KR20140125655A - A composition for enhancing immune system or anti-inflammation comprising a clitosybin derivates as an active infredients - Google Patents
A composition for enhancing immune system or anti-inflammation comprising a clitosybin derivates as an active infredients Download PDFInfo
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- KR20140125655A KR20140125655A KR1020130043749A KR20130043749A KR20140125655A KR 20140125655 A KR20140125655 A KR 20140125655A KR 1020130043749 A KR1020130043749 A KR 1020130043749A KR 20130043749 A KR20130043749 A KR 20130043749A KR 20140125655 A KR20140125655 A KR 20140125655A
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- South Korea
- Prior art keywords
- pharmaceutically acceptable
- derivative
- acceptable salt
- inflammatory diseases
- compound
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Abstract
The present invention relates to a composition for immunosuppression or antiinflammation, which comprises as an active ingredient a chrysothymbin derivative represented by the following general formula (1), wherein the krytothybene derivative specifically inhibits the production of IL-10 which is a Th2 expression cytokine or Secretion and interferon-gamma (interferon-gamma), which is an inflammatory cytokine, by inhibiting the production or secretion of interferon-gamma (Interferon-gamma), which is useful as an effective component of a composition for improving skin immunity or for the prevention and treatment of inflammatory diseases .
[Chemical Formula 1]
(In the above formula (1), R 1 and R 2 are as defined in the specification.)
Description
The present invention relates to a composition for improving skin immunity or for the prophylaxis and treatment of inflammatory diseases, which comprises a clitocybin derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
Inflammatory disease refers to the pathological state of abscesses that are formed by the intrusion of bacteria or physical and chemical stimulation by the internal and external environment. The inflammatory diseases include inflammatory diseases such as dermatitis, atopy, psoriasis, osteoarthritis, rheumatoid arthritis, gout, ankylosing spondylitis, tendinitis, scleritis, rheumatic fever, lupus, fibromyalgia, psoriatic arthritis, asthma, atopy, Crohn's disease, ulcerative colitis Acute chronic inflammatory diseases. Inflammation is a normal and protective in vivo defense manifestation that is localized to physical trauma, harmful chemicals, microbial infections, or tissue damage caused by stimuli in vivo metabolites. These inflammations are triggered by chemical mediators such as various cytokines produced from damaged tissues and migrating cells, and these chemical mediators are known to vary according to the type of inflammation process.
In normal cases, the organism neutralizes or eliminates the cause of inflammation through the inflammation reaction, regenerates the upper tissue and regenerates the normal structure and function, but if not, the disease state such as chronic inflammation also proceeds. In addition, when the inflammation is improperly induced by an autoimmune reaction such as a harmless substance such as pollen, asthma or rheumatoid arthritis, the defense reaction itself rather damages the tissue, and therefore, an inflammatory disease prevention or treatment agent is required. In the case of skin, most of the inflammatory reactions in the inflammation treatment and removal of inflammation enzymes destroy and destroy the surrounding normal tissue, collagen fibers and elastic fibers of the skin is destroyed, the skin aging progresses. Although most inflammatory diseases can be observed in almost all clinical diseases, some of these inflammatory diseases are bacterial diseases that can be cured by administration of antibiotics, but most of them are due to tissue damage due to autoimmune reaction, so there is no specific treatment It is known as an incurable disease.
The most common inflammatory disease preventive or therapeutic agents for treating such inflammatory diseases are largely divided into steroidal and nonsteroidal inflammatory disease preventive or therapeutic agents. Most of synthetic inflammatory disease preventive or therapeutic agents have various side effects It is necessary to develop a prophylactic or therapeutic agent for inflammatory diseases, which is excellent in efficacy and has few side effects. In particular, from the viewpoint of efficacy and side effects, it is believed that natural herbal preparations, which are rich in clinical experience and excellent in safety, will be good candidates for the development of preventive and therapeutic agents for inflammatory diseases.
Various biochemical phenomena are involved in the cause of inflammation in living body. Because various biochemical phenomena interact with each other, intervention at one or more key points can provide therapeutic benefit. Helper T cells in the immune response are necessary for the antigen to be efficiently presented to the B cell, which regulates the cell mediated immune response. Helper T cells are divided into two types: Th1, which stimulates cellular immune responses, and Th2, which stimulates the production of antibodies and suppresses inflammation. Th1 and Th2 are responsible for immunologic functions that are mutually exclusive through the expression of distinctive cytokines. In fact, the activation of Th1 and Th2 cells is presumed to be involved in a complex cytokine network, and it is known that a healthy immune state is maintained when the balance between these two groups of cells is maintained. When the balance of Th1 or Th2 is broken due to the overexpression of either one, an immune disease such as autoimmune disease or allergy disease is induced. Therefore, when a substance capable of controlling the balance of Th1 and Th2 is searched, May be proved as a substance for preventing or treating an effective inflammatory disease.
