WO2017183902A1 - Composition containing artemisia capillaris, sanguisorba officinalis, and curcuma longa extracts and antiviral agent, as active ingredients, for preventing or treating liver disease - Google Patents

Composition containing artemisia capillaris, sanguisorba officinalis, and curcuma longa extracts and antiviral agent, as active ingredients, for preventing or treating liver disease Download PDF

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WO2017183902A1
WO2017183902A1 PCT/KR2017/004184 KR2017004184W WO2017183902A1 WO 2017183902 A1 WO2017183902 A1 WO 2017183902A1 KR 2017004184 W KR2017004184 W KR 2017004184W WO 2017183902 A1 WO2017183902 A1 WO 2017183902A1
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hepatitis
liver disease
antiviral agent
turmeric
extract
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PCT/KR2017/004184
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French (fr)
Korean (ko)
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김범준
이장훈
인경수
장은경
이경태
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경희대학교 산학협력단
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K36/282—Artemisia, e.g. wormwood or sagebrush
    • 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)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • A61K36/739—Sanguisorba (burnet)
    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a composition for preventing or treating liver disease, which comprises phosphorus, fat and turmeric extract, and an antiviral agent as an active ingredient.
  • HBV Human hepatitis B virus
  • diseases such as self-controlling acute hepatitis, blunt hepatitis or chronic active hepatitis.
  • Chronic active hepatitis develops, causes cirrhosis and liver cancer, and can be acutely acute with liver failure (Brechot, C., J. Hepatol., 4, 269-279, 1987).
  • Rechot, C., J. Hepatol., 4, 269-279, 1987 When infected with chronic hepatitis, most patients show persistent or active hepatitis, while some do not. The pathogenesis or causative factors of the viral hepatitis are not clear yet.
  • liver damage caused by the hepatitis B virus is mediated by the host's immune cells (Milich, DR et al., J. Immunol., 143, 3141-3147, 1989).
  • Intensive studies have been conducted on the immune response of specific B and T cells and the direct or pathogenic mechanisms of viral proteins (R. Zschke, O. et al., Nature, 348, 252-254 (1990). ).
  • the causes of the clinical pathways that still vary from patient to patient are not clear.
  • Hepatitis B has been studied with great interest in its treatment because of its severity.
  • drugs and vaccines have been developed and have received good reviews in preclinical and clinical trials, but few drugs have been applied as actual therapeutics.
  • HBV hepatitis B virus
  • the only treatment for hepatitis B virus (HBV) hepatitis patients is human immunity. It depends on the system. Human immune action against HBV removes HBV particles, but on the other hand, destroys hepatocytes, so side effects of these immune actions can lead to fatal diseases.
  • HBV hepatitis B virus
  • infected hepatocytes are destroyed by cytotoxic T lymphocytes (CTLs), and virus particles released from the destroyed hepatocytes remove the neutralizing antibodies against the virus to prevent reinfection into the hepatocytes. Proliferation of should also be suppressed.
  • CTLs cytotoxic T lymphocytes
  • interferon, nucleic acid derivatives or immunomodulators only interferon- ⁇ has been shown to be the only therapeutic effect. have.
  • Interferon- ⁇ was first tested by Sculled et al in the mid-1970s as a treatment for chronic hepatitis B. It has been shown to be effective in inhibiting HBV replication. However, when interferon- ⁇ is administered three times a week for at least three months, on average, 20% of patients show a therapeutic effect that inhibits virus growth but do not show sustained inhibitory effects. Patients or children are resistant to interferon- ⁇ and therefore have a low therapeutic effect. In addition, it has recently been reported that only 50% or less of acute and chronic patients infected with hepatitis B virus are suitable for the treatment of interferon- ⁇ . Among the patients, various enzymes (AST, Only if the amount of SGOT, ALT, SGPT, etc. is increased, the interferon- ⁇ treatment can be expected to be effective. Therefore, it is urgent to develop a hepatitis B virus therapeutic agent that can treat patients who are resistant to interferon- ⁇ , but the research is still insufficient.
  • Still another object of the present invention is to provide a health functional food for preventing and improving liver disease, which comprises phosphorus, fat milk and turmeric extract as active ingredients.
  • Still another object of the present invention is to provide a method for treating liver disease, comprising co-administration of an antiviral agent of hepatitis, hepatitis and turmeric extract and hepatitis B to a subject having a liver disease.
  • the present invention provides a pharmaceutical composition for treating liver disease, which comprises the extract of jinjin, fat milk and turmeric as an active ingredient.
  • the extract may be a mixture of phosphorus, fat milk and turmeric each weight ratio of 3: 1: 1.
  • the liver disease may be any one selected from fatty liver, hepatitis or cirrhosis.
  • the composition may be formulated or used in combination with an antiviral agent of hepatitis B.
  • the antiviral agent of hepatitis B may be at least one selected from entecavir, tenofovir, lamivudine, adefovir and clebudine. have.
  • the composition may inhibit or inhibit the expression of TNF- ⁇ , IL-1 ⁇ , TGF- ⁇ , collagenase I or collagenase IV.
  • the present invention provides a health functional food for preventing and improving liver disease, which comprises phosphorus, fat milk and turmeric extract as active ingredients.
  • the present invention provides a method for treating liver disease, comprising co-administration of the antiviral agent of hepatitis B and hepatitis B, turmeric extract and hepatitis B to a subject having a liver disease.
  • the antiviral agent of hepatitis B may be at least one selected from entecavir, tenofovir, lamivudine, adefovir and clebudine. have.
  • the liver disease may be any one selected from fatty liver, hepatitis or cirrhosis.
  • Combination administration of the antiviral agent of hepatitis, fat and turmeric extract with hepatitis B inhibits hepatitis B virus e antigen and effectively inhibits the expression of inflammatory cytokines TNF- ⁇ , IL-1 ⁇ or TGF- ⁇
  • TNF- ⁇ inflammatory cytokines
  • IL-1 ⁇ IL-1 ⁇
  • TGF- ⁇ inflammatory cytokines
  • Figure 2 confirmed the degree of HBV HBsAg (A) and HBV HBeAg inhibition (B) after administration of 30% ethanol extract of phosphorus, fat and turmeric, and by the combination administration of the antiviral agent (ETV) of the extract and hepatitis B The results of confirming the degree of HBV HBsAg (C) and HBV HBeAg inhibition (D) are shown.
  • Figure 3 shows the results of measuring the amount of pgRNA after administration of 30% ethanol extract of phosphorus, fat milk and turmeric.
  • Figure 4 is a result confirming the efficacy by the combined administration of antiviral agent of hepatitis, fat and turmeric extract and hepatitis B through the inhibition of HBV virion production in acute hepatitis B induced mice.
  • Figure 5 shows the results of measuring the cccDNA concentration after the co-administration of 30% ethanol extract of phosphorus, fat and turmeric and antiviral agent (ETV) of hepatitis B in acute hepatitis B induced mice.
  • Figure 7 shows the factors related to hepatic fibrosis by combination administration of antiviral agent of hepatitis, fat and turmeric extract and hepatitis B in acute hepatitis B induced mice, collagenage I, collagenase (collagenage) IV inhibitory effect was confirmed.
  • the present invention provides a composition for treating liver disease, which comprises an antiviral agent of phosphorus, fat and turmeric extract and hepatitis B as an active ingredient.
  • the currently used hepatitis B or liver disease treatments are inadequate in pharmacological effects due to no fundamental treatment, and in addition to weakening of virus elimination efficacy in long-term use, May cause side effects. Therefore, the inventors of the present invention, when combined with the antiviral agent of hepatitis B and hepatitis B and turmeric extract and the hepatitis B anti-viral proliferation effect compared to the conventional antiviral agent of hepatitis B alone, inflammatory cytokines and hepatic fibrosis Experiments confirmed that it can effectively suppress the expression of factors related to.
  • the present invention provides a composition for treating liver disease, which comprises an antiviral agent of phosphorus, fat and turmeric extract and hepatitis B as an active ingredient.
  • the "antiviral agent of hepatitis B" may be at least one selected from entecavir, tenofovir, lamivudine, adefovir and clebudine, but is not limited thereto. But most preferably may be entercavir.
  • the extract of the phosphorus, fat or turmeric according to the present invention can be used to isolate and obtain the extract for phosphorus, fat and turmeric using a method known in the art extraction and separation, defined in the present invention
  • An 'extract' can be extracted from phosphorus, fat, and turmeric using an appropriate solvent.
  • any suitable solvent that may be used to obtain the extract may be used as long as it is a solvent acceptable in the art, and water or an organic solvent may be used.
  • Solvents such as benzene, chloroform, ethyl acetate, methylene chloride, hexane and cyclohexane may be used alone or in combination. It is not limited.
  • any one of hot water extraction method, cold leaching extraction method, reflux cooling extraction method, solvent extraction method, steam distillation method, ultrasonic extraction method, elution method and compression method can be used.
  • the desired extract may further be subjected to a conventional fractionation process, it may be purified using conventional purification methods.
  • any known method can be used.
  • the pharmaceutical composition of the present invention may be prepared using a pharmaceutically acceptable and physiologically acceptable adjuvant in addition to the active ingredient, and the adjuvant may include an excipient, a disintegrant, a sweetener, a binder, a coating agent, and an expanding agent.
  • the adjuvant may include an excipient, a disintegrant, a sweetener, a binder, a coating agent, and an expanding agent.
  • Lubricants, lubricants or flavoring agents can be used.
  • the pharmaceutical composition may be preferably formulated into a pharmaceutical composition including one or more pharmaceutically acceptable carriers in addition to the above-described active ingredient for administration.
  • Formulation forms of the pharmaceutical compositions may be granules, powders, tablets, coated tablets, capsules, suppositories, solutions, syrups, juices, suspensions, emulsions, drops or injectable solutions.
  • the active ingredient may be combined with an oral, nontoxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders, lubricants, disintegrants and coloring agents may also be included in the mixture.
  • Suitable binders include, but are not limited to, natural and synthetic gums such as starch, gelatin, glucose or beta-lactose, corn sweeteners, acacia, trackercance or sodium oleate, sodium stearate, magnesium stearate, sodium Benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • Acceptable pharmaceutical carriers in compositions formulated as liquid solutions are sterile and biocompatible, which include saline, sterile water, Ringer's solution, buffered saline, albumin injectable solutions, dextrose solutions, maltodextrin solutions, glycerol, ethanol and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers and bacteriostatic agents may be added as necessary. Diluents, dispersants, surfactants, binders and lubricants may also be added in addition to formulate into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Furthermore, the method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA can be formulated according to each disease or component, as appropriate in the art.
  • the antiviral agent of the jinjin, fat milk and turmeric extract and hepatitis B of the present invention may be included in 0.1 to 50% by weight relative to the total weight of the composition.
