WO2013187576A1 - Composition comprising silymarin as active ingredient for preventing and treating peptic ulcers caused by alcohol consumption - Google Patents

Composition comprising silymarin as active ingredient for preventing and treating peptic ulcers caused by alcohol consumption Download PDF

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Publication number
WO2013187576A1
WO2013187576A1 PCT/KR2013/001377 KR2013001377W WO2013187576A1 WO 2013187576 A1 WO2013187576 A1 WO 2013187576A1 KR 2013001377 W KR2013001377 W KR 2013001377W WO 2013187576 A1 WO2013187576 A1 WO 2013187576A1
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Prior art keywords
silymarin
gastric
pharmaceutically acceptable
acceptable salt
gastric ulcer
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PCT/KR2013/001377
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French (fr)
Korean (ko)
Inventor
강종순
신정휴
이창우
김형진
오수진
윤지은
Original Assignee
한국생명공학연구원
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Publication of WO2013187576A1 publication Critical patent/WO2013187576A1/en

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    • 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
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • Alcoholic gastric ulcer prevention and treatment composition comprising silymarin as an active ingredient
  • the present invention relates to a composition for preventing and treating alcoholic gastric ulcer, comprising silymarin (Silymarin) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Silymarin is a flavonoid compound derived from S // y /? Marianu, a fruit belonging to the Asteraceae family, and silymarin is si lybin, silidianin, and sily icristin. It consists of three main components, and contains a variety of flavonoids such as dehydrosilybin.
  • the plant is native to Southern Europe and North Africa, but later settled in the Americas and is now grown for ornamental and medicinal purposes. Thistle is a plant known from the milk mothers to drink milk thistle tea in order to make it milk well. Also, a German natural therapist Rademarker has shown that thistle has excellent effects on liver and gallbladder disease and jaundice. Discovered and began to become more famous after that.
  • pylori is a gastric mucosa Gram-negative bacillus inhabiting epithelial intercellular junctions, the optimum pH is 7.07.4 and grows in an aerobic condition of 3037. When these conditions are not stratified or environmental changes occur, changes in the form of coccoids are observed. do. Its pathogenic factors include strong urease production, which is the most representative feature, and flagella, which allows adhesion and migration to the gastric mucosa layer, as well as Vag A, Cag A, and lipopolysaccharad ( Cytotoxins, including lipopolysaccharides, have been studied.
  • Alcoholic gastric ulcer is one of the essential diseases in modern people. People are going through. In particular, in addition to social stress, frequent intake of alcohol is accompanied by severe gastric ulcers and liver disease, and many medicines and functional foods are being sold to improve this. In other words, efforts are being made to lower alcohol blood levels by activating ADH and ALDH. However, there are few effective substances that show significant detoxification effects by activating enzymes in a short period of time.
  • a gastric ulcer therapeutic agent such as pantoprazole, which is a hydrogen ion pump inhibitor, is effective for gastric ulcers caused by other causes, but is less effective in alcoholic gastric ulcers.
  • Known therapeutic agents for gastric ulcers include hydrogen transfer pump inhibitors that block acid secretion from wall cells, antacids, histamine receptors for promoting acid secretion (H2-ant agonists), and mucin layer enhancers (PGs) Derivatives and antibiotics that can eradicate Helicobacter pylori are typical.
  • silymarin can be used to treat alcoholic gastric ulcers. Accordingly, the present inventors confirmed that treatment with silymarin or its pharmaceutically acceptable salts is effective in reducing the gastric injury area of the ethanol-induced gastric ulcer model animal, improving gastric mucus volume, and is involved in the NP-SH part as a result of NEM pretreatment.
  • the present invention was completed by revealing that the amount of NP-SH is recovered, and that the effect of inhibiting gastric ulceration after N-NAME pretreatment is reduced, thereby being useful for preventing or treating the gastric ulcer caused by excessive drinking. It was.
  • the present invention provides a pharmaceutical composition for the prevention and treatment of gastric injury, gastric ulcer or gastrointestinal disease induced by alcohol containing Silymarin or a pharmaceutically acceptable salt thereof as an active ingredient. do.
  • the present invention provides a health food for the prevention and improvement of gastric damage, gastric ulcer or gastrointestinal diseases induced by alcohol containing silymarin or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a method for the treatment of gastric injuries, gastric ulcers or the like, comprising administering an effective amount of silymarin or a pharmaceutically acceptable salt thereof to an individual suffering from alcohol-induced gastric injury, gastric ulcer or gastrointestinal disease. It provides a method of treating gastrointestinal diseases.
  • the present invention also provides a method for the prevention of gastric injury, gastric ulcer or gastrointestinal disease induced by alcohol, comprising administering to a subject an effective amount of silymarin or a pharmaceutically acceptable salt thereof.
  • the present invention also provides silymarin or a pharmaceutically acceptable salt thereof for use in a composition for the prevention, amelioration or treatment of alcohol-induced gastric injury, gastric ulcer or gastrointestinal disease.
  • the present invention also provides the use of an effective amount of silymarin or a pharmaceutically acceptable salt thereof for the preparation of a composition for the prevention, amelioration or treatment of gastric injury, gastric ulcer or gastrointestinal disease induced by alcohol.
  • the present invention relates to the treatment of silymarin or its pharmaceutically acceptable salts to reduce gastric damage induced by ethanol, to recover gastric mucus, to partially involve or restore the amount of silymarin and to inhibit the amount of gastric ulcers.
  • the composition comprising the silymarin or its pharmaceutically acceptable salt is excessive It may be useful for preventing or treating the stomach ulcer caused by drinking or the like for the pharmaceutical composition and health food.
  • Figure 1 is a gastric ulcer-induced model administered with ethane in the rat, after the pretreatment of silymarin and stilin, a positive control for each concentration, the area of gastric injuries is reduced as a result of confirming gastric area damage.
  • Figure 2 is a diagram showing that the amount of gastric mucus leans the result of measuring the amount of recovery of gastric mucus according to the pretreatment of silymarin by concentration in the ethanol-induced gastric ulcer model.
  • 3 is a diagram showing that the effect of inhibiting gastric ulceration by silymarin is reduced when pretreatment by concentration of NEM to determine the mechanism for the ethanol-induced gastric ulcer of silymarin.
  • Figure 4 shows that the ethanol-induced gastric mucosa model was significantly reduced as a result of the presence of gastric mucosa and the measure of damage to NP-SH, but the amount of NP-SH is recovered as a result of silymarin treatment.
  • FIG. 5 is a diagram showing that the effect of gastric ulceration by silymarin is reduced when L-NAME, an inhibitor of nitric oxide producing enzyme, is pretreated in ethanol-induced gastric ulcer.
  • the present invention provides a pharmaceutical composition for the prevention and treatment of gastric injury, gastric ulcer or gastrointestinal disease induced by alcohol containing Silymarin or a pharmaceutically acceptable salt thereof as an active ingredient.
  • silymarin is a compound represented by the following [Formula 1].
  • the chemical name is
  • the silymarin was determined by measuring the area of the gastric injury site after treating styrene according to the concentration of styrene used in the ethanol-induced gastric ulcer animal rat and styrene widely used as a therapeutic agent for gastric ulcer as a positive control. When pretreatment was performed, it was confirmed that the gastric damage area was reduced in a concentration-dependent manner (see FIG. 1).
  • NP-SH As a result of checking the effect of silymarin treatment on the NP-SH level, NP-SH was significantly reduced when ethane was administered to induce gastric injuries, but when silymarin was treated, the concentration of NP-SH was recovered ( See FIG. 4).
  • the effect of pretreatment of L-NG-nitroarginine methyl ester on the inhibition of silymarin on ethanol-induced gastric ulcer was confirmed that the pretreatment of LN ⁇ E decreased the effect of silymarin on gastric ulcer inhibition. It was confirmed that nitric oxide was partially involved in the gastric ulcer inhibitory effect (see FIG. 5). According to the above results it can be usefully used as a pharmaceutical composition for the prevention and suppression of gastric injury, gastric ulcer or gastrointestinal diseases induced by alcohol containing silymarin or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the silymarin compound according to the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and Obtained from non-toxic organic acids such as alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • These pharmaceutically toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrile 0 phosphate, monohydrogen phosphate, dihydrogen phosphate 0 ⁇ metaphosphate, pyrophosphate chloride, bromide , Iodine o fluoride, acetate, propionate, decanoate, capryl o acrylate, formate, isobutyrate, caprate, heptano o o propirate, oxalate, malonate, succinate, subverate , Sebacque o fumarate, maleate ⁇ butine -1,4-dioate, nucleic acid -1,6-dioe o benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoe o hydroxybenzoate Oxybenzoate, phthalate, terephthale o benzenesulfonate, toluen
  • the acid addition salts according to the invention are prepared by conventional methods, for example, by dissolving the silymarin compound in an excess of an aqueous solution of an acid, using the salt with a miscible organic solvent such as methanol, ethane, acetone or acetonitrile. This mixture may be prepared by evaporation of a solvent or excess acid, followed by drying, or by precipitation filtration of the precipitated salt.
  • a miscible organic solvent such as methanol, ethane, acetone or acetonitrile.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the compound salt at no cost, and evaporating and drying the filtrate.
  • the metal salt it is pharmaceutically suitable to prepare sodium, potassium, or chamomile salt.
  • Corresponding silver salts are also obtained by reacting an alkali or alkaline earth metal salt with a suitable silver salt (eg silver nitrate).
  • Silymarin compounds according to the invention include not only pharmaceutically acceptable salts thereof, but also isomers thereof or possible solvates or hydrates that may be prepared therefrom.
  • silymarin compound according to the present invention may be commercially available or synthesized using conventional synthetic methods known in the art of organic synthesis.
  • the silymarin compound or a pharmaceutically acceptable salt thereof according to the present invention reduces the gastric damage induced by ethanol, restores the amount of gastric mucus, partially participates in or restores the amount of silymarin and NP-SH which has an inhibitory effect on gastric ulcer. By confirming that nitric oxide is involved in gastric ulcer inhibitory effect, it can be usefully used for preventing or treating gastric ulcer.
  • the pharmaceutical composition containing the silymarin compound or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient may be formulated in various oral or parenteral dosage forms as follows, but is not limited thereto.
  • Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and the like.
  • One or more diluents or excipients such as layering agents, extenders, wetting agents, disintegrating agents, lubricants, binders, surfactants, and the like can be used.
  • Agar, starch, alginic acid or its sodium salt, calcium monohydrogen phosphate salt, etc. may be used as the boron , release agent, and silica, talc, stearic acid or its magnesium salt or calcium salt, polyethylene glycol, etc. may be used as a lubricant.
  • a binding agent is a magnesium aluminum silicate, starch paste, gelatin
  • Tra is such kanseu, methyl selreul as agarose, sodium carboxymethylcellulose selreul agarose, a polyvinylidene blood, low-substituted hydroxy propyl selreul agarose can be used, .
  • lactose, text, ossuose sucrose, manny, sorbide, cellulose, glycine and the like can be used as a diluent, and in some cases, commonly known boiling mixture absorbers, colorants, flavors, sweeteners, etc. Can be used together.
  • composition can be administered parenterally, parenteral administration is by the method of injecting subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.
  • silymarin compound or a pharmaceutically acceptable salt thereof is mixed in water together with a stabilizer or a laxative to prepare a formulation for parenteral administration in water or as a solution or suspension, which is in unit dosage form of 3 ⁇ 4ple or vial. It can manufacture.
  • the pharmaceutical composition according to the present invention may be sterilized or contain preservatives, stabilizers, hydrating or emulsifiers, salts for controlling osmotic pressure, adjuvant such as buffers, and other therapeutically useful substances. It can be formulated according to the method of mixing, granulation or coating. If necessary, the additive composition according to the present invention may be combined with other drugs, for example, other therapeutic agents. It may also be administered.
  • composition according to the present invention may further include suitable carriers, excipients and diluents commonly used in the manufacture of a medicament.
  • composition according to the invention formulated into powders, granules, jeongge, capsules, suspensions, emulsions, syrups, oral dosage form for external application, in the form of a suppository, and sterile injection solution, such as an aerosol in a usual manner, respectively Can be used.
  • Carriers, excipients, and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbbi, manny, xili, erythri, maltyl, starch, acacia rubber, alginate, gelatin, Calcium phosphate, calcium silicate, cellulose, methyl cellulose microcrystalline cellulose, polyvinyl pyridone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and the solid preparations include at least one excipient in the composition of the present invention, for example, calcium carbonate, sucrose ( sucrose) or lactose, gelatin and the like are mixed. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral use include suspensions, solvents, emulsions, and syrups.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used.