Interferon (IFN) is a typical cytokine secreted by Th1 and plays an important role in the resistance of mammalian hosts to pathogens. The three main functions of interferon are antiviral, antiproliferative, and immunomodulatory. The antiviral action of interferon is used for the treatment of viral hepatitis, and antiproliferative and immunomodulating actions are used for the treatment of cancer. In particular, interferon gamma (IFN-y) is a homodimer that is well known for immunity or type II IFN and is rapidly produced by activated T cells and natural killer (NK) cells. It also plays a crucial role in the innate and adaptive immunity and tumor treatment of intracellular pathogens. The importance of IFN-y in the immune system directly begins from the inhibitory effect of viral replication, but most importantly, IFN-y has immunostimulatory and immunomodulating effects. In addition to the pivotal role of INF-γ in host defense, abnormal expression of IFN-y is associated with autoinflammatory and autoimmune diseases. Excessive secretion of IFN-y is associated with the onset of chronic inflammation and immune disorders. Therefore, searching for a substance that inhibits IFN-y, an inflammatory cytokine, can be proved as a substance for preventing or treating an effective inflammatory disease.
IL-10 is a typical cytokine secreted by Th2, and has a characteristic of showing both immunity suppression and immunity promotion mediated by various actions or effects in the immune response. IL-10 is known as an anti-inflammatory cytokine of the expression of inflammatory cytokines such as IL-2 and IFN-y, macrophage and the activity of dendritic cells. In addition, it enhances the proliferation and survival rate of B cells and promotes the proliferation of mast cells, thus having an effect on the non-inflammatory immune response.
Accordingly, the inventors of the present invention have found that when a strong immunopotentiating and anti-inflammatory active substance is searched, it is possible to suppress the production or secretion of IL-10, which is a cytokine expressed by Th2, The present invention has been completed by confirming that it can be effectively used as a composition for improving skin immunity and treating inflammatory diseases by effectively inhibiting the production or secretion of interferon-gamma, an inflammatory cytokine.
An object of the present invention is to provide a composition for improving skin immunity or for the prophylaxis and treatment of inflammatory diseases, which comprises a clitocybin derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
Another object of the present invention is to provide a mushroom of the genus Hygrophoropsis aurantiaca strains or fractions thereof as an active ingredient for improving skin immunity or for the prophylaxis and treatment of inflammatory diseases.
In order to achieve the above object, the present invention provides a composition for improving skin immunity or for the prophylaxis and treatment of inflammatory diseases, which comprises a clitocybin derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition is provided:
[Chemical Formula 1]
.
Wherein R 1 and R 2 are independently or alternatively OCH 3 or OH.
The present invention also provides a cosmetic composition for improving skin immunity or preventing or improving inflammatory diseases, which comprises the krytothiamine derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
The present invention also provides an external preparation for skin for improving skin immunity and prophylactic and / or inflammatory diseases, which comprises the krytothiamine derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
In addition, the present invention provides a health food for improving skin immunity and preventing and improving inflammatory diseases, which comprises the krytothiamine derivative represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
In addition, the present invention relates to a method for producing a mushroom ( Hygrophoropsis aurantiaca strains or fractions thereof as an active ingredient for improving skin immunity or for the prophylaxis and treatment of inflammatory diseases.
The present invention also provides a cosmetic composition for improving skin immunity or preventing or ameliorating an inflammatory disease, which comprises a mushroom strain extract or a fraction thereof as an active ingredient.
The present invention also provides an external preparation for skin for improving skin immunity or preventing or ameliorating an inflammatory disease, which comprises a mushroom strain extract or a fraction thereof as an active ingredient.
The present invention also provides a health food for improving skin immunity or preventing or ameliorating an inflammatory disease, comprising an extract of Oriental mushroom strain or a fraction thereof as an active ingredient.
The clitocybin derivative represented by the formula (1) of the present invention inhibits the production or secretion of IL-10, a cytokine expressed by Th2, and inhibits the production of interferon-gamma, which is an inflammatory cytokine expressed by Th1 (Interferon-y) production, or secretion, the krytothybin derivative, the extract of the mushroom strain containing it and the fraction thereof are useful as an effective ingredient of a composition for improving skin immunity or for the prophylaxis and treatment of inflammatory diseases Lt; / RTI >
FIG. 1 is a graph showing the inhibitory activity of IFN-y production of NK92 cells treated with a clitorosybin derivative.
FIG. 2 is a graph showing the inhibitory activity of IL-10 production of NK92 cells treated with a clitosybin derivative. FIG.
Hereinafter, the present invention will be described in detail.
The present invention provides a pharmaceutical composition for improving skin immunity or for the prophylaxis and treatment of inflammatory diseases, comprising a clitocybin derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]
.
Wherein R 1 and R 2 are independently or alternatively OCH 3 or OH.
More specifically, the chrythosybin derivative represented by the above formula (1) is represented by the following general formulas (1a) to (1c):
[Formula 1a]
,
[Chemical Formula 1b]
, And
[Chemical Formula 1c]
.
The immunological improvement is preferably an improvement to any one selected from the group consisting of contact dermatitis, allergy, and atopy caused by Th2 overexpression, but is not limited thereto.
The inflammatory disease is selected from the group consisting of dermatitis, allergy, atopy, asthma, conjunctivitis, periodontitis, rhinitis, otitis, sore throat, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, hemorrhoids, gout, ankylosing spondylitis, rheumatism, ), Rheumatoid arthritis, osteoarthritis, rheumatoid arthritis, periarthritis, tendonitis, hay fever, tendinitis, myositis, hepatitis, cystitis, nephritis, sjogren's syndrome, multiple sclerosis and acute and chronic inflammatory diseases But it is not limited thereto.