  • liver disease which can be treated, prevented, and improved the phosphorus, fat milk and turmeric extract of the present invention is not limited thereto, but may be fatty liver, hepatitis or cirrhosis, most preferably hepatitis B.
  • composition of the present invention can be used as a food composition in addition to the pharmaceutical composition for the treatment and prevention of liver disease
  • the food composition contains a variety of active ingredients, such as ordinary food composition, in addition to containing the active ingredients phosphorus, fat milk and turmeric extract Flavoring agents or natural carbohydrates and the like may be included as additional ingredients.
  • Examples of the natural carbohydrates described above include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • the aforementioned flavoring agents can advantageously be used natural flavoring agents (tautin), stevia extracts (for example rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).
  • the food composition of the present invention may be formulated in the same manner as the pharmaceutical composition, used as a functional food, or added to various foods.
  • Foods to which the composition of the present invention can be added include, for example, beverages, meat, chocolate, foods, confectionery, pizza, ramen, other noodles, gums, candy, ice cream, alcoholic beverages, vitamin complexes, and health supplements. There is this.
  • the food composition is a variety of nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors in addition to the phosphorus, fat and turmeric extracts as active ingredients, colorants and neutralizers (such as cheese, chocolate), Pectic acid 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 beverages and the like.
  • the food composition of the present invention may contain a fruit flesh for producing natural fruit juice and fruit juice beverage and vegetable beverage.
  • fat milk and turmeric extract of the active ingredient of the present invention is a natural substance, so there is little toxicity and side effects, so it can be used with confidence even in long-term use.
  • the health functional food of the present invention may be prepared and processed in the form of tablets, capsules, powders, granules, liquids, pills and the like for the purpose of improving and preventing liver damage.
  • health functional food refers to a food manufactured and processed using raw materials or ingredients having functional properties useful for the human body according to the Health Functional Food Act No. 6767, and nutrients for the structure and function of the human body. It is meant to be consumed for the purpose of regulating or obtaining a useful effect for health use such as physiological action.
  • the health functional food of the present invention may include a conventional food additive, and the suitability as a food additive, unless otherwise specified, in accordance with the General Regulations of the Food Additives and General Test Methods approved by the Food and Drug Administration, etc. Judging by the standards and standards.
  • Food Additive Reduction examples include chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; Natural additives such as dark blue pigment, licorice extract, crystalline cellulose, high color pigment and guar gum; And mixed preparations such as sodium L-glutamate, algae additives, preservatives and tar dyes.
  • the health functional food in the form of tablets is a mixture of the jinjin, fat milk and turmeric extract of the active ingredient of the present invention with excipients, binders, disintegrants and other additives, and then granulated in a conventional manner, and then a lubricant and the like. Compression molding, or the mixture may be directly compression molded.
  • the health functional food in the form of tablets may contain a mating agent, if necessary.
  • Hard capsules among the health functional foods in the form of capsules can be prepared by filling a mixture of additives, such as excipients, phosphorus, fat and turmeric extracts, which are the active ingredients of the present invention, into conventional hard capsules.
  • a mixture of turmeric extract and additives such as excipients may be prepared by filling a capsule base such as gelatin.
  • the soft capsule agent may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, as necessary.
  • the health functional food in the form of a cyclic form can be prepared by molding a mixture of the jinjin, fat milk and turmeric extract and excipients, binders, disintegrating agents and the like as the active ingredients of the present invention, and, if necessary, sucrose or Other coatings may be applied, or the surface may be coated with materials such as starch, talc.
  • the health functional food in the form of granules can be prepared by granulation of a mixture of jinjin, fat milk and turmeric extract and excipients, binders, disintegrants and the like, which are the active ingredients of the present invention, and a flavoring agent, if necessary. And a copper may be contained.
  • the health functional food may be prepared in the form of tablets, capsules, pills or liquids, for example, beverages, meat, chocolate, foods, confectionary, pizza, ramen, other noodles, gums, candy, ice cream, alcoholic beverages, vitamin complexes And health supplements.
  • the present invention provides a method for treating liver disease, comprising co-administration of the antiviral agent of hepatitis B and hepatitis B, turmeric extract and hepatitis B to a subject having a liver disease.
  • the method of treating liver disease of the present invention comprises administering to the individual a therapeutically effective amount of an antiviral agent of hejin, fat and turmeric extract and hepatitis B.
  • the specific therapeutically effective amount for a particular individual can be determined by the specific composition, including the type and severity of the reaction to be achieved, whether or not other agents are used in some cases, the age, weight, general health, sex and diet, time of administration, It is desirable to apply differently depending on the route of administration and the rate of release of the composition, the duration of treatment, and the various factors and similar factors well known in the medical arts, including drugs used with or concurrent with the specific composition. Therefore, the effective amount of the composition suitable for the purpose of the present invention is preferably determined in consideration of the above matters.
  • the subject is applicable to any mammal, and the mammal includes humans and primates, as well as domestic animals such as cattle, pigs, sheep, horses, dogs, and cats.
  • the present inventors washed phosphorus, fat milk, turmeric with water, dried in the shade, and then finely powdered.
  • 45 g of powdered phosphorus, 15 g of fat milk, 15 g of turmeric was added to 70% ethanol and extracted by cold extraction at room temperature for 3 days, filtered under reduced pressure with a filter paper (Watman, USA), and the filtrate was concentrated on a vacuum rotary concentrator. After removing the ethanol solvent at room temperature to give 29.45 g of crude extract of phosphorus, fat milk, turmeric as an extracted residue.
  • KCT-O1 group in the present invention is a complex extract of the phosphorus, fat milk and turmeric of the present invention prepared by the method of Preparation Example 1, KCT-O2 group is 45: 15: 15 : 12: Extracted by mixing in a mixture of 12: KCT-03 group means the extract extracted the Injincheonggantang.
  • the present inventors treated Entecavir or Tenofovir at a concentration of 200 ⁇ g / ml in a HepG2.2.15 HBV-containing cell line, and treated KCT-O1, KCT-O2, KCT-O3 with 10, 25, 50, After further treatment at a concentration of 100 and 250 ⁇ g / ml, the cells were incubated for 24 hours, and the culture solution was recovered and subjected to HBeAg ELISA to measure the concentration of HBeAg.
  • HBeAg was not inhibited as compared to the control group treated with nothing, but the phosphorus, fat, turmeric complex herbal extract of the present invention and hepatitis B antiviral agent In the KCTO1 treatment group administered in combination, it was confirmed that the HBeAg inhibitory effect in a concentration-dependent (see Fig. 1).
  • the KCT-01 prepared by the method of Preparation Example 2 was also treated with HepG2.2.15 HBV-containing cell lines at concentrations of 31.5, 62.5, 125, and 250 ⁇ g / ml, and the culture solution was recovered to carry out HBsAg ELISA and HBeAg ELISA to obtain HBsAg and As a result of measuring the concentration of HBeAg it was confirmed that there is an inhibitory effect depending on the concentration.
  • hepatitis B antiviral alone was not administered, hepatitis B eantigen was not inhibited.
  • the herbal extract of the present invention was administered in combination with the hepatitis B antiviral agent, hepatitis B eantigen was effectively inhibited.
  • the method has the effect that can be used in the treatment of various liver diseases, including hepatitis B.
  • the present inventors further treated KCT-01 prepared by the method of Preparation Example 2 to a HepG2.2.15 HBV-containing cell line at concentrations of 0, 25, and 250 ⁇ g / ml, and then cultured for 48 hours, and recovered the culture solution.
  • RNA was extracted from and the concentration of pgRNA was measured using Real-time RT-qPCR method.
  • the inventors of the present invention have shown that when Entecavir was administered alone and Entecavir and Enjin, using C57BL6 mice in which HBV DNA was injected by hydrodynamic injection to show signs similar to acute hepatitis B. Blood HBsAg concentration was measured when co-administration of fat milk and turmeric complex herbal extracts.
  • mice used were 8-week-old males of about 20 g from Charles Liver Laboratory (MA, USA), and all mice were pAAV / HBV with HBV DNA sequence inserted into adeno-associated virus.
  • Acute hepatitis B was injected by injecting the vector at a rate of 0.3 ml / min through the mouse tail vein at a volume of 8% of the body weight of the experimental animal. After 24 hours, PBS, entecavir, entecavir and jinjin, fat, and turmeric complex herbal extracts were injected. Injection through the tail vein of mice.
  • Serum was isolated by blood collection on the 1st, 4th, 7th and 10th day after injection of test substance (0 hour), and diluted 10-fold with goat serum (Genesis HBsAg ELISA 3.0, Green Cross MS, Korea). Blood HBsAg concentration was measured using the same method, and liver tissue tissues were ground at 14 days after injection, DNA was extracted using phenol and chloroform, and the amount of cccDNA was measured by real-time PCR. .
  • Example 4 Injin, Oil , Turmeric Inhibition of Inflammation Inhibition by Treatment of Complex Herbal Extract and Hepatitis B Antiviral Agent
  • liver tissue from lethal acute hepatitis B-induced mice, pulverized the tissue by adding 1 mL of trizol solution, and centrifuged at 12,000 x g for 10 minutes. The supernatant was transferred to a new tube, 200 ⁇ l of chloroform was added, and vortexed. After transferring the supernatant to a new tube, isopropanol and supernatant were added in a 1: 1 ratio.
  • Primer sequences used in the present invention are shown in Table 1 below.
  • inflammatory cytokines TNF- ⁇ , IL-1 ⁇ and hepatic fibrosis-related factors TGF- ⁇ and collagenase I and IV were treated when hepatitis B antiviral agent entecavir was compared with the control group.
  • the inflammatory cytokine TNF- ⁇ , IL-1 ⁇ and hepatic fibrosis were more effectively treated in the group treated with entecavir, injin, fat, and turmeric complex herbal extracts compared to the group treated with entercavir alone. It was confirmed that the factors related to TGF- ⁇ , collagenase (collagenage) I and IV are inhibited (see FIGS. 6 and 7).

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Abstract

The present invention relates to a composition containing Artemisia capillaris, Sanguisorba officinalis, and Curcuma longa extracts and an antiviral agent, as active ingredients, for preventing or treating liver disease. The co-administration of Artemisia capillaris, Sanguisorba officinalis, and Curcuma longa extracts and an antiviral agent for hepatitis B according to the present invention suppresses the hepatitis B virus e antigen and effectively inhibits the expression of inflammatory cytokine TNF-α, IL-1β, or TGF-β, so that the inhibition of cirrhosis or liver cancer as well as the treatment of hepatitis B can be expected.