  • the active ingredient contains a silymarin compound or a pharmaceutically acceptable salt thereof in a unit dose of about 0.1 to 1,500 mg. Dosage depends on the doctor's prescription depending on factors such as the patient's weight, age and the specific nature and severity of the disease. However, the dosage required for adult treatment typically ranges from about 1 to 500 mg per day, depending on the frequency and intensity of administration. Intramuscular or intravenous administration to adults will be divided into single doses, usually at a total dosage of about 5 to 300 mg per day, but a higher daily dose may be desirable for some patients.
  • the preferred dosage of the pharmaceutical composition according to the present invention depends on the condition and the condition of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected by those skilled in the art.
  • the composition of the present invention is preferably administered at 0.00 to 0.03 g / kg, preferably 0.0 to 8 mg / kg per day. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect.
  • the present invention provides a health food for the prevention and improvement of gastric damage, gastric ulcer or gastrointestinal diseases induced by alcohol containing silymarin or a pharmaceutically acceptable salt thereof as an active ingredient.
  • silymarin is a compound represented by the following [Formula 1].
  • the chemical name is
  • the silymarin compound or a pharmaceutically acceptable salt thereof according to the present invention enjoys gastric damage induced by ethanol, restores gastric mucus volume, partially participates in or restores the amount of NP—SH having an inhibitory effect of gastric ulcer, and By confirming that nitric oxide is involved in the gastric ulcer inhibitory effect of silymarin, alcoholic gastric ulcer prevention and improvement health foods can be usefully used in the composition.
  • alcoholic gastric ulcer prevention and improvement health foods can be usefully used in the composition.
  • Silymarin or a pharmaceutically acceptable salt thereof of the present invention may be added to a food as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method.
  • the mixed amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement).
  • the amount of the extract in the health food can be added to 0.1 to 90 parts by weight of the total food weight.
  • the amount may be below the above range.
  • the active ingredient since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
  • the functional beverage composition of the present invention contains the extract as an essential ingredient in the indicated ratio.
  • the other ingredients may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And sugars such as conventional sugars such as polysaccharides such as dextrin, cyclodextrin and the like, and xylyl, sorbitol, erythritol and the like.
  • natural flavoring agents tautin, stevia extract (e.g., Rebaudioside A, glycyrrhizin, etc.) and synthetic flavorings (saccharin, aspartame, etc.) can be advantageously used.
  • the proportion of natural carbohydrates is generally about 1 to 20 g, preferably about 5 to 12 g per 100 compositions of the present invention.
  • the silymarin or a pharmaceutically acceptable salt thereof of the present invention may contain various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, and flavors, colorants and neutralizers (such as cheese and chocolate). And salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like.
  • the extract of the present invention may contain a fruit flesh for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components can be used independently or in combination.
  • the present invention provides a method for the treatment of gastric injuries, gastric ulcers or It provides a method of treating gastrointestinal diseases.
  • the present invention also provides a method for the prevention of gastric injury, gastric ulcer or gastrointestinal disease induced by alcohol, comprising administering to a subject an effective amount of silymarin or a pharmaceutically acceptable salt thereof.
  • the present invention also provides silymarin or a pharmaceutically acceptable salt thereof for use in a composition for the prevention, amelioration or treatment of alcohol-induced gastric injury, gastric ulcer or gastrointestinal disease.
  • the present invention also provides the use of an effective amount of silymarin or a pharmaceutically acceptable salt thereof for the preparation of a composition for the prevention, amelioration or treatment of gastric injury, gastric ulcer or gastrointestinal disease induced by alcohol.
  • an effective amount of silymarin or a pharmaceutically acceptable salt thereof for the preparation of a composition for the prevention, amelioration or treatment of gastric injury, gastric ulcer or gastrointestinal disease induced by alcohol.
  • the following Examples, Experimental Examples and Preparation Examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following Examples, Experimental Examples, and Preparation Examples.
  • the following Examples, Experimental Examples and Preparation Examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following Examples, Experimental Examples, and Preparation Examples.
  • Example 1 Isolation and Identification of Silymarin
  • Example 1 Five male SD (Spr ague-Daw ley) rats (Cortech, Korea) at 7 weeks of age were fasted for 36 hours with 1 group, and then the silymarin prepared in Example 1 was 25 , 50, 100, 200 mg / kg orally and 30 minutes later, 1 ml of 100% ethanol (ethanol) and fasted water saving for 1 hour After letting it die for co 2 .
  • ligation of the pylorus and esophagus put 10 ml of 2% formalin solution in the stomach, fix it for 10 minutes, and incision of the Taiwanese section, photographing the damaged area with a digital camera. The total was taken as the damage index as measured in (Image-Pro Plus 4.5.1). Damage area is expressed as 3 ⁇ 4> of the total distal area. Stillene was used as a control drug.
  • the gastric ulceration mechanism by ethanol promotes gastric mucosal permeability and inhibits active transport, causing gastric injury.
  • the stomach secretes a protective fluid to protect the mucosal layer.
  • the normal control group had a 235,000 mg / g tissue of Alcian blue, while the solvent control group had a mucus reduction of 161.3 mg / g tissue.
  • silymarin was treated at concentrations of 100 mg / kg and 200 mg / kg, mucus recovered to 200.7 mg / g tissue and 227.9 mg / g tissue, respectively.
  • gastric mucus recovers in a concentration-dependent manner when treated with silymarin (FIG. 2).
  • NP-SH including glutathione
  • glutathione is abundant in the gastrointestinal mucosa and is known as a measure of the presence and extent of gastric mucosal damage. Thus, the effect of silymarin treatment on the amount of NP-SH was confirmed.
  • the amount of NP-SH was reduced to 252.2 mg / g tissue in the normal group, while the amount of NP-SH was reduced to 60.6 mg / g in the solvent control group.
  • silymarin was treated at 100 mg / kg and 200 mg / kg concentrations, the mucus recovered to 113.4 mg / g tissue and 160.6 mg / g tissue, respectively. Although significantly reduced, it was confirmed that the amount of NP-SH was recovered when the silymarin was treated (concentration 4).
  • Nitric oxide is known to have a function of protecting gastric damage by participating in blood flow and vasodilation of the gastrointestinal tract.
  • L-NG-nitroarginine methyl The effect of ester pretreatment on the inhibition of silymarin on ethanol induced gastric ulcer was confirmed.
  • the capsule was prepared by filling in gelatin capsule according to a conventional method for preparing capsules.
  • Silymarin was added to 0.5-5.0 parts by weight of wheat flour, and the mixture was used to prepare bread, cakes, cookies, crackers and noodles to prepare health promoting foods.
  • Silymarin was added to 5 to 10 parts by weight of milk, using the milk to prepare a variety of dairy products such as butter and ice cream.
  • Brown rice, barley, sesame rice, and yulmu were alphad by a known method, and then dried and roasted to prepare a powder having a particle size of 60 mesh.
  • Black beans, black sesame seeds, and sesame seeds were also steamed and dried by a known method, and then ground to a powder having a particle size of 60 mesh.
  • Silymarin was concentrated under reduced pressure in a vacuum concentrator; the dried product obtained by spraying and drying with a hot air dryer was pulverized with a particle size of 60 mesh using a grinder to obtain a dry powder.
  • Cereals (30 parts by weight brown rice, 15 parts by weight brittle, 20 parts by weight of barley) ,
  • Seeds (7 parts by weight perilla, 8 parts by weight black beans, 7 parts by weight black sesame seeds),
  • Vitamin B6 0.5 nig
  • Vitamin B12 0.2 / g
  • composition ratio of the above vitamin and mineral mixture is relatively
  • the ingredients are mixed in a preferred embodiment, the blending ratio may be arbitrarily modified.
  • the above ingredients are mixed according to a conventional health food manufacturing method, then granules are prepared and a health food composition is prepared according to a conventional method. Can be used for
  • the above ingredients were mixed according to the method of preparing 500 general health drinks, and then stirred and heated at 85 ° C. for about 1 hour, and then the resulting solution was filtered and obtained in a sterilized 1 f container and sealed and sterilized. It is then used to prepare the health beverage composition of the present invention.
  • composition ratio is a combination of relatively suitable components for a preferred beverage in a preferred embodiment
  • the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as the demand hierarchy, the country of use, the intended use.
  • the present invention is not limited to the embodiments, experimental examples, and preparation examples described above, and various modifications and changes may be brought by those skilled in the art, and the present invention is defined in the spirit and scope of the present invention as defined in the appended claims. Included. Industrial Applicability
  • the present invention is a composition containing silymarin or a pharmaceutically acceptable salt thereof may be useful for the development of pharmaceutical compositions and health foods for preventing or treating gastric ulcers or gastrointestinal diseases caused by excessive drinking. Can be.

Abstract

The present invention relates to a composition containing silymarin or a pharmaceutically acceptable salt thereof as an active ingredient for inhibiting peptic ulcers caused by alcohol consumption. More particularly, by determining that silymarin reduces gastric damage caused by ethanol, recovers an amount of gastric mucus, and is partially involved in recovering an amount of NP-SH which has the effect of inhibiting peptic ulcers, and that nitric oxide is associated with the peptic ulcer inhibiting effects of silymarin, silymarin and a pharmaceutically acceptable salt thereof can be effectively used for a pharmaceutical composition or health food for preventing, alleviating, or treating peptic ulcers caused by excessive alcohol consumption.

Description

【명세서】  【Specification】
【발명의 명칭】  [Name of invention]
실리마린을 유효성분으로 포함하는 알콜성 위궤양 예방 및 치료용 조성물  Alcoholic gastric ulcer prevention and treatment composition comprising silymarin as an active ingredient
【기술분야】 Technical Field
실리마린 (Silymarin) 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 알콜성 위궤양 예방 및 치료용 조성물에 관한 것이다. 【배경기술】  The present invention relates to a composition for preventing and treating alcoholic gastric ulcer, comprising silymarin (Silymarin) or a pharmaceutically acceptable salt thereof as an active ingredient. Background Art
실리마린은 국화과에 속하는 엉경퀴 (S//y/? marianu )^ 열매에서 추출한 플라보노이드 (flavonoid)계 화합물로서 , 실리마린은 실리빈 (si lybin)， 리디아닌 (silidianin) 및 실리크리스틴 (si 1 icristin)의 3개의 주요성분으로 구성되어 있고， 디히드로실리빈 (dehydrosilybin)등의 다양한 폴라보노이드류가 포함되어 있다. 이 식물은 남유럽과 북아프리카가 원산지이나 이후께 아메리카 대륙에도 정착하여 현재는 관상용이나 약용으로 재배되고 있다. 예로부터 엉겅퀴는 젖을 먹이는 어머니들이 젖이 잘 나오도록 하기 위해서 엉겅퀴 차를 마시게 함으로써 알려진 식물이며， 또한 독일의 자연치료사인 라데마커라는 사람이 엉겅퀴가 간과 담낭의 질환 및 황달 등에 뛰어난 약효가 있음을 발견하여 그 이후로 더욱 유명해지기 시작했다. 현대에 와서도 실리마린은 간질환 치료의 보조요법제로서 이용되고 있으며 , 그 작용기작 또한 점차 밝혀지고 있다. 헬리코박터 필로리는 1983년 워렌 (Warren)과 마살 (Marshal 1 )에 의해 분리된 이래 (Lancet, 1983, 1， 1273-1275) 위염 및 위십이지장 궤양의 원인균으로 밝혀졌으며 (J. infect. Dis. , 1990, 161， 626-633； Am. J. Med. , 1991， 91, 566-572), 현재는 위암 발병 인자의 하나로서까지 인정되어 전세계적인 관심과 연구의 대상이 되고 있다. 헬리코박터 필로리 (H. pylori)는 위점막 상피 세포간 접합부에 서식하는 그램 음성의 간균으로서 최적 pH는 7.07.4이며 3037의 미호기적 조건에서 생장하는데 이러한 조건이 층족되지 못하거나 환경의 변화가 생기면 코코이드 (coccoid) 형태로의 변화가 관찰된다. 그 병원성 인자로는 가장 대표작인 특징인 강력한 우레아제 (urease) 생산능과 위점막 층에 대한 부착 및 이동을 가능하게 하는 플라젤라 (flagella) 등이 있으며 또한 Vag A, Cag A, 리포폴리사카라드 (lipopolysaccharide) 등을 포함하는 사이토톡신 (cytotoxin)이 연구되고 있다. Silymarin is a flavonoid compound derived from S // y /? Marianu, a fruit belonging to the Asteraceae family, and silymarin is si lybin, silidianin, and sily icristin. It consists of three main components, and contains a variety of flavonoids such as dehydrosilybin. The plant is native to Southern Europe and North Africa, but later settled in the Americas and is now grown for ornamental and medicinal purposes. Thistle is a plant known from the milk mothers to drink milk thistle tea in order to make it milk well. Also, a German natural therapist Rademarker has shown that thistle has excellent effects on liver and gallbladder disease and jaundice. Discovered and began to become more famous after that. In modern times, silymarin has been used as an adjuvant therapy for the treatment of liver disease, and its mechanism of action has been gradually revealed. Helicobacter pylori has been shown to be the causative agent of gastritis and gastroduodenal ulcers since it was separated by Warren and Marshal 1 in 1983 (Lancet, 1983, 1, 1273-1275) (J. infect. Dis., 1990, 161, 626-633; Am. J. Med., 1991, 91, 566-572), which is now recognized as one of the causes of gastric cancer and has been the subject of worldwide interest and research. H. pylori is a gastric mucosa Gram-negative bacillus inhabiting epithelial intercellular junctions, the optimum pH is 7.07.4 and grows in an aerobic condition of 3037. When these conditions are not stratified or environmental changes occur, changes in the form of coccoids are observed. do. Its pathogenic factors include strong urease production, which is the most representative feature, and flagella, which allows adhesion and migration to the gastric mucosa layer, as well as Vag A, Cag A, and lipopolysaccharad ( Cytotoxins, including lipopolysaccharides, have been studied.