In a specific example of the present invention, the present inventors isolated a crytosybin derivative from a mushroom-like mushroom strain to confirm immune enhancement and anti-inflammatory activity of a crythosybin derivative, and then used interferon-gamma , NK92 cells (human NK lymphoma), which are dependent on IFN- [gamma]), are treated with various concentrations of IFN-y and Th2, which are one of inflammatory cytokines secreted by Th1 As a result of measuring the amount of IL-10 produced by one of the cytokines secreted by the cells, it was confirmed that the production of IFN-y and IL-10 was decreased depending on the concentration of clitosybin. Specifically, it was confirmed that the production of IL-10 was inhibited and the production of IFN-y was also inhibited as the concentration of the clitosybin derivative increased. It was confirmed that the two cytokines responsible for immunologic function, which are opposite to each other, are simultaneously inhibited, so that they can be balanced to a certain level (see FIGS. 1 and 2).
Therefore, the clitosanbine derivative of formula (I) of the present invention or a pharmaceutically acceptable salt thereof inhibits the production of IL-10 which is a Th2-expressing cytokine and the production of IFN-y which is a Th1-expressing cytokine The activity of effectively controlling the balance of the cytokine, and the clitosybin derivative or a pharmaceutically acceptable salt thereof is useful as an active ingredient of a pharmaceutical composition for improving skin immunity or for the prophylaxis and treatment of inflammatory diseases . ≪ / RTI >
The clitosybin derivative of the present invention can be used in the form of a pharmaceutically acceptable salt. As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.
The acid addition salt according to the present invention can be prepared by a conventional method such as methanol, ethanol, acetone or methylene chloride, acetonitrile and the like, which is obtained by filtering and drying the precipitate formed by adding an organic acid or an inorganic acid, Followed by distillation under reduced pressure, followed by drying or crystallization in an organic solvent.
In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).
Furthermore, the present invention encompasses the above-mentioned clitosybin derivatives or pharmaceutically acceptable salts thereof, as well as possible solvates, hydrates, isomers and the like which can be prepared therefrom.
The pharmaceutical composition containing the above-described clitosybin derivative or a pharmaceutically acceptable salt thereof as an active ingredient can be used in the form of a general pharmaceutical preparation.
The pharmaceutical composition may further comprise a pharmaceutically acceptable additive, wherein pharmaceutically acceptable additives include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, lactose Starch glycolate, sodium starch glycolate, carnauba wax, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, calcium stearate, , White sugar, dextrose, sorbitol, talc, and the like. The pharmaceutically acceptable additives according to the present invention are preferably contained in an amount of 0.1 to 90 parts by weight based on the composition.
The pharmaceutical composition may be administered orally or parenterally in various clinical formulations. In the case of pharmaceutical preparations, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, ≪ / RTI > Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like, which may contain at least one excipient such as starch, Calcium carbonate, sucrose or lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions and syrups, and various excipients such as wetting agents, sweetening agents, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are simple diluents commonly used . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used as the non-aqueous solvent and suspension agent. Examples of suppository bases include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like.
The pharmaceutical composition may be administered orally or parenterally in accordance with the desired method. In the case of parenteral administration, the composition may be administered by external or intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, . The dosage varies depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of disease.
The pharmaceutical composition may be administered orally or parenterally in accordance with the desired method. In the case of parenteral administration, the composition may be administered by external or intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, . The dosage varies depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of disease.
The dosage of the pharmaceutical composition varies depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of the disease. Preferably 0.001 to 10 mg / kg, based on the amount of the fractions thereof, and may be administered 1 to 6 times per day.
The pharmaceutical composition may be used alone or in combination with methods for the prevention and treatment of inflammatory diseases or using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.
The present invention also provides a cosmetic composition for improving skin immunity or preventing or improving inflammatory diseases, which comprises the krytothiamine derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
The immunological improvement is preferably an improvement to any one selected from the group consisting of contact dermatitis, allergy, and atopy caused by Th2 overexpression, but is not limited thereto.
The inflammatory disease is selected from the group consisting of dermatitis, allergy, atopy, asthma, conjunctivitis, periodontitis, rhinitis, otitis, sore throat, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, hemorrhoids, gout, ankylosing spondylitis, rheumatism, It is preferably any one selected from the group consisting of arthritis, osteoarthritis, rheumatoid arthritis, shoulder inflammation, tendinitis, hay fever, tendinitis, myositis, hepatitis, cystitis, nephritis, Sjogren's syndrome, multiple sclerosis and acute and chronic inflammatory diseases. It is not limited.
The krytothybene derivative represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof inhibits the production of IL-10, which is a Th2-expressing cytokine, and the production of IFN-y, a Th1-expressing cytokine, , And thus the clitosybin derivative or a pharmaceutically acceptable salt thereof is useful as an active ingredient of a cosmetic composition for improving skin immunity or preventing or ameliorating an inflammatory disease Can be used.
The cosmetic composition may be prepared from at least one selected from the group consisting of emulsion, cream, essence, essence, body lotion, bar diesel, body essence, body cleanser, cleansing foam, pack and cleansing cream.
The cosmetic composition may be, for example, a solution, a gel, a solid or a paste anhydrous product, an emulsion obtained by dispersing an oil phase in water, a suspension, a microemulsion, a microcapsule, a microgranule or an ionic (liposome) A cream, a skin, a lotion, a powder, an ointment, a spray, or a cone stick. It can also be prepared in the form of a foam or an aerosol composition further containing a compressed propellant.