Description

인진, 지유 및 울금 추출물 및 항바이러스제를 유효성분으로 포함하는 간질환 예방 또는 치료용 조성물Composition for preventing or treating liver disease, which comprises phosphorus, fat and turmeric extract and antiviral agents as active ingredients
본 발명은 인진, 지유 및 울금 추출물 및 항바이러스제를 유효성분으로 포함하는 간질환 예방 또는 치료용 조성물에 관한 것이다. The present invention relates to a composition for preventing or treating liver disease, which comprises phosphorus, fat and turmeric extract, and an antiviral agent as an active ingredient.
사람의 B형 간염 바이러스(HBV)는 급성 및 만성 간염을 유발하며, 자기제어성 급성 간염, 전격성 간염 또는 만성 활동성 간염 등의 병으로 진전될 수 있다. 만성 활동성 간염은 발전되어 간경변 및 간암 등을 유발하고, 간부전을 동반하는 심각한 급성으로 악화될 수 있다(Brechot, C., J. Hepatol., 4, 269-279, 1987). 만성 간염에 감염되었을 때 대부분의 환자들은 지속성 또는 활동성 간염 증세를 보이는 반면 일부 환자들은 증세를 보이지 않는다. 상기 바이러스성 간염의 발병 기전이 나 유발인자는 아직까지 명확히 밝혀지지 않은 실정이다. B형 간염 바이러스가 일으킨 간 손상은 숙주의 면역세포가 매개한다는 일부 증거가 제시된 이래(Milich, D. R. et al., J. Immunol., 143, 3141-3147, 1989) 간세포 괴사를 유발하는 바이러스 항원과 특정 B 세포 및 T 세포의 면역 반응 및 바이러스 단백질의 직접적인 세포 발병 기전 또는 종양 발병 기전에 대한 연구가 집중적으로 이루어졌다 (R. Zschke, O. et al., Nature, 348, 252-254 (1990)). 그러나 여전히 환자마다 다양하게 나타나는 임상 경로의 원인은 분명하지 않다.Human hepatitis B virus (HBV) causes acute and chronic hepatitis, and can progress to diseases such as self-controlling acute hepatitis, blunt hepatitis or chronic active hepatitis. Chronic active hepatitis develops, causes cirrhosis and liver cancer, and can be acutely acute with liver failure (Brechot, C., J. Hepatol., 4, 269-279, 1987). When infected with chronic hepatitis, most patients show persistent or active hepatitis, while some do not. The pathogenesis or causative factors of the viral hepatitis are not clear yet. Since some evidence suggests that liver damage caused by the hepatitis B virus is mediated by the host's immune cells (Milich, DR et al., J. Immunol., 143, 3141-3147, 1989). Intensive studies have been conducted on the immune response of specific B and T cells and the direct or pathogenic mechanisms of viral proteins (R. Zschke, O. et al., Nature, 348, 252-254 (1990). ). However, the causes of the clinical pathways that still vary from patient to patient are not clear.
B형 간염은 그 증세의 심각성 때문에 그 치료에 많은 관심을 갖고 연구되어져 왔다. 현재 몇몇 약물과 백신이 개발되고 또 임상 전 실험과 임상 실험에서 좋은 평가를 받았으나 실제 치료제로 적용된 약은 거의 없는 상태로 지금까지 B형 간염 바이러스(HBV)성 간염 환자에게 시행되는 유일한 치료법은 인체 면역 체계에 의존하는 것이다. HBV에 대한 인체 면역 작용은 HBV입자를 제거하지만 다른 한편으로는 간세포를 파괴하기 때문에 이러한 면역 작용의 부작용으로 치명적인 질환이 유발되기도 한다. 또한, 이러한 문제는 질병의 진행을 예측하기 어렵게 하므로 빠르고 효율적인 간염 치료를 위해서는 항바이러스 요법과 면역 치료법을 복합적으로 사용하는 것이 바람직하다. 즉, 바이러스성 간염의 치료시 감염된 간세포는 T 임파구(cytotoxic T lymphocyte, CTL)에 의해 파괴되고, 파괴된 간세포에서 방출된 바이러스 입자는 바이러스에 대한 중화 항체를 제거하여 간세포로의 재감염도 막으면서 바이러스의 증식도 억제하여야 한다. 지금까지 B형 간염 바이러스를 치료하기 위하여 인터페론, 핵산 유도체 또는 면역 조절물질 등 여러 방법이 시도되었으나 인터페론-α만이 거의 유일하게 치료 효과가 있는 것으로 나타났으며 현재 인터페론-α만이 미국에서 간염 치료제로 사용되고 있다.Hepatitis B has been studied with great interest in its treatment because of its severity. Currently, several drugs and vaccines have been developed and have received good reviews in preclinical and clinical trials, but few drugs have been applied as actual therapeutics. To date, the only treatment for hepatitis B virus (HBV) hepatitis patients is human immunity. It depends on the system. Human immune action against HBV removes HBV particles, but on the other hand, destroys hepatocytes, so side effects of these immune actions can lead to fatal diseases. In addition, since these problems make it difficult to predict disease progression, it is desirable to use a combination of antiviral therapy and immunotherapy for fast and efficient hepatitis treatment. In other words, during the treatment of viral hepatitis, infected hepatocytes are destroyed by cytotoxic T lymphocytes (CTLs), and virus particles released from the destroyed hepatocytes remove the neutralizing antibodies against the virus to prevent reinfection into the hepatocytes. Proliferation of should also be suppressed. Several methods have been tried to treat the hepatitis B virus, including interferon, nucleic acid derivatives or immunomodulators, but only interferon-α has been shown to be the only therapeutic effect. have.
인터페론-α는 스컬레드(Sculled) 등에 의하여 1970년대 중반 처음 만성 B형 간염 치료제로 시험 되었는데 HBV 복제를 억제하는 효과가 있는 것으로 알려졌다. 그러나 인터페론-α는 1주일에 3번씩 최소 3개월 동안 투여하였을 경우 평균 20%의 환자에서 바이러스 증식이 억제되는 치료 효과를 나타낼 뿐 지속적인 억제 효과를 보이지는 못하며, 특히 동양 사람에게 많은 모자간의 수직 감염에 의한 환자 또는 어린이들은 인터페론-α에 내성을 나타내므로 그 치료 효과가 낮다. 또한, B형 간염 바이러스에 감염된 급성 및 만성 환자들 중 50% 이하만이 인터페론-α 치료법에 적합하다는 것이 최근 보고되었는데, 상기 환자들 중 바이러스에 대한 영향으로 간에서 생성되는 각종 효소들(AST, SGOT, ALT, SGPT 등)의 양이 증가하는 경우에만 이 인터페론-α 치료법이 효과를 기대할 수 있다고 한다. 따라서 인터페론-α에 대해 내성을 가지는 환자들을 치료할 수 있는 B형 간염 바이러스 치료제의 개발이 시급한 실정이나 아직까지 그 연구가 미미하다. Interferon-α was first tested by Sculled et al in the mid-1970s as a treatment for chronic hepatitis B. It has been shown to be effective in inhibiting HBV replication. However, when interferon-α is administered three times a week for at least three months, on average, 20% of patients show a therapeutic effect that inhibits virus growth but do not show sustained inhibitory effects. Patients or children are resistant to interferon-α and therefore have a low therapeutic effect. In addition, it has recently been reported that only 50% or less of acute and chronic patients infected with hepatitis B virus are suitable for the treatment of interferon-α. Among the patients, various enzymes (AST, Only if the amount of SGOT, ALT, SGPT, etc. is increased, the interferon-α treatment can be expected to be effective. Therefore, it is urgent to develop a hepatitis B virus therapeutic agent that can treat patients who are resistant to interferon-α, but the research is still insufficient.
본 발명의 목적은 인진, 지유 및 울금 추출물을 유효성분으로 포함하는 간질환 치료용 약학적 조성물을 제공하는 것이다. It is an object of the present invention to provide a pharmaceutical composition for treating liver disease, which comprises jinjin, fat milk and turmeric extract as active ingredients.
본 발명의 또 다른 목적은 인진, 지유 및 울금 추출물을 유효성분으로 포함하는 간질환 예방 및 개선용 건강기능성식품을 제공하는 것이다. Still another object of the present invention is to provide a health functional food for preventing and improving liver disease, which comprises phosphorus, fat milk and turmeric extract as active ingredients.
본 발명의 또 다른 목적은 간질환이 유발된 개체에 인진, 지유 및 울금 추출물과 B형 간염의 항바이러스제를 병용 투여하는 단계를 포함하는, 간질환 치료 방법을 제공하는 것이다. Still another object of the present invention is to provide a method for treating liver disease, comprising co-administration of an antiviral agent of hepatitis, hepatitis and turmeric extract and hepatitis B to a subject having a liver disease.
상기 목적을 달성하기 위하여, 본 발명은 인진, 지유 및 울금 추출물을 유효성분으로 포함하는 간질환 치료용 약학적 조성물을 제공한다. In order to achieve the above object, the present invention provides a pharmaceutical composition for treating liver disease, which comprises the extract of jinjin, fat milk and turmeric as an active ingredient.
본 발명의 일실시예에 있어서, 상기 추출물은 인진, 지유 및 울금이 각각 3:1:1의 중량비로 혼합된 것일 수 있다. In one embodiment of the present invention, the extract may be a mixture of phosphorus, fat milk and turmeric each weight ratio of 3: 1: 1.
본 발명의 일실시예에 있어서, 상기 간질환은 지방간, 간염 또는 간경화로부터 선택되는 어느 하나일 수 있다. In one embodiment of the present invention, the liver disease may be any one selected from fatty liver, hepatitis or cirrhosis.
본 발명의 일실시예에 있어서, 상기 조성물은 B형 간염의 항바이러스제와 함께 제제화하거나 병용하여 사용할 수 있다. In one embodiment of the present invention, the composition may be formulated or used in combination with an antiviral agent of hepatitis B.
본 발명의 일실시예에 있어서, 상기 B형 간염의 항바이러스제는 엔테카비어(entecavir), 테노포비어(tenofovir), 라미부딘(lamibudine), 아데포비어(adefovir) 및 클레부딘(clebudine)에서 선택되는 1종 이상일 수 있다. In one embodiment of the present invention, the antiviral agent of hepatitis B may be at least one selected from entecavir, tenofovir, lamivudine, adefovir and clebudine. have.
본 발명의 일실시예에 있어서, 상기 조성물은 TNF-α, IL-1β, TGF-β, 콜라게나아제(collagenage) Ⅰ 또는 콜라게나아제(collagenage) Ⅳ의 발현을 저해 또는 억제시킬 수 있다. In one embodiment of the present invention, the composition may inhibit or inhibit the expression of TNF-α, IL-1β, TGF-β, collagenase I or collagenase IV.