현재까지는 헬리코박터 필로리 (H. pylori)에 의한 소화기 질환의 예방 및 치료는 3중 화학요법 (triple chemotherapy)으로 대표되는 다양한 항생제에 의존하고 있으나 지속적 사용에 의한 내성균의 출현이나 재발병의 위험이 여전히 그 한계로 지적되고 있다. 이를 극복하기 위한 노력으로서 백신 (vaccine)의 개발을 위한 면역학적 방법이나 유산균을 이용한 접근 (J. Appl. Bacteriol . , 1995， 79， 475-479 ； J. Clin. Microbiol . , 1989, 27, 2328-2330) 등이 시도되고 있다. 최근에는 다양한 천연물 소재로부터 헬리코박터 필로리 (H. pylori)를 억제할 수 있는 활성 성분을 찾기 위한 노력이 지속되고 있다. 오오타 (Ohta)등은 마늘 추출물 (garlic extract)로부터 다양한 활성 물질을 분리 보고하였고 (Ant imicrob. Agents and Chemother.， 1999， 43， 1811—1812)， 마브 (Mabe) 등은 녹차 내의 카테킨 (catechin)류 화합물에 대하여 시험관 내 (in vitro)에서 뿐만 아니라 생체 내 (in vivo) 수준에서 헬리코박터 필로리 (H. pylori)억제능을 확인한 바 있다 (Ant imicrob. Agents and Chemother . , 1999, 43, 1788-1791). 이외에도 백리향 (J. Appl. Bacteriol . , 1996 80, 66그 672)이나 다양한 후라보노이드 (flavonoidsKArzneim.—Forsch. /Drug Res. , 1995， 45， 697-700)로부터도 강력한 활성이 보고되고 있다. 특히 , 최근에는 한방 소재로부터 활성 식물을 탐색하기 위한 노력이 일본과 한국을 중심으로 활발히 전개되고 있다 (J. Trad. Med., 1995, 12, 129-136；新藥^ 臨床 1997， 46， 49-53 ； Biol.Pharm. Bull. , 1998, 21, 990-992). 알콜성 위궤양은 현대인에 있어 빼놓을 수 없는 질환 중 하나로 많은 사람들이 겪고 있다. 특히 사회적 스트레스에 더해 빈번한 알콜의 섭취는 심각한 위궤양과 함께 간질환을 동반하는 경우가 많아 이를 개선하기 위한 많은 의약품과 건강기능성식품들이 판매되고 있다. 즉， ADH 및 ALDH를 활성화시켜 알콜 혈중농도를 낮추기 위한 노력이 집중적으로 이루어지고 있다. 하지만 단기간의 복용으로 효소를 활성화시켜 유의한 해독효과를 나타내는 효과적인 물질은 거의 찾아 볼 수 없다. 특히 수소 이온 펌프 억제제인 판토프라졸과 같은 위궤양 치료제의 경우에도 다른 원인에 의한 위궤양에는 효과적이지만 알콜성 위궤양에는 효과가 미약한 것으로 알려져 있다. To date, the prevention and treatment of gastrointestinal diseases by H. pylori is dependent on various antibiotics represented by triple chemotherapy, but the risk of the emergence or recurrence of resistant bacteria by continued use is still present. It is pointed out by the limitation. In an effort to overcome this, immunological methods for the development of vaccines or approaches using lactic acid bacteria (J. Appl. Bacteriol., 1995, 79, 475-479; J. Clin. Microbiol., 1989, 27, 2328 -2330). Recently, efforts have been made to find active ingredients that can inhibit H. pylori from various natural materials. Ohta et al. Reported the separation of various active substances from garlic extract (Ant imicrob. Agents and Chemother., 1999, 43, 1811—1812), and Mabe et al. Catechin in green tea. Helicobacter pylori inhibitory activity has been confirmed for both compounds in vitro as well as in vivo (Ant imicrob. Agents and Chemother., 1999, 43, 1788-1791). ). In addition, strong activity has been reported from thyme (J. Appl. Bacteriol., 1996 80, 66 672) and various flavonoids (flavonoids KArzneim.—Forsch./Drug Res., 1995, 45, 697-700). In particular, in recent years, efforts to search for active plants from herbal materials have been actively carried out mainly in Japan and Korea (J. Trad. Med., 1995, 12, 129-136; 新藥 ^ ， 1997, 46, 49- 53; Biol. Pharm. Bull., 1998, 21, 990-992). Alcoholic gastric ulcer is one of the essential diseases in modern people. People are going through. In particular, in addition to social stress, frequent intake of alcohol is accompanied by severe gastric ulcers and liver disease, and many medicines and functional foods are being sold to improve this. In other words, efforts are being made to lower alcohol blood levels by activating ADH and ALDH. However, there are few effective substances that show significant detoxification effects by activating enzymes in a short period of time. In particular, a gastric ulcer therapeutic agent such as pantoprazole, which is a hydrogen ion pump inhibitor, is effective for gastric ulcers caused by other causes, but is less effective in alcoholic gastric ulcers.
지금까지 알려진， 위궤양 치료제로는 벽세포로부터의 산 분비를 차단하는 수소 이은 펌프 억제제, 제산제 (antacids), 산 분비를 촉진시키는 히스타민의 수용체차단제 (H2-ant agonists), 뮤신층 강화제인 PGs와 그 유도체, 그리고 헬리코박터 파이로리를 근절할 수 있는 항생제류가 대표적이다.  Known therapeutic agents for gastric ulcers include hydrogen transfer pump inhibitors that block acid secretion from wall cells, antacids, histamine receptors for promoting acid secretion (H2-ant agonists), and mucin layer enhancers (PGs) Derivatives and antibiotics that can eradicate Helicobacter pylori are typical.
그러나 실리마린을 알콜성 위궤양의 치료에 사용될 수 있다는 보고는 없다. 이에， 본 발명자들은 실리마린 또는 이의 약학적으로 허용가능한 염 처리가 에탄올 유도 위궤양 모델 동물 위 손상 면적이 감소시키고， 위 점액량을 개선에 효과가 있으며， NEM 전처리 결과 NP-SH 일부에 관여함을 확인하였고， NP-SH 양을 회복하며， N-NAME 전처리 한 후 위궤양 억제 효과가 감소함을 확인함으로써 과도한 음주 등에 의해 유발되는 상기 위궤양을 예방하거나 치료하는데 유용하게 사용될 수 있음을 밝힘으로써 본 발명올 완성하였다.  However, there are no reports that silymarin can be used to treat alcoholic gastric ulcers. Accordingly, the present inventors confirmed that treatment with silymarin or its pharmaceutically acceptable salts is effective in reducing the gastric injury area of the ethanol-induced gastric ulcer model animal, improving gastric mucus volume, and is involved in the NP-SH part as a result of NEM pretreatment. The present invention was completed by revealing that the amount of NP-SH is recovered, and that the effect of inhibiting gastric ulceration after N-NAME pretreatment is reduced, thereby being useful for preventing or treating the gastric ulcer caused by excessive drinking. It was.
【발명의 상세한 설명】 [Detailed Description of the Invention]
【기술적 과제】  [Technical problem]
본 발명의 목적은 실리마린 (Silymarin)을 이용하여 알콜에 의해 유도되는 위손상, 위궤양 또는 위장질환의 예방， 개선 또는 치료를 위한 약학적 조성물 또는 건강식품 조성물을 제공하는 것이다. 【기술적 해결방법】 It is an object of the present invention to provide a pharmaceutical composition or health food composition for the prevention, amelioration or treatment of alcohol-induced gastric injury, gastric ulcer or gastrointestinal diseases using Silymarin. Technical Solution
상기 목적을 달성하기 위하여， 본 발명은 실리마린 (Silymarin)또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 알콜에 의해 유도되는 위손상， 위궤양 또는 위장질환의 예방 및 치료용 약학적 조성물을 제공한다. 또한， 본 발명은 실리마린 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 알콜에 의해 유도되는 위손상， 위궤양 또는 위장질환의 예방 및 개선용 건강식품을 제공한다.  In order to achieve the above object, the present invention provides a pharmaceutical composition for the prevention and treatment of gastric injury, gastric ulcer or gastrointestinal disease induced by alcohol containing Silymarin or a pharmaceutically acceptable salt thereof as an active ingredient. do. In addition, the present invention provides a health food for the prevention and improvement of gastric damage, gastric ulcer or gastrointestinal diseases induced by alcohol containing silymarin or a pharmaceutically acceptable salt thereof as an active ingredient.
또한， 본 발명은 유효한 양의 실리마린 또는 이의 약학적으로 허용가능한 염을 알콜에 의해 유도되는 위손상， 위궤양 또는 위장질환에 걸린 개체에 투여하는 단계를 포함하는 알콜에 의해 유도되는 위손상， 위궤양 또는 위장질환의 치료 방법을 제공한다.  In addition, the present invention provides a method for the treatment of gastric injuries, gastric ulcers or the like, comprising administering an effective amount of silymarin or a pharmaceutically acceptable salt thereof to an individual suffering from alcohol-induced gastric injury, gastric ulcer or gastrointestinal disease. It provides a method of treating gastrointestinal diseases.
또한， 본 발명은 유효한 양의 실리마린 또는 이의 약학적으로 허용가능한 염을 개체에 투여하는 단계를 포함하는 알콜에 의해 유도되는 위손상， 위궤양 또는 위장질환의 예방 방법을 제공한다.  The present invention also provides a method for the prevention of gastric injury, gastric ulcer or gastrointestinal disease induced by alcohol, comprising administering to a subject an effective amount of silymarin or a pharmaceutically acceptable salt thereof.
또한， 본 발명은 알콜에 의해 유도되는 위손상， 위궤양 또는 위장질환의 예방， 개선 또는 치료용 조성물에 사용하기 위한 실리마린 또는 이의 약학적으로 허용가능한 염을 제공한다.  The present invention also provides silymarin or a pharmaceutically acceptable salt thereof for use in a composition for the prevention, amelioration or treatment of alcohol-induced gastric injury, gastric ulcer or gastrointestinal disease.
또한, 본 발명은 유효한 양의 실리마린 또는 이의 약학적으로 허용가능한 염을 알콜에 의해 유도되는 위손상， 위궤양 또는 위장질환의 예방， 개선 또는 치료용 조성물의 제조에 이용하는 용도를 제공한다.  The present invention also provides the use of an effective amount of silymarin or a pharmaceutically acceptable salt thereof for the preparation of a composition for the prevention, amelioration or treatment of gastric injury, gastric ulcer or gastrointestinal disease induced by alcohol.
【유리한 효과】 Advantageous Effects
본 발명은 실리마린 또는 이의 약학적으로 허용가능한 염의 처리가 에탄올에 의해 유도되는 위 손상을 줄이고, 위 점액량이 회복되었으며 , 위궤양의 억제 효과를 가지는 NP-SH에 일부 관여하거나 양을 회복시키고 및 실리마린의 위궤양 억제 효과에 산화 질소가 관여함을 확인함으로써， 상기 실리마린 또는 이의 약학적으로 허용가능한 염을 포함하는 조성물은 과도한 음주 등에 의해 유발되는 상기 위궤양을 예방하거나 치료용 약학적 조성물 및 건강식품에 유용하게 사용될 수 있다. The present invention relates to the treatment of silymarin or its pharmaceutically acceptable salts to reduce gastric damage induced by ethanol, to recover gastric mucus, to partially involve or restore the amount of silymarin and to inhibit the amount of gastric ulcers. By confirming that nitric oxide is involved in the gastric ulcer inhibitory effect, the composition comprising the silymarin or its pharmaceutically acceptable salt is excessive It may be useful for preventing or treating the stomach ulcer caused by drinking or the like for the pharmaceutical composition and health food.