In addition, the cosmetic composition may further comprise, in addition to the krytothiamine derivative or a pharmaceutically acceptable salt thereof, a lipid, an organic solvent, a solubilizing agent, a thickening agent and a gelling agent, a softening agent, an antioxidant, a suspending agent, surfactants, water, ionic or nonionic emulsifiers, fillers, sequestering and chelating agents, preservatives, vitamins, blockers, wetting agents, essential oils, dyes, pigments, hydrophilic or lipophilic active agents , Lipid vesicles, or any other ingredient conventionally used in cosmetics.
The present invention also provides an external preparation for skin for improving skin immunity or for the prevention and improvement of inflammatory diseases, which comprises the krytothiamine derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
The inflammation may include chronic inflammation that has progressed to a disease state, inflammatory reaction by generally harmless substances such as pollen, and inflammatory reaction by autoimmune reaction such as asthma or rheumatoid arthritis.
The immunological improvement is preferably an improvement to any one selected from the group consisting of contact dermatitis, allergy, and atopy caused by Th2 overexpression, but is not limited thereto.
The inflammatory disease is selected from the group consisting of dermatitis, allergy, atopy, asthma, conjunctivitis, periodontitis, rhinitis, otitis, sore throat, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, hemorrhoids, gout, ankylosing spondylitis, rheumatism, It is preferably any one selected from the group consisting of arthritis, osteoarthritis, rheumatoid arthritis, shoulder inflammation, tendinitis, hay fever, tendinitis, myositis, hepatitis, cystitis, nephritis, Sjogren's syndrome, multiple sclerosis and acute and chronic inflammatory diseases. It is not limited.
The krytothybene derivative represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof inhibits the production of IL-10, which is a Th2-expressing cytokine, and the production of IFN-y, a Th1-expressing cytokine, , The activity of effectively controlling the balance of the cytokine, and the clitosybin derivative or a pharmaceutically acceptable salt thereof is useful as an effective ingredient of a composition for external application for skin for improving skin immunity or for the prevention and improvement of inflammatory diseases Lt; / RTI >
Preferably, the external preparation for skin comprises 0.1 to 50 parts by weight of a chelatosybin derivative or a pharmaceutically acceptable salt thereof, based on the total weight of the composition, but is not limited thereto.
The external preparation for skin may further contain at least one selected from the group consisting of fatty substances, organic solvents, solubilizers, thickening and gelling agents, softening agents, antioxidants, suspending agents, stabilizing agents, foaming agents, fragrances, surfactants, A lipid vesicle or any other ingredient conventionally used in external preparations for skin, and a pharmaceutically acceptable carrier, diluent, emulsifier, filler, sequestering and chelating agent, preservative, vitamin, blocker, wetting agent, essential oil, dye, pigment, hydrophilic or lipophilic active agent And may contain adjuvants conventionally used in the same skin science field. In addition, the components can be introduced in amounts commonly used in the dermatology field.
The present invention also provides a health food for preventing and ameliorating an inflammatory disease containing an active ingredient of a clitosybin derivative or a pharmaceutically acceptable salt thereof.
The immunological improvement is preferably an improvement to any one selected from the group consisting of contact dermatitis, allergy, and atopy caused by Th2 overexpression, but is not limited thereto.
The inflammatory disease is selected from the group consisting of dermatitis, allergy, atopy, asthma, conjunctivitis, periodontitis, rhinitis, otitis, sore throat, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, hemorrhoids, gout, ankylosing spondylitis, rheumatism, It is preferably any one selected from the group consisting of arthritis, osteoarthritis, rheumatoid arthritis, shoulder inflammation, tendinitis, hay fever, tendinitis, myositis, hepatitis, cystitis, nephritis, Sjogren's syndrome, multiple sclerosis and acute and chronic inflammatory diseases. It is not limited.
The krytothybene derivative represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof inhibits the production of IL-10, which is a Th2-expressing cytokine, and the production of IFN-y, a Th1-expressing cytokine, , And thus the clitosanbine derivative or a pharmaceutically acceptable salt thereof is useful as an active ingredient of a health food for improving skin immunity or preventing or ameliorating an inflammatory disease Can be used.
The krytothybene derivative of the present invention or a pharmaceutically acceptable salt thereof may be directly added or used together with other food or food ingredients, and may be suitably used according to a conventional method.
The health food of the present invention includes components that are ordinarily added at the time of food production, and includes, for example, proteins, carbohydrates, fats, nutrients, and seasonings.
There is no particular limitation on the kind of the food. Examples of the food to which the milk mushroom safflower extract or its fractions can be added include dairy products including meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, ice cream, Drinks, tea, drinks, alcoholic beverages, and vitamin complexes, all of which include health foods in a conventional sense.
The health beverage composition of the present invention may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary beverages. Such natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. Examples of sweeteners include natural sweeteners such as tau martin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like. The ratio of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 ml of the composition of the present invention.
In addition to the above, the krytothybene derivative of the present invention or a pharmaceutically acceptable salt thereof may be in the form of various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like. In addition, the clitosybin derivatives of the present invention or pharmaceutically acceptable salts thereof may contain flesh for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not critical, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.
Also, it is preferable that the crystallotybin derivative of formula (1) of the present invention is prepared by the following steps, but not limited thereto:
1) A large mushroom ( Hygrophoropsis aurantiaca ) to obtain a culture;
2) extracting the obtained culture with acetone and ethyl acetate;
3) extracting the extracted extract by concentration gradient silica gel column chromatography using a mixed solvent of chloroform and methanol to obtain an active fraction; And
4) Performing Sephadex LH-20 column chromatography using the above active fraction as a solvent in methanol (100%) to obtain a compound of formula (1).