또한, 본 발명은 인진, 지유 및 울금 추출물을 유효성분으로 포함하는 간질환 예방 및 개선용 건강기능성식품을 제공한다. In addition, the present invention provides a health functional food for preventing and improving liver disease, which comprises phosphorus, fat milk and turmeric extract as active ingredients.
또한, 본 발명은 간질환이 유발된 개체에 인진, 지유 및 울금 추출물과 B형 간염의 항바이러스제를 병용 투여하는 단계를 포함하는, 간질환 치료 방법을 제공한다. In another aspect, the present invention provides a method for treating liver disease, comprising co-administration of the antiviral agent of hepatitis B and hepatitis B, turmeric extract and hepatitis B to a subject having a liver disease.
본 발명의 일실시예에 있어서, 상기 B형 간염의 항바이러스제는 엔테카비어(entecavir), 테노포비어(tenofovir), 라미부딘(lamibudine), 아데포비어(adefovir) 및 클레부딘(clebudine)에서 선택되는 1종 이상일 수 있다. In one embodiment of the present invention, the antiviral agent of hepatitis B may be at least one selected from entecavir, tenofovir, lamivudine, adefovir and clebudine. have.
본 발명의 일실시예에 있어서, 상기 간질환은 지방간, 간염 또는 간경화로부터 선택되는 어느 하나일 수 있다. In one embodiment of the present invention, the liver disease may be any one selected from fatty liver, hepatitis or cirrhosis.
본 발명에 따른 인진, 지유 및 울금 추출물과 B형 간염의 항바이러스제의 병용 투여는 B형 간염 바이러스 e 항원를 억제하고, 염증성 사이토카인인 TNF-α, IL-1β 또는 TGF-β의 발현을 효과적으로 저해하여, B형 간염의 치료 뿐 아니라 간경화 또는 간암의 억제 효과까지 기대할 수 있다. Combination administration of the antiviral agent of hepatitis, fat and turmeric extract with hepatitis B according to the present invention inhibits hepatitis B virus e antigen and effectively inhibits the expression of inflammatory cytokines TNF-α, IL-1β or TGF-β Thus, not only the treatment of hepatitis B but also the inhibitory effect of cirrhosis or liver cancer can be expected.
도 1은 인진, 지유 및 울금의 70% 에탄올 추출물과 B형 간염의 항바이러스제의 병용 투여에 의한 HBV HBeAg 억제 정도를 확인한 결과이다. 1 is a result confirming the degree of inhibition of HBV HBeAg by co-administration of antiviral agent of hepatitis B with 70% ethanol extract of jinjin, fat milk and turmeric.
도 2는 인진, 지유 및 울금의 30% 에탄올 추출물의 투여 후 HBV HBsAg (A) 및 HBV HBeAg 억제(B) 정도를 확인하였고, 상기 추출물과 B형 간염의 항바이러스제(ETV)의 병용 투여에 의한 HBV HBsAg (C) 및 HBV HBeAg 억제(D) 정도를 확인한 결과를 나타낸 것이다. Figure 2 confirmed the degree of HBV HBsAg (A) and HBV HBeAg inhibition (B) after administration of 30% ethanol extract of phosphorus, fat and turmeric, and by the combination administration of the antiviral agent (ETV) of the extract and hepatitis B The results of confirming the degree of HBV HBsAg (C) and HBV HBeAg inhibition (D) are shown.
도 3은 인진, 지유 및 울금의 30% 에탄올 추출물의 투여 후 pgRNA 의 양을 측정한 결과를 나타낸 것이다. Figure 3 shows the results of measuring the amount of pgRNA after administration of 30% ethanol extract of phosphorus, fat milk and turmeric.
도 4는 급성 B형 간염 유도 마우스에서의 HBV 비리온 생성억제를 통한 인진, 지유 및 울금 추출물과 B형 간염의 항바이러스제의 병용 투여에 의한 효능을 확인한 결과이다.Figure 4 is a result confirming the efficacy by the combined administration of antiviral agent of hepatitis, fat and turmeric extract and hepatitis B through the inhibition of HBV virion production in acute hepatitis B induced mice.
도 5는 급성 B형 간염 유도 마우스에서 인진, 지유 및 울금의 30% 에탄올 추출물과 B형 간염의 항바이러스제(ETV)의 병용 투여 후 cccDNA 농도를 측정한 결과를 나타낸 것이다. Figure 5 shows the results of measuring the cccDNA concentration after the co-administration of 30% ethanol extract of phosphorus, fat and turmeric and antiviral agent (ETV) of hepatitis B in acute hepatitis B induced mice.
도 6은 급성 B형 간염 유도 마우스에서의 인진, 지유 및 울금 추출물과 B형 간염의 항바이러스제의 병용 투여에 의한 염증성 사이토카인인 TNF-α, IL-1β 억제 효과를 확인한 결과이다. 6 is a result confirming the inhibitory effect of inflammatory cytokines TNF-α, IL-1β by co-administration of antiviral agents of hepatitis, fat and turmeric extract and hepatitis B in acute hepatitis B induced mice.
도 7은 급성 B형 간염 유도 마우스에서의 인진, 지유 및 울금 추출물과 B형 간염의 항바이러스제의 병용 투여에 의한 간섬유화와 관련된 인자인 TGF-β, 콜라게나아제(collagenage) Ⅰ, 콜라게나아제(collagenage) Ⅳ 억제 효과를 확인한 결과이다. Figure 7 shows the factors related to hepatic fibrosis by combination administration of antiviral agent of hepatitis, fat and turmeric extract and hepatitis B in acute hepatitis B induced mice, collagenage I, collagenase (collagenage) IV inhibitory effect was confirmed.
본 발명은 인진, 지유 및 울금 추출물 및 B형 간염의 항바이러스제를 유효성분으로 포함하는 간질환 치료용 조성물을 제공한다. The present invention provides a composition for treating liver disease, which comprises an antiviral agent of phosphorus, fat and turmeric extract and hepatitis B as an active ingredient.
앞서 종래기술에서도 기술한 바와 같이, 현재 사용되고 있는 B형 간염 또는 간질환 치료제들의 경우 근본적인 치료가 이루어지지 않아 약학적 효능이 미비하며, 장기간 사용 시 바이러스 제거 효능이 약해질 뿐 아니라 약물 내성이나 독성의 부작용을 유발할 수 있다. 이에 본 발명자들은 인진, 지유 및 울금 추출물과 B형 간염의 항바이러스제를 병용 투여하였을 때 기존의 B형 간염의 항바이러스제를 단독으로 처리하였을 때보다 바이러스 증식 억제 효과가 뛰어나고, 염증성 사이토카인 및 간섬유화와 관련된 인자의 발현을 효과적으로 억제할 수 있음을 실험을 통해 확인하였다. As described in the prior art, the currently used hepatitis B or liver disease treatments are inadequate in pharmacological effects due to no fundamental treatment, and in addition to weakening of virus elimination efficacy in long-term use, May cause side effects. Therefore, the inventors of the present invention, when combined with the antiviral agent of hepatitis B and hepatitis B and turmeric extract and the hepatitis B anti-viral proliferation effect compared to the conventional antiviral agent of hepatitis B alone, inflammatory cytokines and hepatic fibrosis Experiments confirmed that it can effectively suppress the expression of factors related to.
따라서, 본 발명은 인진, 지유 및 울금 추출물 및 B형 간염의 항바이러스제를 유효성분으로 포함하는 간질환 치료용 조성물을 제공한다. Accordingly, the present invention provides a composition for treating liver disease, which comprises an antiviral agent of phosphorus, fat and turmeric extract and hepatitis B as an active ingredient.
본 발명에서 “B형 간염의 항바이러스제”는 엔테카비어(entecavir), 테노포비어(tenofovir), 라미부딘(lamibudine), 아데포비어(adefovir) 및 클레부딘(clebudine)에서 선택되는 1종 이상일 수 있으며, 이에 제한되는 것은 아니지만 가장 바람직하게는 엔테카비어(entecavir)일 수 있다. In the present invention, the "antiviral agent of hepatitis B" may be at least one selected from entecavir, tenofovir, lamivudine, adefovir and clebudine, but is not limited thereto. But most preferably may be entercavir.
본 발명에 따른 상기 인진, 지유 및 울금의 추출물은 당업계에 공지된 추출 및 분리하는 방법을 사용하여 인진, 지유 및 울금을 대상으로 추출물을 분리 및 수득한 것을 사용할 수 있으며, 본 발명에서 정의된 ‘추출물’은 적절한 용매를 이용하여 인진, 지유 및 울금으로부터 추출할 수 있다. 이때 추출물을 수득하기 위해 사용할 수 있는 적절한 용매로는 당업계에서 허용되는 용매라면 어느 것을 사용해도 무방하며, 물 또는 유기용매를 사용할 수 있다. 예를 들어, 정제수, 메탄올(methanol), 에탄올(ethanol), 프로판올(propanol), 이소프로판올(isopropanol), 부탄올(butanol) 등을 포함하는 탄소수 1 내지 4의 알코올, 아세톤(acetone), 에테르(ether), 벤젠(benzene), 클로로포름(chloroform), 에틸아세테이트(ethyl acetate), 메틸렌클로라이드(methylene chloride), 헥산(hexane) 및 시클로헥산(cyclohexane) 등의 각종 용매를 단독으로 혹은 혼합하여 사용할 수 있으나, 이에 제한되지는 않는다.The extract of the phosphorus, fat or turmeric according to the present invention can be used to isolate and obtain the extract for phosphorus, fat and turmeric using a method known in the art extraction and separation, defined in the present invention An 'extract' can be extracted from phosphorus, fat, and turmeric using an appropriate solvent. In this case, any suitable solvent that may be used to obtain the extract may be used as long as it is a solvent acceptable in the art, and water or an organic solvent may be used. For example, alcohol having 1 to 4 carbon atoms, acetone, ether including purified water, methanol, ethanol, propanol, isopropanol, butanol, etc. , Solvents such as benzene, chloroform, ethyl acetate, methylene chloride, hexane and cyclohexane may be used alone or in combination. It is not limited.
추출 방법으로는 열수추출법, 냉침추출법, 환류냉각추출법, 용매추출법, 수증기증류법, 초음파추출법, 용출법, 압착법 등의 방법 중 어느 하나를 선택하여 사용할 수 있다. 또한, 목적하는 추출물은 추가로 통상의 분획 공정을 수행할 수도 있으며, 통상의 정제 방법을 이용하여 정제될 수도 있다. 본 발명의 인진, 지유 및 울금 추출물의 제조방법에는 제한이 없으며, 공지되어 있는 어떠한 방법도 이용될 수 있다.As the extraction method, any one of hot water extraction method, cold leaching extraction method, reflux cooling extraction method, solvent extraction method, steam distillation method, ultrasonic extraction method, elution method and compression method can be used. In addition, the desired extract may further be subjected to a conventional fractionation process, it may be purified using conventional purification methods. There is no limitation in the preparation method of the jinjin, fat milk and turmeric extract of the present invention, any known method can be used.