【도면의 간단한 설명】 [Brief Description of Drawings]
도 1은 에탄을을 투여한 위궤양 유발 모델 .랫드에 있어서 실리마린과 양성대조약인 스틸린을 농도별로 전처리한 후 위 면적 손상부위를 확인한 결과 위손상 면적이 감소함을 나타내는 그림이다.  Figure 1 is a gastric ulcer-induced model administered with ethane in the rat, after the pretreatment of silymarin and stilin, a positive control for each concentration, the area of gastric injuries is reduced as a result of confirming gastric area damage.
도 2는 에탄올 유도 위궤양 모델에서 농도별로 실리마린을 전처리에 따른 위 점액량이 회복양을 측정한 결과를 위 점액량이 희복되는 것을 나타내는 그림이다.  Figure 2 is a diagram showing that the amount of gastric mucus leans the result of measuring the amount of recovery of gastric mucus according to the pretreatment of silymarin by concentration in the ethanol-induced gastric ulcer model.
도 3은 실리마린의 에탄을 유도 위궤양에 대한 기전을 규명하기 위하여 NEM의 농도별로 전처리를 할 경우 실리마린에 의한 위궤양 억제 효과가 감소되는 것을 나타내는 그림이다.  3 is a diagram showing that the effect of inhibiting gastric ulceration by silymarin is reduced when pretreatment by concentration of NEM to determine the mechanism for the ethanol-induced gastric ulcer of silymarin.
도 4는 에탄을 유도 위눼양 모델에서 위점막 존재 여부 및 손상의 척도인 NP-SH를 처리한 결과 크게 감소가 되었으나 실리마린을 처리한 결과 NP-SH의 양이 회복되는 것을 나타내는 그림이다.  Figure 4 shows that the ethanol-induced gastric mucosa model was significantly reduced as a result of the presence of gastric mucosa and the measure of damage to NP-SH, but the amount of NP-SH is recovered as a result of silymarin treatment.
도 5는 산화 질소 생성 효소의 억제제인 L-NAME을 에탄올 유도 위궤양에 전처리 할 경우 실리마린에 의한 위궤양 효과가 감소함올 나타내는 그림이다. 【발명의 실시를 위한 최선의 형태】  5 is a diagram showing that the effect of gastric ulceration by silymarin is reduced when L-NAME, an inhibitor of nitric oxide producing enzyme, is pretreated in ethanol-induced gastric ulcer. Best Mode for Implementation of the Invention
이하, 본 발명을 상세하게 설명한다. 본 발명은 실리마린 (Silymarin) 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 알콜에 의해 유도되는 위손상， 위궤양 또는 위장질환의 예방 및 치료용 약학적 조성물을 제공한다.  EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail. The present invention provides a pharmaceutical composition for the prevention and treatment of gastric injury, gastric ulcer or gastrointestinal disease induced by alcohol containing Silymarin or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 실리마린 (Silymarin)은 하기 [화학식 1]로 표시되는 화합물이다. 【화학식 1】
Figure imgf000008_0001
화학명은 The silymarin (Silymarin) is a compound represented by the following [Formula 1]. [Formula 1]
Figure imgf000008_0001
The chemical name is
(2R,3R)-3,5, 7-trihydroxy-2-[(2R， 3R ) -3- ( 4-hydr oxy-3-me t hoxypheny 1 )-2- (hydr oxyme thyl )一2 ,3—di hydrobenzo [b] [1 ,4]dioxin一 6—yl ]chroman一 4—one이다. 본 발명의 실시예에서는 에탄올 유도 위궤양 동물 랫드에 상기 제조된 실리마린과 위궤양 치료제로 널리 사용되고 있는 스틸렌을 양성대조약으로 하여 스틸렌을 농도별로 처리를 한 후 위손상 부위의 면적을 측정한 결과 상기 실리마린을 전처리를 한 경우 농도의존적으로 위손상 면적이 감소함올 확인하였다 (도 1 참조).  (2R, 3R) -3,5, 7-trihydroxy-2-[(2R, 3R) -3- (4-hydr oxy-3-me t hoxypheny 1) -2- (hydr oxyme thyl) 一 2, 3 —Di hydrobenzo [b] [1,4] dioxin 一 6—yl] chroman 一 4—one. In an embodiment of the present invention, the silymarin was determined by measuring the area of the gastric injury site after treating styrene according to the concentration of styrene used in the ethanol-induced gastric ulcer animal rat and styrene widely used as a therapeutic agent for gastric ulcer as a positive control. When pretreatment was performed, it was confirmed that the gastric damage area was reduced in a concentration-dependent manner (see FIG. 1).
에탄올 유도 위궤양 모델에서 위점약 분비에 대한.실리마린의 영향을 확인한 결과 에탄을을 투여하여 위 손상을 유발한 경우 위 점액이 감소되어 있었으나 농도별로 실리마린올 처리하였을 경우 농도의존적으로 위 점액량이 회복되는 것을 확인하였다 (도 2 참조).  In the ethanol-induced gastric ulcer model, the effect of silymarin on gastric secretion was confirmed. Gastric mucus was decreased when ethane was administered, but gastric mucus was recovered depending on the concentration. It was confirmed (see FIG. 2).
NEM을 처리한 후 실리마린의 위궤양 억제 효과에 대한 영향을 확인한 결과 NEM을 전처리를 할 경우 실리마린에 의한 위궤양 억제 효과가 감소함을 확인할 수 있었으며, 이로부터 실리마린의 위궤양 억제 효과에 비—단백질 설프히드릴기 (non-protein sulfhydryl group, NP-SH)이 일부 관여함을 확인하였다 (도 3 참조).  After the treatment of NEM, the effect of silymarin on gastric ulcer inhibition effect was confirmed that pretreatment with NEM reduced the effect of silymarin on gastric ulcer inhibition. Group (non-protein sulfhydryl group, NP-SH) was confirmed that some involvement (see Figure 3).
실리마린 처리가 NP-SH 양에 미치는 영향을 확인한 결과 에탄을을 투여하여 위 손상을 유발한 경우 NP-SH가 크게 감소 되었으나 실리마린을 처리하였을 경우 농도의존적으로 NP-SH의 양아 회복되는 것을 확인하였다 (도 4 참조). L-NG—니트로알기닌 메틸 에스테르의 전처리가 에탄올 유도 위궤양에 대한 실리마린의 억제에 미치는 영향을 확인한 결과 L-N崖 E을 전처리한 경우 실리마린에 의한 위궤양 억제 효과가 감소함을 확인할 수 있었으며， 이로부터 실리마린의 위궤양 억제 효과에 산화질소가 일부 관여함을 확인하였다 (도 5 참조). 상기 결과에 따라 실리마린 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 알콜에 의해 유도되는 위손상, 위궤양 또는 위장질환의 예방 및 억제용 약학적 조성물로 유용하게 사용할 수 있다. As a result of checking the effect of silymarin treatment on the NP-SH level, NP-SH was significantly reduced when ethane was administered to induce gastric injuries, but when silymarin was treated, the concentration of NP-SH was recovered ( See FIG. 4). The effect of pretreatment of L-NG-nitroarginine methyl ester on the inhibition of silymarin on ethanol-induced gastric ulcer was confirmed that the pretreatment of LN 崖 E decreased the effect of silymarin on gastric ulcer inhibition. It was confirmed that nitric oxide was partially involved in the gastric ulcer inhibitory effect (see FIG. 5). According to the above results it can be usefully used as a pharmaceutical composition for the prevention and suppression of gastric injury, gastric ulcer or gastrointestinal diseases induced by alcohol containing silymarin or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에 따른 실리마린 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며， 염으로는 약학적으로 허용 가능한 유리산 (free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산， 질산, 인산， 황산, 브름화수소산， 요드화수소산， 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트， 페닐-치환된 알카노에이트， 하이드록시 알카노에이트 및 알칸디오에이트， 방향족 산류， 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트， 바이설페이트， 설파이트， 바이설파이트， 니트레0 ᄐ 포스페이트， 모노하이드로겐 포스페이트， 디하이드로겐 포스페 0 ᄐ 메타포스페이트， 피로포스페이트 클로라이드， 브로마이드, 아이오다 o 플루오라이드， 아세테이트 , 프로피오네이트， 데카노에이트, 카프릴레 o 아크릴레이트， 포메이트， 이소부티레이트 , 카프레이트， 헵타노에 o 프로피을레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트， 세바케 o 푸마레이트, 말리에이트ᅳ 부틴 -1,4-디오에이트, 핵산 -1,6—디오에 o 벤조에이트， 클로로벤조에이트， 메틸벤조에이트， 디니트로 벤조에 o 하이드록시벤조에이트， 메록시벤조에이트， 프탈레이트， 테레프탈레 o ᄐ 벤젠설포네이트, 를루엔설포네이트， 클로로벤젠설포네이트， 크실렌설포네 o 페닐아세테이트， 페닐프로피오네이트， 페닐부티레이트, 시트레이트， 락테 o -하이드록시부티레이트 , 글리콜레이트 , 말레이트 , 타트레이트， 메탄설포네 o 프로판설포네이트， 나프탈렌 -1-설포네이트, 나프탈렌 -2-설포네이트 또는 만델레이트를 포함한다. The silymarin compound according to the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and Obtained from non-toxic organic acids such as alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids. These pharmaceutically toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrile 0 phosphate, monohydrogen phosphate, dihydrogen phosphate 0 ᄐ metaphosphate, pyrophosphate chloride, bromide , Iodine o fluoride, acetate, propionate, decanoate, capryl o acrylate, formate, isobutyrate, caprate, heptano o o propirate, oxalate, malonate, succinate, subverate , Sebacque o fumarate, maleate ᅳ butine -1,4-dioate, nucleic acid -1,6-dioe o benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoe o hydroxybenzoate Oxybenzoate, phthalate, terephthale o benzenesulfonate, toluenesulfonate, clo Chlorobenzenesulfonate, xylenesulfonone o phenylacetate, phenylpropionate, phenylbutyrate, citrate, lacte o-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonone o Propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.
" 본 발명에 따른 산 부가염은 통상의 방법, 예를 들면， 실리마린 화합물을 과량의 산 수용액 중에 용해시키고， 이 염을 수흔화성 유기 용매， 예를 들면 메탄올， 에탄을， 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다ᅳ 또한 이 흔합물에서 용매나 과량의 산을 증발시킨 후 건조시키거나 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다. The acid addition salts according to the invention are prepared by conventional methods, for example, by dissolving the silymarin compound in an excess of an aqueous solution of an acid, using the salt with a miscible organic solvent such as methanol, ethane, acetone or acetonitrile. This mixture may be prepared by evaporation of a solvent or excess acid, followed by drying, or by precipitation filtration of the precipitated salt.
또한， 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고， 비용해 화합물 염을 여과하고， 여액을 증발， 건조시켜 얻는다. 이때， 금속 염으로는 나트륨， 칼륨 또는 칼슴염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 은 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은 염 (예, 질산은)과 반웅시켜 얻는다. 본 발명에 따른 실리마린 화합물은 이의 약학적으로 허용되는 염뿐만 아니라， 이의 이성질체 또는 이로부터 제조될 수 있는 가능한 용매화물 또는 수화물을 모두 포함한다.  Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the compound salt at no cost, and evaporating and drying the filtrate. In this case, as the metal salt, it is pharmaceutically suitable to prepare sodium, potassium, or chamomile salt. Corresponding silver salts are also obtained by reacting an alkali or alkaline earth metal salt with a suitable silver salt (eg silver nitrate). Silymarin compounds according to the invention include not only pharmaceutically acceptable salts thereof, but also isomers thereof or possible solvates or hydrates that may be prepared therefrom.