In the above production method, the culture solution of step 1) is preferably, but not limited to, obtained by cultivating the Aspergillus species in a yeast extract (YPS) liquid medium.
In the above production method, the extraction method of the step 2) may be an extraction method commonly used in the art, and it is preferable to extract it with acetone and re-extract it with ethyl acetate, but it is not limited thereto. After re-extraction an ethyl acetate layer is used in the next step.
In the above preparation process, the concentration gradient of the mixed solvent of chloroform and methanol used in step 3) is preferably 50: 1 to 1: 1, and eluted at a rate of 10 to 15 ml / Fractions can be obtained, but are not limited thereto.
In the above production method, the active fraction obtained in step 3) was eluted at a rate of 1 to 1.6 ml / min using methanol (100%) as an eluent using Sephadex LH-20 column chromatography, and after 140 minutes To obtain a brightly brown novel crytho silicine derivative (Formula 1a).
In addition, the present invention relates to a method for producing a mushroom ( Hygrophoropsis aurantiaca strains or fractions thereof as an active ingredient for improving skin immunity or for the prophylaxis and treatment of inflammatory diseases.
The present invention also provides a cosmetic composition for improving skin immunity or preventing or ameliorating an inflammatory disease, which comprises a mushroom strain extract or a fraction thereof as an active ingredient.
The present invention also provides an external preparation for skin for improving skin immunity or preventing or ameliorating an inflammatory disease, which comprises a mushroom strain extract or a fraction thereof as an active ingredient.
In addition, the present invention provides a health food composition for improving skin immunity or preventing or ameliorating an inflammatory disease, comprising an extract of a mushroom strain or a fraction thereof as an active ingredient.
The extracts or fractions thereof containing the compound of the present invention inhibit the production of IL-10, which is a Th2-expressing cytokine, and also significantly inhibit the production of IFN-y, a Th1-expressing cytokine, , And the extract of the mushroom strain or the fraction thereof containing the compound can be usefully used as an active ingredient of a composition for improving skin immunity or for the prophylaxis and treatment of inflammatory diseases.
Hereinafter, the present invention will be described in detail with reference to Examples and Production Examples.
However, the following examples and preparative examples are merely illustrative of the present invention,
Is not limited to the following examples and production examples.
< Example 1> Kratosevin Preparation of derivatives 1 ( Mushroom mushroom Extraction, isolation and purification from strains)
Hygrophoropsis aurantiaca strain was inoculated in a 500 ml Erlenmeyer flask containing 100 ml of yeast extract (YPS) liquid medium and incubated for 5 days in a reciprocal shaking incubator at 140 rpm at 27 캜. Thereafter, 3 liters of yeast extract (YPS) liquid medium was placed in a 5 liter immersion culture jar fermentor (Korea Fermentor Co. Ltd), sterilized, and 100 ml of the cultured culture was inoculated And cultured under the same conditions. After culturing for 7 days, it was extracted with 70% acetone, re-extracted with ethyl acetate, and separated into ethyl acetate layer and water layer.
The ethyl acetate extract obtained above was subjected to concentration gradient silica gel column chromatography using a mixed solvent of chloroform and methanol (50: 1 to 1: 1), followed by sequential chromatography on Sephadex LH-20 column chromatography (100% methanol) To give pure compound (6.5 mg) as a light brown solid. It was confirmed by reverse phase (ODS) column chromatography at 35% methanol solvent condition that it was 100% purified pure compound.
< Example 2> Kratosevin Preparation of Derivative 2 (Organic Synthesis)
(One) Kratosevin Preparation of C compounds
4-Aminophenol (1.1 g, 10.0 mmol) was added to a solution of methyl 2-peryl-3,5-dimethoxybenzoate (2,24 g, 10.0 mmol) in methanol (40 mL) Respectively. Then, NaBH4 (0.75 g, 20.0 mmol) was added to the reaction solution at 0 占 폚, the temperature was raised to room temperature, and the mixture was stirred for 18 hours. The reaction solution was concentrated under reduced pressure, and water (50 ml) and a small amount of acetic acid were added. The resulting precipitate was filtered through a glass filter, and the resulting solid was washed with water and dried to obtain the desired compound, krytotasybin C compound (1c; 2.6 g, 91%).
1 H NMR (300 MHz, DMSO -d6) δ 9.38 (s, 1H), 7.65 (s, 1H), 7.62 (s, 1H), 6.82-6.76 (m, 4H), 4.73 (s, 2H), 3.87 (s, 3 H);
13 C NMR (75 MHz, DMSO -d6) δ 165.9, 161.4, 154.9, 154.2, 134.7, 131.1, 121.5, 115.2, 102.5, 97.8, 55.7, 55.6, 48.3
(2) Kratosevin Preparation of A compound
A 48% aqueous solution of bromic acid (10 ml) and acetic acid (20 ml) were added to the compound (2.0 g, 7.0 mmol) prepared in the above (1) and the mixture was heated under reflux for 18 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain 1.5 g of a target compound, Respectively.