또한, 상기 본 발명의 약학적 조성물은 상기 유효성분 이외에 약제학적으로 적합하고 생리학적으로 허용되는 보조제를 사용하여 제조될 수 있으며, 상기 보조제로는 부형제, 붕해제, 감미제, 결합제, 피복제, 팽창제, 윤활제, 활택제 또는 향미제 등을 사용할 수 있다.In addition, the pharmaceutical composition of the present invention may be prepared using a pharmaceutically acceptable and physiologically acceptable adjuvant in addition to the active ingredient, and the adjuvant may include an excipient, a disintegrant, a sweetener, a binder, a coating agent, and an expanding agent. , Lubricants, lubricants or flavoring agents can be used.
상기 약제학적 조성물은 투여를 위해서 상기 기재한 유효성분 이외에 추가로약제학적으로 허용 가능한 담체를 1종 이상 포함하여 약제학적 조성물로 바람직하게 제제화할 수 있다.The pharmaceutical composition may be preferably formulated into a pharmaceutical composition including one or more pharmaceutically acceptable carriers in addition to the above-described active ingredient for administration.
상기 약제학적 조성물의 제제 형태는 과립제, 산제, 정제, 피복정, 캡슐제,좌제, 액제, 시럽, 즙, 현탁제, 유제, 점적제 또는 주사 가능한 액제 등이 될 수 있다. 예를 들어, 정제 또는 캡슐제의 형태로의 제제화를 위해, 유효 성분은 에탄올, 글리세롤, 물 등과 같은 경구, 무독성의 약제학적으로 허용 가능한 불활성 담체와 결합될 수 있다. 또한, 원하거나 필요한 경우, 적합한 결합제, 윤활제, 붕해제 및 발색제 또한 혼합물로 포함될 수 있다. 적합한 결합제는 이에 제한되는 것은아니나, 녹말, 젤라틴, 글루코스 또는 베타-락토오스와 같은 천연 당, 옥수수 감미제, 아카시아, 트래커캔스 또는 소듐올레이트와 같은 천연 및 합성 검, 소듐 스테아레이트, 마그네슘 스테아레이트, 소듐 벤조에이트, 소듐 아세테이트, 소듐 클로라이드 등을 포함한다. 붕해제는 이에 제한되는 것은 아니나, 녹말, 메틸 셀룰로스, 아가, 벤토니트, 잔탄 검 등을 포함한다. 액상 용액으로 제제화되는 조성물에있어서 허용 가능한 약제학적 담체로는, 멸균 및 생체에 적합한 것으로서, 식염수,멸균수, 링거액, 완충 식염수, 알부민 주사용액, 덱스트로즈 용액, 말토 덱스트린용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 더 나아가 해당분야의 적절한 방법으로 Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제제화 할 수 있다.Formulation forms of the pharmaceutical compositions may be granules, powders, tablets, coated tablets, capsules, suppositories, solutions, syrups, juices, suspensions, emulsions, drops or injectable solutions. For example, for formulation in the form of tablets or capsules, the active ingredient may be combined with an oral, nontoxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. In addition, if desired or necessary, suitable binders, lubricants, disintegrants and coloring agents may also be included in the mixture. Suitable binders include, but are not limited to, natural and synthetic gums such as starch, gelatin, glucose or beta-lactose, corn sweeteners, acacia, trackercance or sodium oleate, sodium stearate, magnesium stearate, sodium Benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. Acceptable pharmaceutical carriers in compositions formulated as liquid solutions are sterile and biocompatible, which include saline, sterile water, Ringer's solution, buffered saline, albumin injectable solutions, dextrose solutions, maltodextrin solutions, glycerol, ethanol and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers and bacteriostatic agents may be added as necessary. Diluents, dispersants, surfactants, binders and lubricants may also be added in addition to formulate into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Furthermore, the method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA can be formulated according to each disease or component, as appropriate in the art.
본 발명의 일실시예에 있어서, 본 발명의 인진, 지유 및 울금 추출물 및 B형 간염의 항바이러스제는 조성물 총 중량에 대하여 0.1 ~ 50 중량%로 포함될 수 있다.In one embodiment of the present invention, the antiviral agent of the jinjin, fat milk and turmeric extract and hepatitis B of the present invention may be included in 0.1 to 50% by weight relative to the total weight of the composition.
이러한 본 발명의 인진, 지유 및 울금 추출물이 치료, 예방, 개선할 수 있는 상기 간질환은 이에 제한되지는 않으나, 지방간, 간염 또는 간경화일 수 있으며, 가장 바람직하게는 B형 간염이다. The liver disease which can be treated, prevented, and improved the phosphorus, fat milk and turmeric extract of the present invention is not limited thereto, but may be fatty liver, hepatitis or cirrhosis, most preferably hepatitis B.
나아가 본 발명의 조성물은 간질환 치료 및 예방을 위한 약학적 조성물 이외에도 식품 조성물로 사용될 수 있는데, 이러한 식품 조성물은 유효성분인 인진, 지유 및 울금 추출물을 함유하는 것 외에 통상의 식품 조성물과 같이 여러 가지 향미제 또는 천연탄수화물 등을 추가 성분으로서 함유할 수 있다.Furthermore, the composition of the present invention can be used as a food composition in addition to the pharmaceutical composition for the treatment and prevention of liver disease, the food composition contains a variety of active ingredients, such as ordinary food composition, in addition to containing the active ingredients phosphorus, fat milk and turmeric extract Flavoring agents or natural carbohydrates and the like may be included as additional ingredients.
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 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 향미제는 천연 향미제 (타우마틴), 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등) 및 합성 향미제 (사카린, 아스파르탐 등)를 유리하게 사용할 수 있다.Examples of the natural carbohydrates described above include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. The aforementioned flavoring agents can advantageously be used natural flavoring agents (tautin), stevia extracts (for example rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).
본 발명의 식품 조성물은 상기 약제학적 조성물과 동일한 방식으로 제제화되어 기능성 식품으로 이용하거나, 각종 식품에 첨가할 수 있다. 본 발명의 조성물을첨가할 수 있는 식품으로는 예를 들어, 음료류, 육류, 초코렛, 식품류, 과자류, 피자, 라면, 기타 면류, 껌류, 사탕류, 아이스크림류, 알코올 음료류, 비타민 복합제및 건강보조식품류 등이 있다.The food composition of the present invention may be formulated in the same manner as the pharmaceutical composition, used as a functional food, or added to various foods. Foods to which the composition of the present invention can be added include, for example, beverages, meat, chocolate, foods, confectionery, pizza, ramen, other noodles, gums, candy, ice cream, alcoholic beverages, vitamin complexes, and health supplements. There is this.
또한, 상기 식품 조성물은 유효성분인 인진, 지유 및 울금 추출물 외에 여러 가지 영양제, 비타민, 광물 (전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제 (치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 식품 조성물은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.In addition, the food composition is a variety of nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors in addition to the phosphorus, fat and turmeric extracts as active ingredients, colorants and neutralizers (such as cheese, chocolate), Pectic acid 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 beverages and the like. In addition, the food composition of the present invention may contain a fruit flesh for producing natural fruit juice and fruit juice beverage and vegetable beverage.
본 발명의 유효성분인 인진, 지유 및 울금 추출물은 천연물질로서 독성 및 부작용은 거의 없으므로 장기간 복용시에도 안심하고 사용할 수 있다.Injin, fat milk and turmeric extract of the active ingredient of the present invention is a natural substance, so there is little toxicity and side effects, so it can be used with confidence even in long-term use.
본 발명의 건강기능식품은 간손상을 개선 및 예방하기 위한 목적으로, 정제,캅셀, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공할 수 있다.The health functional food of the present invention may be prepared and processed in the form of tablets, capsules, powders, granules, liquids, pills and the like for the purpose of improving and preventing liver damage.
본 발명에서 “건강기능식품”이라 함은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 말하며, 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.In the present invention, "health functional food" refers to a food manufactured and processed using raw materials or ingredients having functional properties useful for the human body according to the Health Functional Food Act No. 6767, and nutrients for the structure and function of the human body. It is meant to be consumed for the purpose of regulating or obtaining a useful effect for health use such as physiological action.
본 발명의 건강기능식품은 통상의 식품 첨가물을 포함할 수 있으며, 식품 첨가물로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전청에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.The health functional food of the present invention may include a conventional food additive, and the suitability as a food additive, unless otherwise specified, in accordance with the General Regulations of the Food Additives and General Test Methods approved by the Food and Drug Administration, etc. Judging by the standards and standards.
상기 “식품 첨가물 공전”에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼슘, 니코틴산, 계피산 등의 화학적 합성물; 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물; L-글루타민산나트륨제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류 등을 들 수 있다.Examples of the items listed in the "Food Additive Reduction" include chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; Natural additives such as dark blue pigment, licorice extract, crystalline cellulose, high color pigment and guar gum; And mixed preparations such as sodium L-glutamate, algae additives, preservatives and tar dyes.
예를 들어, 정제 형태의 건강기능식품은 본 발명의 유효성분인 인진, 지유 및 울금 추출물을 부형제, 결합제, 붕해제 및 다른 첨가제와 혼합한 혼합물을 통상의 방법으로 과립화한 다음, 활택제 등을 넣어 압축성형하거나, 상기 혼합물을 직접 압축 성형할수 있다. 또한 상기 정제 형태의 건강기능식품은 필요에 따라 교미제 등을 함유할수도 있다.For example, the health functional food in the form of tablets is a mixture of the jinjin, fat milk and turmeric extract of the active ingredient of the present invention with excipients, binders, disintegrants and other additives, and then granulated in a conventional manner, and then a lubricant and the like. Compression molding, or the mixture may be directly compression molded. In addition, the health functional food in the form of tablets may contain a mating agent, if necessary.
캅셀 형태의 건강기능식품 중 경질 캅셀제는 통상의 경질 캅셀에 본 발명의유효성분인 인진, 지유 및 울금 추출물을 부형제 등의 첨가제와 혼합한 혼합물을 충진하여 제조할수 있으며, 연질 캅셀제는 인진, 지유 및 울금 추출물을 부형제 등의 첨가제와 혼합한 혼합물을 젤라틴과 같은 캅셀기제에 충진하여 제조할 수 있다. 상기 연질 캅셀제는 필요에 따라 글리세린 또는 소르비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다.Hard capsules among the health functional foods in the form of capsules can be prepared by filling a mixture of additives, such as excipients, phosphorus, fat and turmeric extracts, which are the active ingredients of the present invention, into conventional hard capsules. A mixture of turmeric extract and additives such as excipients may be prepared by filling a capsule base such as gelatin. The soft capsule agent may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, as necessary.