또한， 본 발명에 따른 실리마린 화합물은 시판되는 것을 사용하거나 유기합성분야에서 알려진 통상의 합성방법을 이용하여 합성된 것을 사용할 수 있다. 본 발명에 따른 실리마린 화합물 또는 이의 약학적으로 허용가능한 염은 에탄올에 의해 유도되는 위 손상을 줄이고 위 점액량이 회복시키며 , 위궤양의 억제 효과를 가지는 NP-SH에 일부 관여하거나 양을 회복시키고 및 실리마린의 위궤양 억제 효과에 산화 질소가 관여함을 확인함으로써 위궤양을 예방하거나 치료에 유용하게 사용될 수 있다. 본 발명에 따른 실리마린 화합물 또는 이의 약학적으로 허용되는 염을 유효성분으로 함유하는 약학적 조성물은 하기의 다양한 경구 또는 비경구 투여 형태로 제형화할 수 있으나, 이에 한정되는 것은 아니다. In addition, the silymarin compound according to the present invention may be commercially available or synthesized using conventional synthetic methods known in the art of organic synthesis. The silymarin compound or a pharmaceutically acceptable salt thereof according to the present invention reduces the gastric damage induced by ethanol, restores the amount of gastric mucus, partially participates in or restores the amount of silymarin and NP-SH which has an inhibitory effect on gastric ulcer. By confirming that nitric oxide is involved in gastric ulcer inhibitory effect, it can be usefully used for preventing or treating gastric ulcer. The pharmaceutical composition containing the silymarin compound or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient may be formulated in various oral or parenteral dosage forms as follows, but is not limited thereto.
경구 투여용 제형으로는 예를 들면 정제， 환제， 경 /연질 캅셀제， 액제， 현탁제 , 유화제， 시럽게 , 과립제， 엘릭시르제 (elixirs) 등이 있는데 , 이들 제형은 상기 유효성분 이외에 통상적으로 사용되는 층진제， 증량제， 습윤제， 붕해제， 활택제， 결합제, 계면활성제 등의 희석제 또는 부형제를 1종 이상 사용할 수 있다. 붕,해제로는 한천, 전분， 알긴산 또는 이의 나트륨염， 무수인산일수소 칼슘염 등이 사용될 수 있고， 활택제로는 실리카， 탈크， 스테아르산 또는 이의 마그네슴염 또는 칼슘염， 폴리에틸렌 글리콜 둥이 사용될 수 있으며， 결합제로는 마그네슘 알루미늄 실리케이트， 전분 페이스트， 젤라틴， 트라가칸스， 메틸셀를로오스， 나트륨 카복시메틸셀를로오스, 폴리비닐피를리딘, 저치환도 하이드록시프로필셀를로오스 등이'사용될 수 있다. 이외에도 락토즈， 텍스트로.오스ᅳ 수크로오스， 만니를, 소르비를， 셀를로오스， 글리신 등을 회석제로 사용할 수 있으며, 경우에 따라서는 일반적으로 알려진 비등 흔합물 흡수제 , 착색제， 향미제， 감미제 등을 함께 사용할 수 있다. Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and the like. One or more diluents or excipients such as layering agents, extenders, wetting agents, disintegrating agents, lubricants, binders, surfactants, and the like can be used. Agar, starch, alginic acid or its sodium salt, calcium monohydrogen phosphate salt, etc. may be used as the boron , release agent, and silica, talc, stearic acid or its magnesium salt or calcium salt, polyethylene glycol, etc. may be used as a lubricant. , a binding agent is a magnesium aluminum silicate, starch paste, gelatin, Tra is such kanseu, methyl selreul as agarose, sodium carboxymethylcellulose selreul agarose, a polyvinylidene blood, low-substituted hydroxy propyl selreul agarose can be used, . In addition, lactose, text, ossuose sucrose, manny, sorbide, cellulose, glycine and the like can be used as a diluent, and in some cases, commonly known boiling mixture absorbers, colorants, flavors, sweeteners, etc. Can be used together.
또한， 상기 조성물은 비경구 투여할 수 있으며， 비경구 투여는 피하주사제， 정맥주사제， 근육 내 주사제 또는 흉부 내 주사제를 주입하는 방법에 의한다. 이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 실리마린 화합물 또는 약학적으로 허용되는 이의 염을 안정제 또는 완층제와 함께 물에서 흔합하여 용액 또는 현탁액으로 제조하고, 이를 ¾플 또는 바이알의 단위 투여형으로 제조할 수 있다. 또한， 본 발명에 따른 상기 약학적 조성물은 멸균되거나 또는 방부제， 안정화제， 수화제 또는 유화 촉진제， 삼투압 조절을 위한 염， 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 함유할 수 있으며，통상적인 방법인 흔합， 과립화 또는 코팅 방법에 따라 제제화할 수 있다. 필요한 경우， 본 발명에 따른 상가 조성물은 기타의 약제, 예를 들면， 다른 치료제와 조합하여 투여할 수도 있다. In addition, the composition can be administered parenterally, parenteral administration is by the method of injecting subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection. At this time, the silymarin compound or a pharmaceutically acceptable salt thereof is mixed in water together with a stabilizer or a laxative to prepare a formulation for parenteral administration in water or as a solution or suspension, which is in unit dosage form of ¾ple or vial. It can manufacture. In addition, the pharmaceutical composition according to the present invention may be sterilized or contain preservatives, stabilizers, hydrating or emulsifiers, salts for controlling osmotic pressure, adjuvant such as buffers, and other therapeutically useful substances. It can be formulated according to the method of mixing, granulation or coating. If necessary, the additive composition according to the present invention may be combined with other drugs, for example, other therapeutic agents. It may also be administered.
또한， 본 발명에 따른 상기 약학적 조성물은 약제의 제조에 통상적으로 사용하는 적절한 담체， 부형제 및 희석제를 더 포함할 수 있다. In addition, the pharmaceutical composition according to the present invention may further include suitable carriers, excipients and diluents commonly used in the manufacture of a medicament.
본 발명에 따른 상기 약학적 '조성물은， 각각 통상의 방법에 따라 산제， 과립제， 정게， 캡슐제， 현탁액， 에멀젼, 시럽, 에어로졸 등의 경구형 제형， 외용제, 좌제 및 멸균 주사용액의 형태로 제형화 하여 사용될 수 있다. 본 발명의 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스， 솔비를， 만니를， 자일리를, 에리스리를， 말티틀， 전분， 아카시아 고무， 알지네이트， 젤라틴， 칼슘 포스페이트， 칼슘 실리케이트， 셀를로즈, 메틸 셀를로즈 미정질 셀를로스, 폴리비닐 피를리돈， 물， 메틸히드록시벤조에이트， 프로필히드록시벤조에이트， 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. The pharmaceutical 'composition according to the invention, formulated into powders, granules, jeongge, capsules, suspensions, emulsions, syrups, oral dosage form for external application, in the form of a suppository, and sterile injection solution, such as an aerosol in a usual manner, respectively Can be used. Carriers, excipients, and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbbi, manny, xili, erythri, maltyl, starch, acacia rubber, alginate, gelatin, Calcium phosphate, calcium silicate, cellulose, methyl cellulose microcrystalline cellulose, polyvinyl pyridone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
제제화할 경우에는 보통 사용하는 층진제， 증량제, 결합제， 습윤제, 붕해제， 계면활성제 등의 회석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제，환제，산제,과립제， 캡슐제 등이 포함되며, 이러한 고형제제는 본 발명의 조성물에 적어도 하나 이상의 부형제 예를 들면, 전분 탄산칼슘 (calcium carbonate),슈크로스 (sucrose)또는 락토오스 ( lactose)， 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트， 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제， 내용액제, 유제, 시럽게 등이 해당되는데 흔히 사용되는 단순희석제인 물，리퀴드 파라핀 이외에 여러 가지 부형제， 예를 들면 습윤제,감미제,방향거 1, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액， 비수성용제， 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제， 현탁제로는 프로필렌글리콜 (propylene glycol), 플리에틸렌 글리콜， 올리브 오일과 같은 식물성 기름， 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위템솔 (witepsol), 마크로골， 트원 (tween) 61, 카카오지， 라우린지， 글리세를젤라틴 등이 사용될 수 있다. 또한, 본 발명에 따른 약학적 조성물을 단위 용량 형태로 제형화하는 경우, 유효성분으로서 실리마린 화합물 또는 이의 약학적으로 허용가능한 염을 약 0.1 ~ 1,500 mg의 단위 용량으로 함유되는 것이 바람직하다. 투여량은 환자의 체중， 나이 및 질병의 특수한 성질과 심각성과 같은 요인에 따라 의사의 처방에 따른다. 그러나, 성인 치료에 필요한 투여량은 투여의 빈도와 강도에 따라 하루에 약 1 ~ 500 mg 범위가 보통이다. 성인에게 근육 내 또는 정맥 내 투여 시 일 회 투여량으로 분리하여 하루에 보통 약 5~ 300 mg의 전체 투여량이면 층분할 것이나， 일부 환자의 경우 더 높은 일일 투여량이 바람직할 수 있다. In the case of formulation, it is prepared by using a diluent or excipient such as commonly used layering agents, extenders, binders, wetting agents, disintegrating agents and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and the solid preparations include at least one excipient in the composition of the present invention, for example, calcium carbonate, sucrose ( sucrose) or lactose, gelatin and the like are mixed. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include suspensions, solvents, emulsions, and syrups. Water, liquid paraffin, and other excipients, such as wetting agents, sweeteners, fragrances 1, and preservatives, are commonly used as simple diluents. May be included. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used. As a suppository base, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerin gelatin and the like can be used. In addition, when the pharmaceutical composition according to the present invention is formulated in unit dose form, it is preferable that the active ingredient contains a silymarin compound or a pharmaceutically acceptable salt thereof in a unit dose of about 0.1 to 1,500 mg. Dosage depends on the doctor's prescription depending on factors such as the patient's weight, age and the specific nature and severity of the disease. However, the dosage required for adult treatment typically ranges from about 1 to 500 mg per day, depending on the frequency and intensity of administration. Intramuscular or intravenous administration to adults will be divided into single doses, usually at a total dosage of about 5 to 300 mg per day, but a higher daily dose may be desirable for some patients.
또한, 본 발명에 따른 약학적 조성물의 바람직한 투여량은 환자의 상태 및 체증， 질병의 정도， 약물형태， 투여경로 및 기간에 따라 다르지만， 당업자에 의해 적절하게 선택될 수 있다. 그러나 바람직한 효과를 위해서， 본 발명의 조성물은 1일 0.00이내지 0.03g/kg으로, 바람직하게는 0.0이내지 8mg/kg으로 투여하는 것이 좋다. 투여는 하루에 한번 투여할 수도 있고， 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 또한， 본 발명은 실리마린 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 알콜에 의해 유도되는 위손상, 위궤양 또는 위장질환의 예방 및 개선용 건강식품을 제공한다.  In addition, the preferred dosage of the pharmaceutical composition according to the present invention depends on the condition and the condition of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected by those skilled in the art. However, for the desired effect, the composition of the present invention is preferably administered at 0.00 to 0.03 g / kg, preferably 0.0 to 8 mg / kg per day. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect. In addition, the present invention provides a health food for the prevention and improvement of gastric damage, gastric ulcer or gastrointestinal diseases induced by alcohol containing silymarin or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 실리마린 (Silymarin)은 하기 [화학식 1]로 표시되는 화합물이다. [화학식 1]
Figure imgf000014_0001
화학명은 The silymarin (Silymarin) is a compound represented by the following [Formula 1]. [Formula 1]
Figure imgf000014_0001
The chemical name is
(2R,3R)-3,5,7-trihydr oxy-2- [(2R,3R)-3-( 4-hydr oxy-3-met hoxypheny l)-2-(hydr oxymet hyl )-2,3-di hydrobenzo [b] [l,4]dioxin-6-yl]chr oman-4-one이다. 본 발명에 따른 실리마린 화합물 또는 이의 약학적으로 허용가능한 염은 에탄올에 의해 유도되는 위 손상을 즐이고, 위 점액량이 회복시키며， 위궤양의 억제 효과를 가지는 NP— SH에 일부 관여하거나 양을 회복시키고 및 실리마린의 위궤양 억제 효과에 산화 질소가 관여함을 확인함으로써 알콜성 위궤양 예방 및 개선용 건강식품을 조성물에 유용하게 사용할 수 있다. 상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 드링크제， 육류, 소세지, 빵, 비스켓， 떡 , 쵸코렛, 캔디류， 스넥류，과자류，피자，라면,기타 면류, ¾류,아이스크림류를 포함한 낙농제품， 각종 스프， 음료수， 알콜 음료 및 비타민 복합제 등이 있으며， 통상적인 의미에서의 건강 식품을 모두 포함한다.  (2R, 3R) -3,5,7-trihydr oxy-2- [(2R, 3R) -3- (4-hydr oxy-3-met hoxypheny l) -2- (hydr oxymet hyl) -2,3 -di hydrobenzo [b] [l, 4] dioxin-6-yl] chr oman-4-one. The silymarin compound or a pharmaceutically acceptable salt thereof according to the present invention enjoys gastric damage induced by ethanol, restores gastric mucus volume, partially participates in or restores the amount of NP—SH having an inhibitory effect of gastric ulcer, and By confirming that nitric oxide is involved in the gastric ulcer inhibitory effect of silymarin, alcoholic gastric ulcer prevention and improvement health foods can be usefully used in the composition. There is no particular limitation on the kind of food. Examples of foods to which the substance may be added include drinks, meat, sausages, breads, biscuits, rice cakes, chocolates, candy, snacks, sweets, pizza, ramen, other noodles, ¾, ice creams including ice cream, and various soups. , Beverages, alcoholic beverages and vitamin complexes, and includes all healthy foods in the usual sense.