1 H NMR (300 MHz, DMSO -d6) δ 9.98 (s, 1H), 9.61 (s, 1H), 9.36 (s, 1H), 7.61 (dd, J = 6.6, 1.8 Hz, 2H), 6.79 (dd J = 6.6, 1.8 Hz, 2H), 6.56 (dd, J = 1.8 Hz, 1H), 6.49 (dd, J = 1.8 Hz, 1H), 4.65 (s, 2H);
13 C NMR (75 MHz, DMSO-d6)? 166.4, 161.4, 158.9, 154.1, 153.0, 134.9, 131.3, 121.5, 117.8, 115.2, 105.9, 100.1, 48.5
(3) Kratosevin Preparation of B compound
A 48% aqueous solution of bromic acid (10 ml) and acetic acid (20 ml) were added to the compound (2.0 g, 7.0 mmol) prepared in the above (1) and the mixture was heated under reflux for 18 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The organic layer was then purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain the target compound clitosybinine B compound 0.76 g, 40%).
1 H NMR (300MHz, DMSO- d6) δ 9.85 (s, 1H), 9.36 (s, 1H), 7.62 (d, J = 9.3 Hz, 2H), 6.78 (d, J = 9.3 Hz, 2H), 6.67 (d, J = 1.8 Hz, 1H), 6.63 (d, J = 1.8 Hz, 1H), 4.70 (s, 2H), 3.84 (s, 3H);
13 C NMR (75 MHz, DMSO-d 6)? 166.0, 159.3, 154.9, 154.1, 134.7, 131.2, 121.5, 119.0, 115.2, 102.5, 100.5, 55.4, 48.3.
<Structural Analysis>
The physicochemical properties of the compounds obtained in Examples 1 and 2 were measured as follows.
Optical rotation was measured using a polarizer (JASCO DIP-370 polarimeter). The ultraviolet absorption spectrum was measured with an ultraviolet spectrophotometer (Shimadzu UV-260 spectrophotometer, Japan), and the infrared absorption spectrum was measured with an ultraviolet spectrophotometer (FT-IR Equinox 55 spectrometer, Burker, USA). The molecular structure of the HR-ESI-MS spectrum was determined by using a mass spectrometer (JEOL JMS HX-110 mass spectrometer, JEOL, Japan).
The measurement results are shown in Table 1.
Calculated: 258.07608
Calculated: 272.0923
Calculated: 286.1079
As shown in Table 1, the crytosybin A compound according to the present invention was obtained as a light brown powder, and the value of (M + H + ) as a result of high-resolution ESI-MS analysis was 258.07758 m / z, and the molecular formula was determined to be C 14 H 11 O 4 N. As a result of measurement of UV spectrum, maximum absorption wavelength was shown at 211 nm and 286 nm. As a result of IR spectroscopy, a band due to a hydroxyl group was observed at 3399 cm -1 . As a result, the chrythosybin A compound was identified as a novel isoindolone compound.
The klyitasibin B compound according to the present invention was obtained as a pale yellow powder and the value of (M + H + ) from the high-resolution ESI-MS analysis was 272.0923 m / z, which was in agreement with the calculated value 272.0923 m / z the molecular formula was determined to be C 15 H 13 O 4 N. As a result of measurement of UV spectrum, maximum absorption wavelength was shown at 211 nm and 286 nm. As a result of IR spectroscopy, a band due to a hydroxyl group was observed at 3399 cm -1 . Accordingly, the clitosybin B compound was identified as a novel isoindolone compound.
The krytosybin C compound according to the present invention was obtained as a pale yellow powder, and the value of (M + H + ) from the high-resolution ESI-MS analysis was 286.1079 m / z, which corresponds to 286.1079 m / z The molecular formula was determined as C 16 H 15 O 4 N. As a result of measurement of UV spectrum, maximum absorption wavelength was shown at 211 nm and 286 nm. As a result of IR spectroscopy, a band due to a hydroxyl group was observed at 3399 cm -1 . As a result, the clitosibin C compound was identified as a novel isoindolone compound.
Further, 1 H and 13 C NMR, HMHC ((1H-detected heteronuclear Multiplier-Quantum Coherence) of z-crythosybin A to C compounds were measured through nuclear magnetic resonance (NMR) analysis (Burker AMX 300, , And HMBC (Heteronuclear Multiple-Bond Cohence) spectra were obtained.
(position)
& Lt; 1 > H NMR: 600 MHz
≪ 13 > C NMR: 150 MHz
< Example 3> Crytha tobin Identification of anti-inflammatory activity of derivatives
<3-1> Krytocytobin Treatment of Derivatives
In order to examine the anti-inflammatory activity of the clitosybin derivative of the present invention through the IFN-? And IL-10 inhibitory activity, NK92 cells treated with the clitosybin A prepared in the above example were treated with IFN-? And IL -10. ≪ / RTI > Specifically, 5.0 × 10 5 cells / ml of NK92 cells (human type NK lymphoma) (American type culture collection, American type culture collection), an IFN-γ-dependent natural killer cell line, were cultured in a 48 well culture plate with 20% fetal bovine serum fetal calf serum (HyClone, Logan, UT, USA), 2 mM L-glutamate, 100 ug ml -1 penicillin, 100 ㎍ ml -1 streptomycin (Life Technologies) ㎖ -1 in the α-MEM medium containing IL-2 (Chiron, Emeryville, CA, USA), and cultured at 37 ℃ and 5% CO 2 humidity environment. NK92 cells cultured in this manner were treated with various concentrations (4, 20, 100 or 400 μM) of clitosybin A. At this time, NK92 cells were cultured in the negative control group, and positive control group was induced by using 100
<3-2> IFN Quantification of -γ
Quantification of human IFN-y was performed according to the manufacturer's protocol using commercially available mAb pairs (Endogen, Woburn, Mass., USA). To induce inflammation at 37 DEG C for 18 hours, the NK92 cells were treated with 500 ng of P-10 together with clitosybin A, and then the supernatant was obtained except for the cells, and the enzyme immunoassay (Enzyme Linked Immunosorbent Assay , ELISA) kit was used to detect IFN- ?. The results are expressed as the mean value of 3 repeated wells ± s.e.m.