환 형태의 건강기능식품은 본 발명의 유효성분인 인진, 지유 및 울금 추출물과 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 성형하여 조제할 수 있으며, 필요에 따라 백당이나 다른 제피제로 제피할 수 있으며, 또는 전분, 탈크와 같은 물질로 표면을 코팅할 수도 있다.The health functional food in the form of a cyclic form can be prepared by molding a mixture of the jinjin, fat milk and turmeric extract and excipients, binders, disintegrating agents and the like as the active ingredients of the present invention, and, if necessary, sucrose or Other coatings may be applied, or the surface may be coated with materials such as starch, talc.
과립 형태의 건강기능식품은 본 발명의 유효성분인 인진, 지유 및 울금 추출물과 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 입상으로 제조할 수있으며, 필요에 따라 착향제, 교미제 등을 함유할 수 있다.The health functional food in the form of granules can be prepared by granulation of a mixture of jinjin, fat milk and turmeric extract and excipients, binders, disintegrants and the like, which are the active ingredients of the present invention, and a flavoring agent, if necessary. And a copper may be contained.
상기 건강기능식품은 정제, 캡슐제, 환제 또는 액제 형태로 제조될 수 있으며, 예로 음료류, 육류, 초코렛, 식품류, 과자류, 피자, 라면, 기타 면류, 껌류, 사탕류, 아이스크림류, 알코올 음료류, 비타민 복합제 및 건강보조식품류 등일 수 있다.The health functional food may be prepared in the form of tablets, capsules, pills or liquids, for example, beverages, meat, chocolate, foods, confectionary, pizza, ramen, other noodles, gums, candy, ice cream, alcoholic beverages, vitamin complexes And health supplements.
또한, 본 발명은 간질환이 유발된 개체에 인진, 지유 및 울금 추출물과 B형 간염의 항바이러스제를 병용 투여하는 단계를 포함하는, 간질환 치료 방법을 제공한다. In another aspect, the present invention provides a method for treating liver disease, comprising co-administration of the antiviral agent of hepatitis B and hepatitis B, turmeric extract and hepatitis B to a subject having a liver disease.
본 발명의 간질환 치료 방법은 인진, 지유 및 울금 추출물과 B형 간염의 항바이러스제를 치료적 유효량으로 개체에 투여하는 것을 포함한다. 특정 개체에 대한 구체적인 치료적 유효량은 달성하고자 하는 반응의 종류와 정도, 경우에 따라 다른 제제가 사용되는지의 여부를 비롯한 구체적 조성물, 개체의 연령, 체중, 일반건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율, 치료기간, 구체적 조성물과 함께 사용되거나 동시 사용되는 약물을 비롯한 다양한 인자와 의약 분야에 잘 알려진 유사 인자에 따라 다르게 적용하는 것이 바람직하다. 따라서 본 발명의 목적에 적합한 조성물의 유효량은 전술한 사항을 고려하여 결정하는 것이 바람직하다.The method of treating liver disease of the present invention comprises administering to the individual a therapeutically effective amount of an antiviral agent of hejin, fat and turmeric extract and hepatitis B. The specific therapeutically effective amount for a particular individual can be determined by the specific composition, including the type and severity of the reaction to be achieved, whether or not other agents are used in some cases, the age, weight, general health, sex and diet, time of administration, It is desirable to apply differently depending on the route of administration and the rate of release of the composition, the duration of treatment, and the various factors and similar factors well known in the medical arts, including drugs used with or concurrent with the specific composition. Therefore, the effective amount of the composition suitable for the purpose of the present invention is preferably determined in consideration of the above matters.
상기 개체는 임의의 포유동물에 적용가능하며, 상기 포유동물은 인간 및 영장류뿐만 아니라, 소, 돼지, 양, 말, 개 및 고양이 등의 가축을 포함한다.The subject is applicable to any mammal, and the mammal includes humans and primates, as well as domestic animals such as cattle, pigs, sheep, horses, dogs, and cats.
이하, 본 발명을 실시예를 통하여 더욱 상세히 설명하기로 한다. 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are intended to illustrate the present invention more specifically, but the scope of the present invention is not limited to these examples.
제조예Production Example 1. 인진,  1.jinjin, 지유Oil , , 울금Turmeric 복합 한방 70% 에탄올 추출물 제조방법 Method of manufacturing complex herbal 70% ethanol extract
본 발명자들은 인진, 지유, 울금을 물로 깨끗이 세척하여 그늘에서 건조한 후, 곱게 분말화시켰다. 분말화된 인진 45g, 지유 15g, 울금 15g의 비율로 혼합된 150g을 70% 에탄올에 넣고 실온에서 3일간 냉침 추출한 후, 여지(와트만사, 미국)로 감압 여과한 다음, 여과 추출물은 진공회전농축기로 실온에서 에탄올 용매를 제거한 후 추출된 잔사로서 인진, 지유, 울금의 조추출물 29.45g을 수득하였다. The present inventors washed phosphorus, fat milk, turmeric with water, dried in the shade, and then finely powdered. 45 g of powdered phosphorus, 15 g of fat milk, 15 g of turmeric was added to 70% ethanol and extracted by cold extraction at room temperature for 3 days, filtered under reduced pressure with a filter paper (Watman, USA), and the filtrate was concentrated on a vacuum rotary concentrator. After removing the ethanol solvent at room temperature to give 29.45 g of crude extract of phosphorus, fat milk, turmeric as an extracted residue.
하기의 실험을 위하여 수득된 인진, 지유, 울금의 조추출물을 DMSO에 10mg/ml로 녹여서 사용하였다. Crude extracts of phosphorus, fat milk and turmeric obtained for the following experiment were used by dissolving 10 mg / ml in DMSO.
제조예Production Example 2. 인진,  2. Injin, 지유Oil , , 울금Turmeric 복합 한방 30% 에탄올 Complex Herbal 30% Ethanol 추출물 제조방법Extract Preparation Method
인진 12 kg, 지유 4 kg, 울금 4 kg 각각의 생약을 30 mm의 파쇄기를 이용하여 적당한 크기로 파쇄한 후, 원료약품의 분량대로 생약을 달아 추출기에 넣고 10 배의 30% 에탄올(KP)을 넣어 80 ∼ 90 ℃에서 3 시간 추출하여 추출액을 5 ㎛ 크기의 마이크로필터를 이용하여 여과하고 잔사를 동일 조건으로 2차 추출하고 여과 후 60 ℃이하에서 감압농축한 후 건조엑스 3.74∼4.56 kg을 수득하였다. 평균수득률은 약 20.75 % 이었다. 12 kg of phosphorus, 4 kg of fat milk, 4 kg of turmeric are crushed to the appropriate size using a 30 mm crusher, and then the crude drugs are weighed into the extractor, and 10 times 30% ethanol (KP) is added to the extractor. The mixture was extracted at 80-90 ° C. for 3 hours, and the extract was filtered using a 5 μm microfilter. The residue was extracted secondarily under the same conditions, and the resultant was concentrated under reduced pressure at 60 ° C. or lower to obtain 3.74 to 4.56 kg of dry extract. It was. The average yield was about 20.75%.
실시예Example 1. 인진,  1.jinjin, 지유Oil , , 울금Turmeric 복합 한방 추출물 및 B형 간염 항바이러스제 처리에 따른 B형 간염  Hepatitis B by Complex Herbal Extracts and Hepatitis B Antiviral Treatment e항원eantigen 억제 효과 확인 Confirm inhibitory effect
본 발명에서 KCT-O1 군은 제조예 1의 방법으로 제조된 본 발명의 인진, 지유 및 울금의 복합 추출물이고, KCT-O2 군은 인진, 지유, 울금, 단삼 및 복분자가 각각 45 : 15 : 15 : 12 :　12의 혼합비로 섞여 추출된 추출물이며, KCT-03 군은 인진청간탕을 추출한 추출물을 의미한다. KCT-O1 group in the present invention is a complex extract of the phosphorus, fat milk and turmeric of the present invention prepared by the method of Preparation Example 1, KCT-O2 group is 45: 15: 15 : 12: Extracted by mixing in a mixture of 12: KCT-03 group means the extract extracted the Injincheonggantang.
본 발명자들은 HepG2.2.15 HBV 포함 세포주에 엔테카비어(Entecavir) 혹은 테노포비어(Tenofovir)를 200 ㎍/ml의 농도로 처리하고, KCT-O1, KCT-O2, KCT-O3을 10, 25, 50, 100, 250 ㎍/ml의 농도로 추가 처리한 후 24시간 배양하고 배양액을 회수하여 HBeAg ELISA를 수행하여 HBeAg의 농도를 측정하였다.The present inventors treated Entecavir or Tenofovir at a concentration of 200 μg / ml in a HepG2.2.15 HBV-containing cell line, and treated KCT-O1, KCT-O2, KCT-O3 with 10, 25, 50, After further treatment at a concentration of 100 and 250 ㎍ / ml, the cells were incubated for 24 hours, and the culture solution was recovered and subjected to HBeAg ELISA to measure the concentration of HBeAg.
그 결과, 엔테카비어(Entecavir) 혹은 테노포비어(Tenofovir)를 처리한 군에서는 아무것도 처리하지 않은 대조군과 비교하여 HBeAg가 억제되지 않았으나, 본 발명의 인진, 지유, 울금 복합 한방 추출물 및 B형 간염 항바이러스제를 병용 투여한 KCTO1 처리군에서는 농도의존적으로 HBeAg 억제 효과가 있음을 확인할 수 있었다(도 1 참조). As a result, in the group treated with Entecavir or Tenenofovir, HBeAg was not inhibited as compared to the control group treated with nothing, but the phosphorus, fat, turmeric complex herbal extract of the present invention and hepatitis B antiviral agent In the KCTO1 treatment group administered in combination, it was confirmed that the HBeAg inhibitory effect in a concentration-dependent (see Fig. 1).