본 발명의 실리마린 또는 이의 약학적으로 허용가능한 염은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효 성분의 흔합양은 그의 사용 목적 (예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로， 건강식품 중의 상기 추출물의 양은 전체 식품 중량의 0.1 내지 90 중량부로 가할 수 있다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며， 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다. Silymarin or a pharmaceutically acceptable salt thereof of the present invention may be added to a food as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method. The mixed amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement). In general, the amount of the extract in the health food can be added to 0.1 to 90 parts by weight of the total food weight. However, in the case of prolonged ingestion for health and hygiene purposes or for health control purposes, the amount may be below the above range. In addition, since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
본 발명의 건강 기능성 음료 조성물은 지시된 비율로 필수 성분으로서 상기 추출물을 함유하는.외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드， 예를 들어， 포도당, 과당 등; 디사카라이드, 예를 들어 말토스， 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린， 시클로덱스트린 등과 같은 통상적인 당， 및 자일리를， 소르비를， 에리트리를 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제 (타우마틴， 스테비아 추출물 (예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미게 (사카린， 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 당 일반적으로 약 1 내지 20g, 바람직하게는 약 5 내지 12 g이다.  The functional beverage composition of the present invention contains the extract as an essential ingredient in the indicated ratio. There are no particular restrictions on the other ingredients, and it may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. . Examples of the above described natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And sugars such as conventional sugars such as polysaccharides such as dextrin, cyclodextrin and the like, and xylyl, sorbitol, erythritol and the like. As flavoring agents other than those described above, natural flavoring agents (tautin, stevia extract (e.g., Rebaudioside A, glycyrrhizin, etc.) and synthetic flavorings (saccharin, aspartame, etc.) can be advantageously used. The proportion of natural carbohydrates is generally about 1 to 20 g, preferably about 5 to 12 g per 100 compositions of the present invention.
상기 외에 본 발명의 실리마린 또는 이의 약학적으로 허용가능한 염은 여러 가지 영양제, 비타민， 광물 (전해질)， 합성 풍미제 및 천연 풍미제 둥와 풍미제 , 착색제 및 중진제 (치즈， 초콜릿 등)ᅳ펙트산 및 그의 염， 알긴산 및 그의 염， 유기산， 보호성 콜로이드 증점제， pH 조절제, 안정화제， 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 추출물은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 추출물 100 중량부 당 0.1 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다. 또한， 본 발명은 유효한 양의 실리마린 또는 이의 약학적으로 허용가능한 염을 알콜에 의해 유도되는 위손상， 위궤양 또는 위장질환에 걸린 개체에 투여하는 단계를 포함하는 알콜에 의해 유도되는 위손상， 위궤양 또는 위장질환의 치료 방법을 제공한다. 또한, 본 발명은 유효한 양의 실리마린 또는 이의 약학적으로 허용가능한 염을 개체에 투여하는 단계를 포함하는 알콜에 의해 유도되는 위손상， 위궤양 또는 위장질환의 예방 방법을 제공한다. 또한, 본 발명은 알콜에 의해 유도되는 위손상, 위궤양 또는 위장질환의 예방， 개선 또는 치료용 조성물에 사용하기 위한 실리마린 또는 이의 약학적으로 허용가능한 염을 제공한다. In addition to the above, the silymarin or a pharmaceutically acceptable salt thereof of the present invention may contain various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, and flavors, colorants and neutralizers (such as cheese and chocolate). And salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like. In addition, the extract of the present invention may contain a fruit flesh for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components can be used independently or in combination. The proportion of such additives is not so critical but is generally selected in the range of 0.1 to about 20 parts by weight per 100 parts by weight of the extract of the present invention. In addition, the present invention provides a method for the treatment of gastric injuries, gastric ulcers or It provides a method of treating gastrointestinal diseases. The present invention also provides a method for the prevention of gastric injury, gastric ulcer or gastrointestinal disease induced by alcohol, comprising administering to a subject an effective amount of silymarin or a pharmaceutically acceptable salt thereof. The present invention also provides silymarin or a pharmaceutically acceptable salt thereof for use in a composition for the prevention, amelioration or treatment of alcohol-induced gastric injury, gastric ulcer or gastrointestinal disease.
또한， 본 발명은 유효한 양의 실리마린 또는 이의 약학적으로 허용가능한 염을 알콜에 의해 유도되는 위손상， 위궤양 또는 위장질환의 예방， 개선 또는 치료용 조성물의 제조에 이용하는 용도를 제공한다. 이하， 본 발명의 실시예， 실험예 및 제조예에 의하여 상세히 설명한다. 단, 하기 실시예， 실험예 및 제조예는 본 발명을 예시하는 것일 뿐， 본 발명의 내용이 하기 실시예, 실험예 및 제조예에 의해 한정되는 것은 아니다. 이하， 본 발명의 실시예， 실험예 및 제조예에 의하여 상세히 설명한다. 단， 하기 실시예, 실험예 및 제조예는 본 발명올 예시하는 것일 뿐， 본 발명의 내용이 하기 실시예， 실험예 및 제조예에 의해 한정되는 것은 아니다. <실시예 1>실리마린의 분리 및 확인  The present invention also provides the use of an effective amount of silymarin or a pharmaceutically acceptable salt thereof for the preparation of a composition for the prevention, amelioration or treatment of gastric injury, gastric ulcer or gastrointestinal disease induced by alcohol. Hereinafter, it will be described in detail by Examples, Experimental Examples and Preparation Examples of the present invention. However, the following Examples, Experimental Examples and Preparation Examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following Examples, Experimental Examples, and Preparation Examples. Hereinafter, it will be described in detail by Examples, Experimental Examples and Preparation Examples of the present invention. However, the following Examples, Experimental Examples and Preparation Examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following Examples, Experimental Examples, and Preparation Examples. Example 1 Isolation and Identification of Silymarin
엉경퀴 //yZ z? ar )로부터 실리마린 (ctalogue#:S0292, Awkward // yZ z? ar from silymarin (ctalogue #: S0292,
Sigma-Aklrich)를 분리하였다. Sigma-Aklrich) was isolated.
<실시예 2> 에탄올 유도 위궤양 모델 동물의 제조 Example 2 Preparation of Ethanol-Induced Gastric Ulcer Model Animal
7주령의 체중 200~250 g 정도의 수컷 SD(Spr ague-Daw ley) 랫드 (코아텍,대한민국) 5마리를 1군으로 하여 36시간 절식시킨 후 상기 <실시예 1>에서 제조된 실리마린을 25， 50, 100, 200 mg/kg로 각각 경구투여 하고 30분 후 100%에탄올 (ethanol) 1 ml을 경구투여 하고 절식 절수하여 1시간 동안 방치 후 co2로 치사시켰다. 위를 적출한 후 유문부와 식도를 결찰하여 위내에 2% 포르말린 (formalin)용액 10 ml을 넣어 10분간 고정하고 대만부를 절개하여 발생 된 손상부위를 디지털 카메라 (digital camera)로 촬영하여, 분석용 프로그램 (Image-Pro Plus 4.5.1)에서 측정하여 그 총합을 손상 지수로 하였다. 손상부위 면적은 전체 선위부 면적에 대한 ¾>로 표현하였다. 대조 약물로는 스틸렌 (stillen)을 사용하였다. Five male SD (Spr ague-Daw ley) rats (Cortech, Korea) at 7 weeks of age were fasted for 36 hours with 1 group, and then the silymarin prepared in Example 1 was 25 ， 50, 100, 200 mg / kg orally and 30 minutes later, 1 ml of 100% ethanol (ethanol) and fasted water saving for 1 hour After letting it die for co 2 . After extraction of the stomach, ligation of the pylorus and esophagus, put 10 ml of 2% formalin solution in the stomach, fix it for 10 minutes, and incision of the Taiwanese section, photographing the damaged area with a digital camera. The total was taken as the damage index as measured in (Image-Pro Plus 4.5.1). Damage area is expressed as ¾> of the total distal area. Stillene was used as a control drug.
<실험예 1>실리마린의 위손상 보호 효과 검정 Experimental Example 1 Silymarin's Protective Effect on Gastric Damage
상기 <실시예 2>에서 제조된 SD 랫트에 상기 <실시예 1>에 제조된 실리마린과 양성대조약인 스틸렌을 각각 30분간 전처리를 한 후 랫드 당 1 ml의 100% 에탄을을 경구 투여하여 위궤양을 유발하였다. 1시간 후 C02로 치사하고 위를 적출하여 위손상 부위와면적을 측정하였다. After 30 minutes of pretreatment of each of the silymarin prepared in <Example 1> and styrene, which is a positive control, to the SD rat prepared in <Example 2>, 1 ml of 100% ethane per rat was orally administered to gastric ulcer. Induced. After 1 hour, the plate was lethal to C0 2 and the stomach was extracted to measure the area and area of gastric injury.
그 결과, 용매대조군에서는 21.1=4.71. )의 위손상이 관찰되었으나， 실리마린을 25 mg/kg, 50 mg/kg, 100 mg/kg 및 200 mg/kg의 농도로 처리하였을 경우 각각 11.9=1.36 , 7.8=2.87 %， 5.8=2.28 % 및 1.5=1.19 %의 위손상이 관찰되어 농도의존적으로 위손상이 감소하였다. 양성대조약으로 사용한 스티렌의 경우 100 mg/kg의 농도로 처리하였을 때 3.4=2.23 %의 위손상이 관찰되어 상기 실리마린을 전처리를 한 경우 농도의존적으로 위손상 면적이 감소함을 확인하였다 (도 1). As a result, 21.1 = 4.71 in the solvent control group . ), But when silymarin was treated at concentrations of 25 mg / kg, 50 mg / kg, 100 mg / kg and 200 mg / kg, 11.9 = 1.36, 7.8 = 2.87%, 5.8 = 2.28% and Gastric damage of 1.5 = 1.19% was observed, and gastric damage was reduced in a concentration-dependent manner. In case of styrene used as a positive control, gastric damage of 3.4 = 2.23% was observed when treated at a concentration of 100 mg / kg, and it was confirmed that gastric damage area was reduced depending on concentration when pretreatment of the silymarin (FIG. 1). ).
<실험예 2>실리마린의 위점액 분비 개선 효과 검정 Experimental Example 2 Test for Effect of Silymarin on Gastric Mucus Secretion
에탄올에 의한 위궤양 기전 중 위 점막 투과성을 항진시키고 능동수송을 저해하는 기전을 통해 위 손상을 일으키는 것이 있는데， 위는 이에 대한 방어 기전으로 점막층을 보호하기 위하여 방어 인자인 절액을 분비하게 된다. 이에， 실리마린 처리가 위 점액 분비에 미치는 영향을 확인하였다.  The gastric ulceration mechanism by ethanol promotes gastric mucosal permeability and inhibits active transport, causing gastric injury. The stomach secretes a protective fluid to protect the mucosal layer. Thus, the effect of silymarin treatment on gastric mucus secretion was confirmed.