As a result, as shown in Fig. 1, the production of IFN-y was suppressed in NK92 cells treated with clitosybin A, which is a significantly lower amount of IFN-γ than that of inflammation-induced positive control , And concentration-dependent (Fig. 1). Thus, it was confirmed that clitosybin A significantly inhibited IFN-y production in NK cells.
<3-3> IL Quantity of -10
Quantification of human IL-10 was performed according to the manufacturer's protocol using commercially available mAbs pairs (Endogen, Woburn, MA, USA). IL-10 was detected using an Enzyme Linked Immunosorbent Assay (ELISA) kit after treating the NK92 cells with clitosybine A at 37 DEG C for 18 hours and then obtaining supernatants except for cells . The results are expressed as the mean value of 3 repeated wells ± s.e.m.
As a result, as shown in FIG. 2, the production of IL-10 was suppressed in NK92 cells treated with clitosybin A, which is significantly lower than that of the inflammation-induced positive control , And concentration-dependent (FIG. 2). Thus, it was confirmed that clitosybin A significantly inhibited the production of IL-10 in NK cells.
< Manufacturing example 1> Preparation of pharmaceutical preparations
<1-1> Sanje Produce
2 g of the chrythosybin derivative of Example 1 of the present invention
Lactose 1 g
The above components were mixed and packed in airtight bags to prepare powders.
<1-2> Preparation of tablets
100 mg of the chrythosybin derivative of Example 1 of the present invention
Corn starch 100 mg
100 mg of milk
2 mg of magnesium stearate
After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.
≪ 1-3 > Preparation of capsules
100 mg of the chrythosybin derivative of Example 1 of the present invention
Corn starch 100 mg
100 mg of milk
2 mg of magnesium stearate
After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.
≪ 1-4 >
1 g of the crythosybin derivative of Example 1 of the present invention
Lactose 1.5 g
Glycerin 1 g
0.5 g of xylitol
After mixing the above components, they were prepared so as to be 4 g per one ring according to a conventional method.
<1-5> Preparation of granules
150 mg of the chrythosybin derivative of Example 1 of the present invention
Soybean extract 50 mg
200 mg of glucose
600 mg of starch
After mixing the above components, 100 mg of 30% ethanol was added and the mixture was dried at 60 캜 to form granules, which were then filled in a capsule.
< Manufacturing example 2> Manufacture of cosmetics
A cosmetic for preventing and improving an inflammatory disease containing the krytothiamine derivative of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be produced. The inventors of the present invention prepared cosmetic products of emulsified form such as nutritional lotion, cream, essence and the like, and cosmetics of solubilized form such as softened longevity.
<2-1> Cosmetic manufacturing of emulsified formulations
An emulsifier-type cosmetic was produced in the composition shown in the following [Table 3]. The production method is as follows.
1) A mixture of raw materials 1 to 9 was heated to 65 to 70 占 폚.
2) The starting material of 10 was added to the mixture of step 1).
3) The mixture of raw materials 11 to 13 was completely dissolved by heating at 65 to 70 ° C.
4) Through the above step 3), the mixture of 2) was gradually added and emulsified at 6,000 rpm for 2 to 3 minutes.
5) The raw material of 14 was dissolved in a small amount of water and then added to the mixture of step 4) and further emulsified for 2 minutes.
6) The raw materials of 15 to 17 were each weighed, and then the mixture of step 5) was further emulsified at 40 DEG C for 30 seconds.
7) The mixture of step 6) was degassed after emulsification and cooled to 25-35 ° C to prepare an emulsifier-type cosmetic.
Monolauric acid ester
<2-2> Solubilization Cosmetic manufacturing of formulations
Cosmetic products of the solubilized formulations were prepared with the compositions shown in the following [Table 4]. The production method is as follows.
1) 2 to 6 raw materials were put into 1 raw material (purified water) and dissolved using a mixer.
2) Raw materials 8 to 11 were completely dissolved in 7 raw materials (alcohol).
3) The mixture of step 2) was slowly solubilized by adding it to the mixture of step 1).