제조예 2의 방법으로 제조한 KCT-01에 대해서도, HepG2.2.15 HBV 포함 세포주에 31.5, 62.5, 125, 250 ㎍/ml의 농도로 처리하고 배양액을 회수하여 HBsAg ELISA와 HBeAg ELISA를 수행하여 HBsAg과 HBeAg의 농도를 측정한 결과 농도의존적으로 억제 효과가 있음을 확인할 수 있었다. 또한 엔테카비어(Entecavir)만 처리한 군과 비교하였을 때, 본 발명의 인진, 지유, 울금 복합 한방 추출물과 B형 간염 항바이러스제를 병용 투여하였을 때 농도의존적으로 HBsAg과 HBeAg 억제 효과가 있음을 확인할 수 있었다(도 2 참조).The KCT-01 prepared by the method of Preparation Example 2 was also treated with HepG2.2.15 HBV-containing cell lines at concentrations of 31.5, 62.5, 125, and 250 µg / ml, and the culture solution was recovered to carry out HBsAg ELISA and HBeAg ELISA to obtain HBsAg and As a result of measuring the concentration of HBeAg it was confirmed that there is an inhibitory effect depending on the concentration. In addition, when compared with the group treated with only Entecavir (Entecavir), it was confirmed that the combination of the jinjin, fat milk, turmeric complex herbal extract of the present invention and the hepatitis B antiviral agent has a concentration-dependent effect of inhibiting HBsAg and HBeAg. (See Figure 2).
따라서, 기존 B형 간염 항바이러스제 단독 투여에서는 B형 간염 e항원이 억제되지 않았으나, 본 발명의 한방 복합 추출물을 B형 간염 항바이러스제와 병용 투여하였을 때에는 B형 간염 e항원이 효과적으로 억제되어, 본 발명의 방법은 B형 간염을 비롯한 다양한 간질환의 치료에 사용될 수 있는 효과가 있다. Therefore, while hepatitis B antiviral alone was not administered, hepatitis B eantigen was not inhibited. However, when the herbal extract of the present invention was administered in combination with the hepatitis B antiviral agent, hepatitis B eantigen was effectively inhibited. The method has the effect that can be used in the treatment of various liver diseases, including hepatitis B.
실시예Example 2. 인진,  2. Injin, 지유Oil , , 울금Turmeric 복합 한방 추출물의 B형 간염 항바이러스  Hepatitis B Antiviral of Complex Herbal Extracts pgpg RNA 억제 효과 확인 Confirmation of RNA Inhibitory Effect
본 발명자들은 HepG2.2.15 HBV 포함 세포주에 제조예 2의 방법으로 제조한 KCT-01을 0, 25, 250 ㎍/ml의 농도로 추가 처리한 후 48시간 배양하고 배양액을 회수하여 버린 후 남아 있는 세포로부터 RNA를 추출하고 실시간 유전자증폭법 (Real-time RT-qPCR)법을 사용하여 pgRNA의 농도를 측정하였다.The present inventors further treated KCT-01 prepared by the method of Preparation Example 2 to a HepG2.2.15 HBV-containing cell line at concentrations of 0, 25, and 250 µg / ml, and then cultured for 48 hours, and recovered the culture solution. RNA was extracted from and the concentration of pgRNA was measured using Real-time RT-qPCR method.
그 결과, 본 발명의 인진, 지유, 울금 복합 한방 추출물인 KCT-01 처리군에서 농도의존적으로 HepG2.2.15 HBV 포함 세포주에서의 pgRNA 억제 효과가 있음을 확인할 수 있었다(도 3 참조). As a result, it was confirmed that there is a concentration-dependent pgRNA inhibitory effect in HepG2.2.15 HBV-containing cell line in the KCT-01 treated group of the jinjin, fat milk, turmeric complex herbal extract of the present invention (see Fig. 3).
실시예Example 3. 급성 B형 간염 유도 마우스를 이용한  3. Acute Hepatitis B-induced Mouse in in vivovivo 효력 시험 확인 Validation test confirmation
본 발명자들은 유체역학 주입법(Hydrodynamic injection)으로 HBV DNA를 주입하여 급성 B형간염과 유사한 징후를 나타내도록 만든 C57BL6 마우스를 이용하여 엔테카비어(Entecavir)를 단독으로 투여했을 때와 엔테카비어(Entecavir) 및 인진, 지유, 울금 복합 한방 추출물을 병용 투여하였을 때의 혈중 HBsAg 농도를 측정하였다.The inventors of the present invention have shown that when Entecavir was administered alone and Entecavir and Enjin, using C57BL6 mice in which HBV DNA was injected by hydrodynamic injection to show signs similar to acute hepatitis B. Blood HBsAg concentration was measured when co-administration of fat milk and turmeric complex herbal extracts.
실험 방법을 보다 자세히 설명하면, 사용된 C57BL6 마우스는 Charles Liver Laboratory(MA, USA)로부터 20g 내외의 8주령 수컷을 사용하였으며, 모든 마우스는 adeno-associated virus에 HBV DNA 염기서열이 삽입된 pAAV/HBV 벡터를 실험동물 체중의 8% 부피로 마우스 꼬리 정맥을 통해 0.3 ㎖/min의 속도로 주사하여 급성 B형 간염을 유발하였으며, 24시간 후 PBS, 엔테카비어, 엔테카비어 및 인진, 지유, 울금 복합 한방 추출물을 마우스의 꼬리정맥을 통해 주사하였다. 시험물질 주사 전(0시간), 주사 후 1일, 4일, 7일 및 10일째에 채혈하여 혈청을 분리하였으며 염소 혈청(goat serum)으로 10배 희석한 후 Genedia HBsAg ELISA 3.0 (녹십자 MS, 한국)을 이용하여 혈중 HBsAg 농도를 측정하였고, 주사 후 14일째에 liver tissue 조직을 갈아서 페놀과 클로로포름을 이용하여 DNA를 추출하고 cccDNA의 양을 실시간유전자증폭법(Real-time PCR)을 이용하여 측정하였다.In more detail, the C57BL6 mice used were 8-week-old males of about 20 g from Charles Liver Laboratory (MA, USA), and all mice were pAAV / HBV with HBV DNA sequence inserted into adeno-associated virus. Acute hepatitis B was injected by injecting the vector at a rate of 0.3 ml / min through the mouse tail vein at a volume of 8% of the body weight of the experimental animal. After 24 hours, PBS, entecavir, entecavir and jinjin, fat, and turmeric complex herbal extracts were injected. Injection through the tail vein of mice. Serum was isolated by blood collection on the 1st, 4th, 7th and 10th day after injection of test substance (0 hour), and diluted 10-fold with goat serum (Genesis HBsAg ELISA 3.0, Green Cross MS, Korea). Blood HBsAg concentration was measured using the same method, and liver tissue tissues were ground at 14 days after injection, DNA was extracted using phenol and chloroform, and the amount of cccDNA was measured by real-time PCR. .
그 결과, 대조군과 비교하였을 때 B형 간염 항바이러스제인 엔테카비어를 처리하였을 때 B형 간염 바이러스를 억제하는 효과가 있음을 알 수 있었으며, 엔테카비어와 인진, 지유, 울금 복합 한방 추출물을 병용 투여한 군에서는 동일양의 엔터카비어를 처리한 군에 비하여 더욱 효과적으로 혈중 내 HBsAg 농도 및 cccDNA 농도가 억제되었음을 확인할 수 있었다(도 4 및 도 5 참조).As a result, it was found that treatment with the hepatitis B antiviral agent entecavir was effective in inhibiting the hepatitis B virus when compared to the control group. It was confirmed that blood HBsAg concentration and cccDNA concentration were more effectively inhibited compared to the group treated with the same amount of entercavir (see FIGS. 4 and 5).
실시예Example 4. 인진,  4. Injin, 지유Oil , , 울금Turmeric 복합 한방 추출물 및 B형 간염 항바이러스제 처리에 따른 염증 억제 효과 확인 Inhibition of Inflammation Inhibition by Treatment of Complex Herbal Extract and Hepatitis B Antiviral Agent
본 발명자들은 치사된 급성 B형 간염 유도 마우스에서 간조직을 분리하였으며, 트리졸 용액 1 mL을 첨가하여 조직을 분쇄한 후, 4℃, 12,000×g에서 10분간 원심분리하였다. 상층액을 새 튜브로 옮긴 후 클로로포름(chloroform) 200 ㎕을 첨가하고, 볼텍스(vortex) 하였다. 상층액을 새 튜브로 옮긴 후 이소프로판올(isoprophanol)과 상층액을 1:1 비율로 첨가하였다. 15초 세게 흔든 다음 실온에서10분 동안 방치한 후, 12,000×g, 4℃에서 10분간 원심분리시킨 후 상층액을 제거하고, 남은 침전물에 70 % 에탄올 1 ㎖을 가한 후, 7,500×g, 4℃에서 5분 동안 원심분리하였다. 에탄올을 제거한 후 RNA 침전물이 담긴 튜브를 실온에서 5분 동안 건조시키고, 뉴클레아제 프리 워터(nuclease free water)를 사용하여 RNA 펠릿(pellet)을 용해시켰다. UV/VIS 분광분석기(Nanodrop, Thermo, 미국)를 이용하여 260 nm 및 280 nm 파장에서 추출된 RNA 시료의 농도를 측정하고 RT kit를 이용하여 cDNA를 합성한 후 Real time PCR를 이용하여 염증성 사이토카인인 TNF-α, IL-1β 및 간섬유화와 관련된 인자인 TGF-β, 콜라게나아제(collagenage) Ⅰ과 Ⅳ의 mRNA 발현 변화를 확인하였다. 본 발명에서 사용한 프라이머 서열은 하기 표 1과 같다. cccDNA의 probe 서열은 5'-[FAM]-TCTCAATCGCCGCGTCGCAGA-[TAMRA]-3' (서열번호 27)으로 수행하였다. We isolated liver tissue from lethal acute hepatitis B-induced mice, pulverized the tissue by adding 1 mL of trizol solution, and centrifuged at 12,000 x g for 10 minutes. The supernatant was transferred to a new tube, 200 μl of chloroform was added, and vortexed. After transferring the supernatant to a new tube, isopropanol and supernatant were added in a 1: 1 ratio. Shake vigorously for 15 seconds and leave at room temperature for 10 minutes, centrifuge at 12,000 × g, 4 ° C for 10 minutes, remove supernatant, add 1 ml of 70% ethanol to the remaining precipitate, and then add 7,500 × g, 4 Centrifuge for 5 minutes at < RTI ID = 0.0 > After ethanol was removed, the tube containing the RNA precipitate was dried at room temperature for 5 minutes, and the RNA pellet was dissolved using nuclease free water. Measure the concentration of RNA samples extracted at 260 nm and 280 nm using a UV / VIS spectrometer (Nanodrop, Thermo, USA), synthesize cDNA using RT kit, and then use inflammatory cytokines using real time PCR. The mRNA expression changes of TNF-α, IL-1β and TGF-β, collagenase I and IV, which are factors related to hepatic fibrosis, were identified. Primer sequences used in the present invention are shown in Table 1 below. The probe sequence of cccDNA was performed with 5 '-[FAM] -TCTCAATCGCCGCGTCGCAGA- [TAMRA] -3' (SEQ ID NO: 27).