7주령의 체중 200 250 g 정도의 수컷 SD 랫드 5마리를 1군으로 하여 36시간 절식시킨 후 실리마린을 경구투여하고 1시간 후에 100% 에탄올 1 ml을 경구투여 하였다. 1시간 후에 C02로 치사시키고 위를 적출하고 0.25 M 1 수크로스 (sucrose)용액 10 ml로 세척하고 0.1% (w/v)알시안 블루 (alcian blue) 8GX용액 (0.16M수크로스 in0.05M소듐 아세테이트 (sodium acetate)， pH 5.8) 15 ml에 2시간 동안 염색을 한 후 0.25 M수크로스 용액에 세척하고 조직을 0.5 mol/L 염화마그네슘 용액 15 ml에 2시간 동안 담궈 위 점액과 결합 된 시약을 추출해서 얻어진 푸른색의 추출액을 동량의 디에틸에테르 (diethylether)와 흔합하고 3,500 g에서 10 분간 원심분리하여 상층액을 취하여 580 ηηι에서 흡광도를 측정하였다. 표준용액은 o.l% (w/v) 알시안 블루 용액을 0.25 M 수크로스 용액으로 회석하여 사용하였고 알시안 블루 g/g 조직으로 표현하였다. Five male SD rats weighing about 200 250 g at 7 weeks of age were fasted for 36 hours with 1 group, followed by oral administration of silymarin and 1 ml of 100% ethanol after 1 hour. After 1 hour, lethal with C0 2 , remove stomach, 0.25 M 1 Wash with 10 ml of sucrose solution and 2 ml of 15% 0.1% (w / v) alkian blue 8GX solution (0.16 M sucrose in 0.05 M sodium acetate, pH 5.8) After staining for a period of time, washed with a 0.25 M sucrose solution, the tissue was immersed in 15 ml of 0.5 mol / L magnesium chloride solution for 2 hours to extract the reagent associated with the gastric mucus extracted blue equivalent solution of the same amount of diethyl ether was absorbed at 580 ηηι by mixing with (diethylether) and centrifugation at 3,500 g for 10 min. The standard solution was used by diluting the ol% (w / v) alcian blue solution with a 0.25 M sucrose solution and expressed in alcian blue g / g tissue.
그 결과， 정상군의 경우 알시안 블루 238.5 mg/g 조직으로 나온 반면에 용매대조군은 161.3 mg/g 조직으로 점액량이 줄어들었다. 그러나， 실리마린을 100mg/kg및 200 mg/kg의 농도로 처리하였을 때 각각 200.7 mg/g조직 및 227.9 mg/g 조직으로 점액량이 회복되어 에탄올을 투여하여 위 손상을 유발한 경우 위 점액이 감소되어 있었으나 실리마린을 처리하였을 경우 농도의존적으로 위 점액량이 회복되는 것을 확인하였다 (도 2).  As a result, the normal control group had a 235,000 mg / g tissue of Alcian blue, while the solvent control group had a mucus reduction of 161.3 mg / g tissue. However, when silymarin was treated at concentrations of 100 mg / kg and 200 mg / kg, mucus recovered to 200.7 mg / g tissue and 227.9 mg / g tissue, respectively. However, it was confirmed that gastric mucus recovers in a concentration-dependent manner when treated with silymarin (FIG. 2).
<실험예 3> NEM(N-ethylmaleimide)의 전처리에 의한 실리마린의 위궤양에 대한 억제 효과 분석 Experimental Example 3 Analysis of Inhibitory Effect of Silymarin on Gastric Ulcers by Pretreatment of NEM (N-ethylmaleimide)
실리마린의 에탄을 유도 위궤양에 대한 기전을 규명하기 위하여 위점막 보호작용에 관여하는 NP— SH의 기능을 억제하는 NEM을 처리한 후 NP-SH가 기능을 하지 못하는 상태에서 에탄올 유도 위궤양에 대한 실리마린의 영향을 확인하였다.  In order to elucidate the mechanism of silymarin ethane for induced gastric ulcer, the treatment of silymarin for ethanol-induced gastric ulcer in the condition of NP-SH not functioning after treatment of NEM that inhibits the function of NP—SH involved in gastric mucosal protection The effect was confirmed.
그 결과， 용매대조군과 NEM 처리군의 경우 37.1 % 및 56.9 %의 위손상이 관찰되었으며， 여기에 실리마린을 처리하였을 경우 각각 5.3 % 및 24.9 %의 위손상이 관찰되어 NEM을 처리를 확인하여 NEM을 전처리를 할 경우 실리마린에 의한 위궤양 억제 효과가 감소함을 확인할 수 있었으며, 이로부터 실리마린의 위궤양 억제 효과에 비-단백질 설프히드릴기 (non-protein sulfhydryl group, NP-SH)이 일부 관여함을 확인하였다 (도 3). <실험예 4>실리마린의 NP-SH에 대한 영향 확인 As a result, 37.1% and 56.9% of gastric damage was observed in the solvent control group and the NEM-treated group, and 5.3% and 24.9% of gastric damage were observed in the case of silymarin treatment. In pretreatment, it was confirmed that the effect of suppressing gastric ulcers by silymarin was reduced. From this, it was confirmed that the non-protein sulfhydryl group (NP-SH) is partially involved in the gastric ulcer inhibitory effect of silymarin. (FIG. 3). Experimental Example 4 Influence of Silymarin on NP-SH
글루타치온을 비롯한 NP-SH는 위장관 점막에 풍부하게 존재하고 위점막 손상의 존재 여부 및 손상 정도의 척도로 알려졌다. 이에， 실리마린 처리가 NP-SH 양에 미치는 영향을 확인하였다.  NP-SH, including glutathione, is abundant in the gastrointestinal mucosa and is known as a measure of the presence and extent of gastric mucosal damage. Thus, the effect of silymarin treatment on the amount of NP-SH was confirmed.
7주령의 체중 200 250 g 정도의 수컷 SD 랫드 5마리를 1군으로 하여 36시간 절식시킨 후 실리마린을 경구 투여하고 1시간 후에 100% 에탄올 1 i 을 경구투여 하였다. 1시간 후에 C02로 치사시키고 위를 적출하고 손상 부위 (50~100mg)를 0.02 M EDTA 1 ml에 균일화 되게 (100 mg당 1 )하고 이 용액 400 ^와 동량의 증류수 320 ， 50%트라이클로로아세트산 (trichloroacetic acid)80 ^와 흔합한 후 3,000 g에서 15분간 원심분리 하였다. 400 의 상층액과 0.4 M 트리스 버퍼 (Tris buffer) 800 μί, DTNBFive male SD rats weighing 200 250 g at 7 weeks of age were fasted for 36 hours in a group of 1, and then orally administered with silymarin and orally administered 100% ethanol 1 i after 1 hour. After 1 hour, killed with C0 2 , the stomach was removed and the damaged area (50-100 mg) was homogenized (1 per 100 mg) in 1 ml of 0.02 M EDTA, and this solution 400 ^ and the same amount of distilled water 320, 50% trichloroacetic acid After mixing with (trichloroacetic acid) 80 ^ was centrifuged for 15 minutes at 3,000 g. Supernatant of 400 and 0.4 M Tris buffer 800 μί, DTNB
(5,5-디티오비스 (ditiobis)(2-니트로벤조산 (nitrobenzoic acid)) 20 ^와 흔합 후 3분간 쉐이킹 (shaking)을 하였다. DTNB 흔합 후 5분 이내로 412 nm에서 흡광도 측정을 하였으며 표준용액은 글루타치온 (glutathione)으로 하고 NP一 SH의 양을 gig 조직으로 표현하였다. Shaking was performed for 3 minutes after mixing with (5,5-ditiobis (2-nitrobenzoic acid) 20 ^. Absorbance was measured at 412 nm within 5 minutes after DTNB mixing. Glutathione was used and the amount of NP SH SH was expressed in gig tissue.
그 결과， 정상군의 경우 NP-SH의 양이 252.2 mg/g 조직으로 나온 반면에 용매대조군은 60.6 mg/g 조직으로 NP-SH의 양이 줄어들었다. 그러나, 실리마린을 100 mg/kg 및 200 mg/kg의 농도로 처리하였을 때 각각 113.4 mg/g 조직 및 160.6 mg/g 조직으로 점액량이 회복되어 에탄올을 투여하여 위 손상을 유발한 경우 NP-SH가 크게 감소 되었으나 실리마린을 처리하였을 경우 농도의존적으로 NP-SH의 양이 회복되는 것을 확인하였다 (도 4).  As a result, the amount of NP-SH was reduced to 252.2 mg / g tissue in the normal group, while the amount of NP-SH was reduced to 60.6 mg / g in the solvent control group. However, when silymarin was treated at 100 mg / kg and 200 mg / kg concentrations, the mucus recovered to 113.4 mg / g tissue and 160.6 mg / g tissue, respectively. Although significantly reduced, it was confirmed that the amount of NP-SH was recovered when the silymarin was treated (concentration 4).
<실험예 5>L-NG-니트로알기닌 메틸 에스테르 (L-NG-Nitroarginine methyl ester, L-NAME)의 전처리에 의한 실리마린의 에탄올 유도 위궤양에 대한 억제 효과 분석 Experimental Example 5 Analysis of Inhibitory Effect of Silymarin on Ethanol-Induced Gastric Ulcer by Pretreatment of L-NG-Nitroarginine Methyl Ester (L-NAME)
산화질소는 위장관의 혈류 이동 및 혈관 확장에 관여하여 위 손상을 보호하는 기능이 있는 것으로 알려져 있다. 이에 L-NG-니트로알기닌 메틸 에스테르의 전처리가 에탄올 유도 위궤양에 대한 실리마린의 억제에 미치는 영향을 확인하였다. Nitric oxide is known to have a function of protecting gastric damage by participating in blood flow and vasodilation of the gastrointestinal tract. L-NG-nitroarginine methyl The effect of ester pretreatment on the inhibition of silymarin on ethanol induced gastric ulcer was confirmed.
실리마린의 에탄올 유도 위궤양에 대한 기전의 규명을 위하여 산화질소 신타아제 (Nitric oxide synthase)의 억제제인 L— NAME을 처리한 후 실리마린의 위궤양 억제 효과에 대한 영향을 확인하였다.  In order to elucidate the mechanism of ethanol-induced gastric ulceration of silymarin, L-NAME, an inhibitor of nitric oxide synthase, was treated.
그 결과， 용매대조군과 L-NAME 처리군의 경우 33.3 % 및 41.7 %의 위손상이 관찰되었으며， 여기에 실리마린을 처리하였을 경우 각각 5.8 % 및 15.4 %의 위손상이 관찰되어 L-NAME을 처리하여 산화질소를 제거하였을 경우 실리마린의 위궤양 억제효과가 줄어드는 것을 확인하여 L-NAME을 전처리 할 경우 실리마린에 의한 위궤양 억제 효과가 감소함을 확인할 수 있었으며， 이로부터 실리마린의 위궤양 억제 효과에 산화질소가 일부 관여함을 확인하였다 (도 5). 이하, 실리마린 또는 이의 약학적으로 허용가능한 염을 포함하는 약학적 제제를 다음과 같이 제조하였다.  As a result, 33.3% and 41.7% of gastric damage was observed in the solvent control group and L-NAME treatment group, and 5.8% and 15.4% gastric damage was observed in the case of silymarin treatment. When nitric oxide was removed, it was confirmed that gastric ulcer inhibitory effect of silymarin was reduced, and thus pretreatment of L-NAME reduced gastric ulcer inhibitory effect by silymarin. It was confirmed that (Fig. 5). Hereinafter, a pharmaceutical formulation comprising silymarin or a pharmaceutically acceptable salt thereof was prepared as follows.
：제조예 1> 약학적 제제의 제조 Preparation Example 1 Preparation of Pharmaceutical Formulation
<1-1>산제의 제조  <1-1> Preparation of powder
실리마린 2 g  2 g of silymarin
유당 1 g  1 g lactose
상기의 성분을 혼합하고 기밀포에 충진하여 산제를 제조하였다.  The above ingredients were mixed and filled in airtight cloth to prepare a powder.
<1-2> 정제의 제조 <1-2> Preparation of Tablet
실리마린 100 mg  Silymarin 100 mg
극ᄀ r r 100 mg  Pole a r r 100 mg
유 당 100 mg  Lactose 100 mg
스테아린산 마그네슘 2 mg  2 mg magnesium stearate
상기의 성분을 흔합한 후， 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다. After mixing the above components, tableting according to a conventional method for producing tablets Tablets were prepared.
<1-3> 캡슐제의 제조 <1-3> Preparation of Capsule
실리마린 100 mg  Silymarin 100 mg
옥수수전분 100 mg  Corn starch 100 mg
유 당 100 mg  Lactose 100 mg
스테아린산 마그네슘 2 rag  Magnesium Stearate 2rag
상기의 성분을 흔합한 후， 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡술에 충전하여 캡슐제를 제조하였다.  After mixing the above components, the capsule was prepared by filling in gelatin capsule according to a conventional method for preparing capsules.
<1-4> 환의 제조 <1-4> Preparation of the ring
실리마린 1 g  1 g of silymarin
유당 1.5 g  Lactose 1.5 g
글리세린 1 g  1 g of glycerin
자일리를 0.5 g  0.5 g of Xili
상기의 성분을 흔합한 후， 통상의 방법에 따라 환 당 4 g이 되도록 제조하였다.  After mixing the above components, it was prepared to be 4 g per ring according to a conventional method.
