
KR20140134560 2014-10-06

Publications (1)

Publication Number Publication Date
WO2016056769A1 true WO2016056769A1 (fr) 2016-04-14

Family

ID=55653336

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2015/009809 Ceased WO2016056769A1 (fr) 2014-10-06 2015-09-18 Composition pharmaceutique pour la prévention ou le traitement de maladies inflammatoires, contenant, en tant que principe actif, de la cérulénine ou un dérivé de la cérulénine

Country Status (2)

Country Link
KR (1) KR101705253B1 (fr)
WO (1) WO2016056769A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113499338A (zh) * 2021-06-17 2021-10-15 南方海洋科学与工程广东省实验室(湛江) 二鹅掌菜酚在作为和/或制备铁死亡抑制剂中的应用
EP4138877A4 (fr) * 2020-04-24 2024-05-22 Cornell University Ciblage du cycle de palmitoylation/dépalmitoylation pour traiter des maladies inflammatoires

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050053631A1 (en) * 2003-09-10 2005-03-10 Unilever Home & Personal Care Usa, Division Of Conopco, Inc. Method of decreasing sebum production
KR20070023730A (ko) * 2004-06-14 2007-02-28 유니레버 엔.브이. 피지 생성 및 모공 크기 감소 방법
JP2012067055A (ja) * 2010-09-27 2012-04-05 Kowa Co セルレニンを含有する経皮吸収促進剤
WO2013155528A2 (fr) * 2012-04-13 2013-10-17 Fasgen, Inc. Méthodes de réduction de l'inflammation cérébrale, de renforcement de la sensibilité à l'insuline et de réduction des taux de céramides

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050053631A1 (en) * 2003-09-10 2005-03-10 Unilever Home & Personal Care Usa, Division Of Conopco, Inc. Method of decreasing sebum production
KR20070023730A (ko) * 2004-06-14 2007-02-28 유니레버 엔.브이. 피지 생성 및 모공 크기 감소 방법
JP2012067055A (ja) * 2010-09-27 2012-04-05 Kowa Co セルレニンを含有する経皮吸収促進剤
WO2013155528A2 (fr) * 2012-04-13 2013-10-17 Fasgen, Inc. Méthodes de réduction de l'inflammation cérébrale, de renforcement de la sensibilité à l'insuline et de réduction des taux de céramides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MATSUO, SHINGO ET AL.: "Fatty acid synthase inhibitor C75 ameliorates experimental colitis", MOLECULAR MEDICINE, vol. 20, 2013, pages 1 - 9 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4138877A4 (fr) * 2020-04-24 2024-05-22 Cornell University Ciblage du cycle de palmitoylation/dépalmitoylation pour traiter des maladies inflammatoires
CN113499338A (zh) * 2021-06-17 2021-10-15 南方海洋科学与工程广东省实验室(湛江) 二鹅掌菜酚在作为和/或制备铁死亡抑制剂中的应用

Also Published As

Publication number Publication date
KR101705253B1 (ko) 2017-02-22
KR20160040995A (ko) 2016-04-15

Similar Documents

Publication Publication Date Title
KR101290745B1 (ko) 라말린을 함유하는 염증질환 또는 면역질환의 예방 또는 치료용 약학 조성물
WO2017150934A1 (fr) Composition comprenant de la panduratine ou un extrait de curcuma rond (boesenbergia pandurata) pour le traitement, la prévention ou l'amélioration d'une maladie de perte osseuse
KR100729436B1 (ko) ＩκＢ키나아제 저해용 식품첨가제 및 이를 포함하는 식품
WO2016056769A1 (fr) Composition pharmaceutique pour la prévention ou le traitement de maladies inflammatoires, contenant, en tant que principe actif, de la cérulénine ou un dérivé de la cérulénine
Phuong Tran et al. Alkaloids from Piper longum L and their Anti‐inflammatory Properties
WO2014098306A1 (fr) Composition pharmaceutique pour prévenir ou traiter la démence
WO2019098461A1 (fr) Composition destinée à la prévention ou au traitement des maladies inflammatoires, contenant des métabolites de type curvularine issus de penicillium sp. sf-5859 de champignon marin
KR101646916B1 (ko) 베타-카르볼린 알칼로이드 화합물을 함유하는 염증성 질환의 예방 또는 치료용 조성물
JP2010195831A (ja) ＩκＢキナーゼ阻害剤
WO2019125058A1 (fr) Composition comprenant un extrait de marron d'inde
WO2022270760A1 (fr) Méthode de traitement de la stéatohépatite non alcoolique par la co-administration d'un dérivé de la curcumine et d'un inhibiteur du récepteur de tgf-β
KR101592373B1 (ko) 고장초 추출물을 포함하는 미백 조성물 및 그 제조 방법
WO2019031655A1 (fr) Composition comprenant du thymol comme principe actif pour prévenir ou traiter les rides de la peau ou la dermatite atopique
JP2013177355A (ja) メタボリックシンドロームを予防及び治療するための有機体由来の天然成分及び抽出物
KR20110088991A (ko) 신규 카나비노이드 유도체 및 이의 의학적 용도
KR102272637B1 (ko) 올벚나무를 포함하는 항염증용 조성물
KR101056878B1 (ko) 신규 자스모네이트 유도체 및 이의 의약적 용도
WO2020189911A1 (fr) Composition comprenant de la noranhydroicaritine, pour la prévention ou le traitement de maladies métaboliques cardiovasculaires
KR102757268B1 (ko) 여정실에서 유래한 신규 화합물 및 이를 포함한 염증질환 개선, 치료 또는 예방용 약학적 조성물
KR101712184B1 (ko) Nrf2 활성화 효능의 세스퀴터핀 화합물 및 이를 유효성분으로 포함하는 약학조성물
KR101602799B1 (ko) 항염증 활성 조성물 및 이를 포함하는 염증 질환 예방 또는 치료용 약학적 조성물
KR102307045B1 (ko) 카페익산 에스테르 유도체를 유효성분으로 함유하는 아토피 피부염 예방 또는 치료용 조성물 및 이의 합성방법
KR101634100B1 (ko) 클리오퀴놀 또는 그 유도체를 유효성분으로 포함하는 jmjd 관련 질환의 예방 및 치료용 약학적 조성물
KR20160032310A (ko) 회향 열매 추출물의 분획물을 유효성분으로 포함하는 피부염 치료용 약학적 조성물
WO2023224166A1 (fr) Composition anti-inflammatoire contenant du 5-hydroxymaltol

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15849351

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15849351

Country of ref document: EP

Kind code of ref document: A1