Hydro genide ester
< Manufacturing example 3> Manufacture of external skin preparation
<3-1> Production of cream
Cetostearyl alcohol 2.8 parts by weight
2.6 parts by weight
Stearic acid 1.4 parts by weight
Glycerin monostearate 2 parts by weight
≪ tb > < tb >
Sorbitol sesquioleate 1.4 parts by weight
Jojoba oil 4 parts by weight
Squalane 3.8 parts by weight
Polysorbate 60 1.1 parts by weight
Macadia oil 2 parts by weight
Tocopheryl acetate 0.2 part by weight
Methylpolysiloxane 0.4 part by weight
Ethylparaben 0.1 part by weight
Propylparaben 0.1 part by weight
Euxyl K-400 0.1 part by weight
1,3-butylene glycol 7 parts by weight
Methylparaben 0.05 part by weight
Glycerin 6 parts by weight
d-Pandenol 0.2 part by weight
4.6 parts by weight of chrythosybin derivative
Triethanolamine 0.2 part by weight
pt 41891 0.2 part by weight
pH 2 O 46.05 parts by weight
<3-2> Production of Lotion
Cetostearyl alcohol 1.6 parts by weight
Stearic acid 1.4 parts by weight
Glycerin monostearate of pro-type 1.8 parts by weight
≪ tb > < tb >
Sorbitol sesquioleate 0.6 parts by weight
Squalene 4.8 parts by weight
Macadia oil 2 parts by weight
Jojoba oil 2 parts by weight
Tocopheryl acetate 0.4 part by weight
0.2 part by weight of methylpolysiloxane
Ethylparaben 0.1 part by weight
Propylparaben 0.1 part by weight
4 parts by weight of 1,3-butylene glycol
0.1 part by weight of methylparaben
Xanthan gum 0.1 part by weight
Glycerin 4 parts by weight
d-Pandenol 0.15 part by weight
Allantoin 0.1 part by weight
3.5 parts by weight of chrythosybin derivative
Cargar (2% aq. Sol) 4 parts by weight
Triethanolamine 0.15 part by weight
Ethanol 3 parts by weight
pt 41891 0.1 part by weight
pH 20 48.3 parts by weight
< Manufacturing example 4> Manufacturing of food
Foods comprising the krytotasybin derivative of the present invention or a pharmaceutically acceptable salt thereof were prepared as follows.
<4-1> Production of flour food
0.5-5.0 parts by weight of the krytothiamine derivative of the present invention or a pharmaceutically acceptable salt thereof is added to wheat flour, and the mixture is used to prepare bread, cake, cookies, crackers and noodles.
<4-2> soup And juicy ( gravies )
0.1 to 5.0 parts by weight of the chrythosybin derivative of the present invention or a pharmaceutically acceptable salt thereof is added to soups and gravies to prepare meat products for health promotion, soups of noodles and juices.
<4-3> Ground Beef Produce
10 parts by weight of the chrythosybin derivative of the present invention or a pharmaceutically acceptable salt thereof was added to ground beef to prepare ground beef for health promotion.
<4-4> Dairy products ( dairy products )
5-10 parts by weight of the krytothiamine derivative of the present invention or a pharmaceutically acceptable salt thereof is added to milk, and a variety of dairy products such as butter and ice cream are prepared using the milk.
<4-5> Solar Produce
Brown rice, barley, glutinous rice, and yulmu were dried by a known method and dried, and the mixture was granulated to a powder having a particle size of 60 mesh.
Black soybeans, black sesame seeds, and perilla seeds were steamed and dried by a conventional method, and then they were prepared into powder having a particle size of 60 mesh by a pulverizer.
The krytothybene derivative of the present invention or its pharmaceutically acceptable salt was concentrated under reduced pressure in a vacuum concentrator, dried by spraying, and dried with a hot air drier, and the dried product was pulverized to a size of 60 mesh with a pulverizer to obtain a dried powder.
The grains, seeds and krytothiabine derivatives or pharmaceutically acceptable salts thereof prepared above were blended in the following proportions.
(30 parts by weight of brown rice, 15 parts by weight of yulmu, 20 parts by weight of barley)
Seeds (7 parts by weight of perilla, 8 parts by weight of black beans, 7 parts by weight of black sesame seeds)
(3 parts by weight) of a crytosybin derivative or a pharmaceutically acceptable salt thereof,
(0.5 part by weight),
(0.5 parts by weight)
< Manufacturing example 5> Manufacturing of beverages
<5-1> Health drink Produce
(Such as liquid fructose (0.5%), oligosaccharide (2%), sugar (2%), salt (0.5%) and water (75%) and the creatocybin derivatives of the present invention or their pharmaceutically acceptable salts 5 g were uniformly blended and sterilized in an instant, and then packaged in glass bottles and plastic bottles.
<5-2> Preparation of vegetable juice
Vegetable juice was prepared by adding 5 g of the chrythosybin derivative of the present invention or a pharmaceutically acceptable salt thereof to 1,000 ml of tomato or carrot juice.
<5-3> Preparation of fruit juice
A fruit juice was prepared by adding 1 g of the clitosybin derivative of the present invention or a pharmaceutically acceptable salt thereof to 1,000 ml of apple or grape juice.
Claims (9)
[Chemical Formula 1]
.
Wherein R 1 and R 2 are independently or alternatively OCH 3 or OH.
[Formula 1a]
,
[Chemical Formula 1b]
, And
[Chemical Formula 1c]
.
1) A large mushroom ( Hygrophoropsis aurantiaca ) to obtain a culture;
2) extracting the obtained culture with acetone and ethyl acetate;
3) extracting the extracted extract by concentration gradient silica gel column chromatography using a mixed solvent of chloroform and methanol to obtain an active fraction; And
4) Performing sephadex LH-20 column chromatography using the above active fraction as a solvent in methanol (100%) to obtain a compound of formula (1) Or prophylaxis and treatment of inflammatory diseases.
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105348171A (en) * | 2015-12-08 | 2016-02-24 | 彭冬青 | Pharmaceutical composition for treating knee osteoarthritis |
-
2013
- 2013-04-19 KR KR1020130043749A patent/KR20140125655A/en not_active Application Discontinuation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105348171A (en) * | 2015-12-08 | 2016-02-24 | 彭冬青 | Pharmaceutical composition for treating knee osteoarthritis |
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