<1-5> 과립의 제조 <1-5> Preparation of Granules
Figure imgf000021_0001
Figure imgf000021_0001
상기의 성분을 '흔합한 후， 30% 에탄올
Figure imgf000021_0002
After the components of the "common combined, 30% ethanol
Figure imgf000021_0002
건조하여 과립을 형성한 후 포에 층진하였다. Dried to form granules and layered on fabric.
<제조예 2> 식품의 제조 이하， 실리마린 또는 이의 약학적으로 허용가능한 염을 포함하는 식품들을 다음과 같이 제조하였다. Production Example 2 Preparation of Food Hereinafter, foods containing silymarin or a pharmaceutically acceptable salt thereof were prepared as follows.
<2-1> 밀가루 식품의 제조 <2-1> Preparation of Flour Food
실리마린을 0.5-5.0중량부를 밀가루에 첨가하고， 이 흔합물을 이용하여 빵, 케이크， 쿠키， 크래커 및 면류를 제조하여 건강 증진용 식품을 제조하였다.  Silymarin was added to 0.5-5.0 parts by weight of wheat flour, and the mixture was used to prepare bread, cakes, cookies, crackers and noodles to prepare health promoting foods.
<2-2>유제품 (dairy products)의 제조 <2-2> Manufacture of dairy products
실리마린을 5 ~ 10중량부를 우유에 첨가하고，상기 우유를 이용하여 버터 및 아이스크림과 같은 다양한 유제품을 제조하였다.  Silymarin was added to 5 to 10 parts by weight of milk, using the milk to prepare a variety of dairy products such as butter and ice cream.
<2-3> 선식의 제조 <2-3> manufacture of wire
현미， 보리， 참쌀， 율무를 공지의 방법으로 알파화시켜 건조시킨 것을 배전한 후 분쇄기로 입도 60 메쉬의 분말로 제조하였다.  Brown rice, barley, sesame rice, and yulmu were alphad by a known method, and then dried and roasted to prepare a powder having a particle size of 60 mesh.
검정콩， 검정깨， 들깨도 공지의 방법으로 찌서 건조시킨 것을 배전한 후 분쇄기로 입도 60 메쉬의 분말로 제조하였다.  Black beans, black sesame seeds, and sesame seeds were also steamed and dried by a known method, and then ground to a powder having a particle size of 60 mesh.
실리마린을 진공 농축기에서 감압농축하고;분무， 열풍건조기로 건조하여 얻은 건조물을 분쇄기로 입도 60 메쉬로 분쇄하여 건조분말을 얻었다.  Silymarin was concentrated under reduced pressure in a vacuum concentrator; the dried product obtained by spraying and drying with a hot air dryer was pulverized with a particle size of 60 mesh using a grinder to obtain a dry powder.
상기에서 제조한 곡물류, 종실류 및 실리마린의 건조분말을 다음의 비율로 배합하여 제조하였다.  The dry powders of the grains, seeds and silymarin prepared above were formulated in the following ratios.
곡물류 (현미 30 중량부, 율무 15 중량부， 보리 20 중량부)，  Cereals (30 parts by weight brown rice, 15 parts by weight brittle, 20 parts by weight of barley) ，
종실류 (들깨 7 중량부, 검정콩 8 중량부, 검정깨 7 중량부)，  Seeds (7 parts by weight perilla, 8 parts by weight black beans, 7 parts by weight black sesame seeds),
실리마린 (3 중량부)，  Silymarin (3 parts by weight) ，
영지 (0.5 중량부)， 및  Ganoderma lucidum (0.5 parts by weight), and
지황 (0.5 중량부).  Foxglove (0.5 part by weight).
<2-4> 건강보조식품의 제조 <2-4> Preparation of Health Supplements
실리마린 100 rag 비타민 흔합물 ι ό 비타민 A 아세테이트 70 β Silymarin 100 rag Vitamin Complex ι ό Vitamin A Acetate 70 β
비타민 E 1.0 nig  Vitamin E 1.0 nig
비타민 B1 0.13 mg  Vitamin B1 0.13 mg
비타민 B2 0.15 mg  Vitamin B2 0.15 mg
비타민 B6 0.5 nig  Vitamin B6 0.5 nig
비타민 B12 0.2 /g  Vitamin B12 0.2 / g
비타민 C 10 mg  Vitamin C 10 mg
비오틴 10  Biotin 10
니코틴산아미드 ' 1.7 mg Nicotinamide '' 1.7 mg
엽산 50 g  Folic acid 50 g
판토텐산 칼슘 0.5 rag  Calcium pantothenate 0.5 rag
무기질 흔합물 적량  Mineral Mixtures Proper
황산제 1철 1.75 rag  Ferrous Sulfate 1.75 rag
산화아연 0.82 mg  Zinc Oxide 0.82 mg
탄산마그네슘 25.3 mg  Magnesium carbonate 25.3 mg
게 1인산칼륨 - 15 rag  Crab potassium phosphate-15 rag
제 2인산칼슴 55 mg  55 mg of dibasic phosphate
구연산칼륨 90 mg  Potassium Citrate 90 mg
탄산칼슘 100 mg  Calcium Carbonate 100 mg
염화마그네슘 24.8 rag  Magnesium chloride 24.8 rag
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적
Figure imgf000023_0001
The composition ratio of the above vitamin and mineral mixture is relatively
Figure imgf000023_0001
성분을 바람직한 실시예로 흔합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며， 통상의 건강식품 제조방법에 따라 상기의 성분을 흔합한 다음，과립을 제조하고 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다. Although the ingredients are mixed in a preferred embodiment, the blending ratio may be arbitrarily modified. The above ingredients are mixed according to a conventional health food manufacturing method, then granules are prepared and a health food composition is prepared according to a conventional method. Can be used for
<제조예 3> 건강음료의 제조 실리마린 100 mg 구연산 100 mg Preparation Example 3 Preparation of Health Beverage Silymarin 100 mg Citric Acid 100 mg
올리고당 100 mg  Oligosaccharide 100 mg
매실농축액 2 mg  Plum concentrate 2 mg
타우린 100 mg  Taurine 100 mg
정제수를 가하여 전체 500 통상의 건강음료 제조방법에 따라 상기의 성분을 흔합한 다음， 약 1시간 동안 85°C에서 교반 가열한 후， 만들어진 용액을 여과하여 멸균된 1 f용기에 취득하여 밀봉 멸균한 뒤 넁장 보관한 다음 본 발명의 건강음료 조성물 제조에 사용한다.  After adding purified water, the above ingredients were mixed according to the method of preparing 500 general health drinks, and then stirred and heated at 85 ° C. for about 1 hour, and then the resulting solution was filtered and obtained in a sterilized 1 f container and sealed and sterilized. It is then used to prepare the health beverage composition of the present invention.
상기 조성비는 비교적 기호 음료에 적합한 성분을 바람직한 실시예로 흔합 조성하였지만，수요계층,수요국가，사용 용도 등 지역적，민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다. 이상의 본 발명은 상기에 기술된 실시예， 실험예 및 제조예들에 의해 한정되지 않고， 당업자들에 의해 다양한 변형 및 변경올 가져올 수 있으며, 이는 첨부된 청구항에서 정의되는 본 발명의 취지와 범위에 포함된다. 【산업상 이용가능성】  Although the composition ratio is a combination of relatively suitable components for a preferred beverage in a preferred embodiment, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as the demand hierarchy, the country of use, the intended use. The present invention is not limited to the embodiments, experimental examples, and preparation examples described above, and various modifications and changes may be brought by those skilled in the art, and the present invention is defined in the spirit and scope of the present invention as defined in the appended claims. Included. Industrial Applicability
상술한 바와 같이， 본 발명은 실리마린 또는 이의 약학적으로 허용가능한 염을 포함하는 조성물은 과도한 음주 등에 의해 유발되는 위손상 위궤양 또는 위장질환을 예방 또는 치료용 약학적 조성물 및 건강식품 개발에 유용하게 사용될 수 있다.  As described above, the present invention is a composition containing silymarin or a pharmaceutically acceptable salt thereof may be useful for the development of pharmaceutical compositions and health foods for preventing or treating gastric ulcers or gastrointestinal diseases caused by excessive drinking. Can be.

Claims

【청구의 범위】 [Range of request]
【청구항 1】  [Claim 1]
실리마린 (Silymariri) 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 알콜성 위궤양의 예방 및 치료용 약학적 조성물.  Pharmaceutical composition for the prevention and treatment of alcoholic gastric ulcer containing Silymariri (Silymariri) or a pharmaceutically acceptable salt thereof as an active ingredient.
【청구항 2】 [Claim 2]
거 1 1항에 있어서， 상기 실리마린은 엉경퀴 (5//yZ » r/ami )로부터 분리된 것을 특징으로 하는 알콜성 위궤양의 예방 및 치료용 약학적 조성물.  According to claim 1, wherein the silymarin is a pharmaceutical composition for the prevention and treatment of alcoholic gastric ulcer, characterized in that separated from the ulcers (5 / / yZ »r / ami).
【청구항 3] [Claim 3]
제 1항에 있어서， 상기 실리마린은 하기 화학식 1로 표시되는 것을 특징으로 하는 알콜성 위궤양의 예방 및 치료용 약학적 조성물:  According to claim 1, wherein the silymarin is a pharmaceutical composition for the prevention and treatment of alcoholic gastric ulcer, characterized in that represented by the formula (1):
[화학식 1] [Formula 1]
Figure imgf000025_0001
Figure imgf000025_0001
【청구항 4】 [Claim 4]
제 1항에 있어서, 상기 실리마린 또는 이의 약학적으로 허용가능한 염은 알콜에 의한 위손상을 보호하는 것을 특징으로 하는 알콜성 위궤양의 예방 및 치료용 약학적 조성물.  The pharmaceutical composition for preventing and treating alcoholic gastric ulcer according to claim 1, wherein the silymarin or a pharmaceutically acceptable salt thereof protects gastric injury by alcohol.
【청구항 5] [Claim 5]
제 1항에 있어서， 상기 실리마린 또는 이의 약학적으로 허용가능한 염은 위 손상에 의한 위 점액 분비량의 감소를 회복시키는 것을 특징으로 하는 알콜성 위궤양의 예방 및 치료용 약학적 조성물 The method of claim 1, wherein the silymarin or a pharmaceutically acceptable salt thereof recovers a decrease in gastric mucus secretion caused by gastric injury Pharmaceutical composition for the prevention and treatment of alcoholic gastric ulcer
【청구항 6] [Claim 6]
제 1항에 있어서， 상기 실리마린 또는 이의 약학적으로 허용가능한 염은 위 손상에 의한 위장관 내 비-단백질 설프히드릴기 (non-protein sulfhydryl group, NP-SH)양의 감소를 회복시키는 것을 특징으로 하는 알콜성 위궤양의 예방 및 치료용 약학적 조성물.  The method of claim 1, wherein the silymarin or a pharmaceutically acceptable salt thereof recovers a decrease in the amount of non-protein sulfhydryl group (NP-SH) in the gastrointestinal tract due to gastric injury Pharmaceutical composition for the prevention and treatment of alcoholic gastric ulcer.
【청구항 7】 [Claim 7]
실리마린 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 알콜성 위궤양의 예방 및 개선용 건강식품.  Health food for the prevention and improvement of alcoholic gastric ulcer comprising silymarin or a pharmaceutically acceptable salt thereof as an active ingredient.
【청구항 8】 [Claim 8]
약학적으로 유효한 양의 실리마린 또는 이의 약학적으로 허용가능한 염을 알콜성 위궤양에 걸린 개체에 투여하는 단계를 포함하는 알콜성 위궤양의 치료 방법.  A method of treating alcoholic gastric ulcer comprising administering a pharmaceutically effective amount of silymarin or a pharmaceutically acceptable salt thereof to an individual suffering from alcoholic gastric ulcer.
【청구항 9】 [Claim 9]
약학적으로 유효한 양의 실리마린 또는 이의 약학적으로 허용가능한 염을 개체에 투여하는 단계를 포함하는 알콜성 위궤양의 예방 방법.  A method of preventing alcoholic gastric ulcers comprising administering to a subject a pharmaceutically effective amount of silymarin or a pharmaceutically acceptable salt thereof.
【청구항 10】 [Claim 10]
알콜성 위궤양의 예방， 개선 또는 치료를 위해 사용하는 실리마린 또는 이의 약학적으로 허용가능한 염을 포함하는 조성물.  A composition comprising silymarin or a pharmaceutically acceptable salt thereof for use in the prevention, amelioration or treatment of alcoholic gastric ulcers.
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