ForwardForward ReverseReverse referencereference Genbank accession No.Genbank accession No.
m185m185 5'-AGTCCCTGCCCTTTGTACACA-3' (서열번호 1)5'-AGTCCCTGCCCTTTGTACACA-3 '(SEQ ID NO: 1) 5'-CGATCCGAGGGCCTCACTA-3' (서열번호 2)5'-CGATCCGAGGGCCTCACTA-3 '(SEQ ID NO: 2) Am J Physiol Gastrointest Liver Physiol.302:G1310G1321,2012Am J Physiol Gastrointest Liver Physiol. 302: G1310G1321,2012
mF4/80mF4 / 80 5'-CATAAGCTGGGCAAGTGGTA-3' (서열번호 3)5'-CATAAGCTGGGCAAGTGGTA-3 '(SEQ ID NO: 3) 5'-GGATGTACAGATGGGGGATG-3' (서열번호 4)5'-GGATGTACAGATGGGGGATG-3 '(SEQ ID NO: 4) Am J Physiol Gastrointest Liver Physiol.302:G1310G1321,2012Am J Physiol Gastrointest Liver Physiol. 302: G1310G1321,2012
IL-1βIL-1β 5'-GGTCAAAGGTTTGGAAGCAG-3' (서열번호 5)5'-GGTCAAAGGTTTGGAAGCAG-3 '(SEQ ID NO: 5) 5'-TGTGAAATGCCACCTTTTGA-3' (서열번호 6)5'-TGTGAAATGCCACCTTTTGA-3 '(SEQ ID NO: 6) Am J Physiol Gastrointest Liver Physiol.302:G1310G1321,2012Am J Physiol Gastrointest Liver Physiol. 302: G1310G1321,2012
mTGF-β1mTGF-β1 5'-GTGGAAATCAACGGGATCAG-3' (서열번호 7)5'-GTGGAAATCAACGGGATCAG-3 '(SEQ ID NO: 7) 5'-ACTTCCAACCCAGGTCCTTC-3' (서열번호 8)5'-ACTTCCAACCCAGGTCCTTC-3 '(SEQ ID NO: 8) Am J Physiol Gastrointest Liver Physiol.302:G1310G1321,2012Am J Physiol Gastrointest Liver Physiol. 302: G1310G1321,2012
mTNF-αmTNF-α 5'-AGGGTCTGGGCCATAGAACT-3' (서열번호 9)5'-AGGGTCTGGGCCATAGAACT-3 '(SEQ ID NO: 9) 5'-CCACCACGCTCTTCTGTCTAC-3' (서열번호 10)5'-CCACCACGCTCTTCTGTCTAC-3 '(SEQ ID NO: 10) Am J Physiol Gastrointest Liver Physiol.302:G1310G1321,2012Am J Physiol Gastrointest Liver Physiol. 302: G1310G1321,2012
mCCR2mCCR2 5'-AGCACATGTGGTGAATCCAA-3' (서열번호 11)5'-AGCACATGTGGTGAATCCAA-3 '(SEQ ID NO: 11) 5'-TGCCATCATAAAGGAGCCA-3' (서열번호 12)5'-TGCCATCATAAAGGAGCCA-3 '(SEQ ID NO: 12) Am J Physiol Gastrointest Liver Physiol.302:G1310G1321,2012Am J Physiol Gastrointest Liver Physiol. 302: G1310G1321,2012
mMCP-1mMCP-1 5'-ATTGGGATCATCTTGCTGGT-3' (서열번호 13)5'-ATTGGGATCATCTTGCTGGT-3 '(SEQ ID NO: 13) 5'-CCTGCTGTTCACAGTTGCC-3' (서열번호 14)5'-CCTGCTGTTCACAGTTGCC-3 '(SEQ ID NO: 14) Am J Physiol Gastrointest Liver Physiol.302:G1310G1321,2012Am J Physiol Gastrointest Liver Physiol. 302: G1310G1321,2012
mCD68mCD68 5'-ACCGCCATGTAGTCCAGGTA-3' (서열번호 15)5'-ACCGCCATGTAGTCCAGGTA-3 '(SEQ ID NO: 15) 5'-ATCCCCACCTGTCTCTCTCA-3' (서열번호 16)5'-ATCCCCACCTGTCTCTCTCA-3 '(SEQ ID NO: 16) Am J Physiol Gastrointest Liver Physiol.302:G1310G1321,2012Am J Physiol Gastrointest Liver Physiol. 302: G1310G1321,2012
mIL-6mIL-6 5'-GACAACTTTGGCATTGTGG-3' (서열번호 17)5'-GACAACTTTGGCATTGTGG-3 '(SEQ ID NO: 17) 5'-ATGCAGGGATGATGTTCTG-3' (서열번호 18)5'-ATGCAGGGATGATGTTCTG-3 '(SEQ ID NO: 18) Immunol Invest.2004 May:22(2):213-233Immunol Invest. 2004 May: 22 (2): 213-233 NM-031168NM-031168
mCollagen α1(I)mCollagen α1 (I) 5'-TAGGCCATTGTGTATGCAGC-3' (서열번호 19)5'-TAGGCCATTGTGTATGCAGC-3 '(SEQ ID NO: 19) 5'-ACATGTTCAGCTTTGTGGACC-3' (서열번호 20)5'-ACATGTTCAGCTTTGTGGACC-3 '(SEQ ID NO: 20) Am J Physiol Gastrointest Liver Physiol.302:G1310G1321,2012Am J Physiol Gastrointest Liver Physiol. 302: G1310G1321,2012
mCollagen α1(IV)mCollagen α1 (IV) 5'-CACATTTTCCACAGCCAGAG-3' (서열번호 21)5'-CACATTTTCCACAGCCAGAG-3 '(SEQ ID NO: 21) 5'-GTCTGGCTTCTGCTGCTCTT-3'(서열번호 22)5'-GTCTGGCTTCTGCTGCTCTT-3 '(SEQ ID NO: 22) Am J Physiol Gastrointest Liver Physiol.302:G1310G1321,2012Am J Physiol Gastrointest Liver Physiol. 302: G1310G1321,2012
pgRNApgRNA 5'-GGTCCCCTAGAAGAAGAACTCCCT-3' (서열번호 23) 5'-GGTCCCCTAGAAGAAGAACTCCCT-3 '(SEQ ID NO: 23) 5'-CATTGAGATTCCCGAGATTGAGAT-3' (서열번호 24)5'-CATTGAGATTCCCGAGATTGAGAT-3 '(SEQ ID NO: 24)
cccDNAcccDNA 5'-GGTCCCCTAGAAGAAGAACTCCCT-3' (서열번호 25)5'-GGTCCCCTAGAAGAAGAACTCCCT-3 '(SEQ ID NO: 25) 5'-CATTGAGATTCCCGAGATTGAGAT-3' (서열번호 26)5'-CATTGAGATTCCCGAGATTGAGAT-3 '(SEQ ID NO: 26)
그 결과, 대조군과 비교하였을 때 B형 간염 항바이러스제인 엔테카비어를 처리하였을 때 염증성 사이토카인인 TNF-α, IL-1β 및 간섬유화와 관련된 인자인 TGF-β 및 콜라게나아제(collagenage) Ⅰ과 Ⅳ가 억제되었음을 알 수 있었으며, 엔테카비어와 인진, 지유, 울금 복합 한방 추출물을 병용 투여한 군에서는 엔터카비어을 단독으로 처리한 군에 비하여 더욱 더 효과적으로 염증성 사이토카인인 TNF-α, IL-1β 및 간섬유화와 관련된 인자인 TGF-β, 콜라게나아제(collagenage) Ⅰ과 Ⅳ가 억제됨을 확인할 수 있었다(도 6 및 7 참조).As a result, inflammatory cytokines TNF-α, IL-1β and hepatic fibrosis-related factors TGF-β and collagenase I and IV were treated when hepatitis B antiviral agent entecavir was compared with the control group. The inflammatory cytokine TNF-α, IL-1β and hepatic fibrosis were more effectively treated in the group treated with entecavir, injin, fat, and turmeric complex herbal extracts compared to the group treated with entercavir alone. It was confirmed that the factors related to TGF-β, collagenase (collagenage) I and IV are inhibited (see FIGS. 6 and 7).

Claims (10)

  1. 인진, 지유 및 울금 추출물을 유효성분으로 포함하는 간질환 치료용 약학적 조성물.Pharmaceutical composition for the treatment of liver disease, comprising a jinjin, fat milk and turmeric extract as an active ingredient.
  2. 제1항에 있어서,The method of claim 1,
    상기 추출물은 인진, 지유 및 울금이 각각 3:1:1의 중량비로 혼합된 것을 특징으로 하는, 간질환 치료용 약학적 조성물.The extract is characterized in that the phosphorus, fat milk and turmeric are each mixed in a weight ratio of 3: 1: 1, liver pharmaceutical composition for the treatment of disease.
  3. 제1항에 있어서,The method of claim 1,
    상기 간질환은 지방간, 간염 또는 간경화로부터 선택되는 어느 하나인 것을 특징으로 하는, 간질환 치료용 약학적 조성물.The liver disease is characterized in that any one selected from fatty liver, hepatitis or cirrhosis, pharmaceutical composition for treating liver disease.
  4. 제1항에 있어서,The method of claim 1,
    상기 조성물은 B형 간염의 항바이러스제와 함께 제제화하거나 병용하여 사용하는 것을 특징으로 하는, 간질환 치료용 약학적 조성물.The composition is characterized in that it is formulated or used in combination with an antiviral agent of hepatitis B, pharmaceutical composition for treating liver disease.
  5. 제4항에 있어서,The method of claim 4, wherein
    상기 B형 간염의 항바이러스제는 엔테카비어(entecavir), 테노포비어(tenofovir), 라미부딘(lamibudine), 아데포비어(adefovir) 및 클레부딘(clebudine)에서 선택되는 1종 이상인 것을 특징으로 하는, 간질환 치료용 약학적 조성물.The antiviral agent of hepatitis B is entcavir (entecavir), tenofovir (tenofovir), lamivudine (lamibudine), adefovir (adefovir) and clevudine (clebudine), characterized in that at least one selected from the drug for treating liver disease Composition.
  6. 제1항에 있어서, The method of claim 1,
    상기 조성물은 TNF-α, IL-1β, TGF-β, 콜라게나아제(collagenage) Ⅰ 또는 콜라게나아제(collagenage) Ⅳ의 발현을 저해 또는 억제시키는 것을 특징으로 하는, 간질환 치료용 약학적 조성물.The composition is characterized in that to inhibit or inhibit the expression of TNF-α, IL-1β, TGF-β, collagenase (collagenage) I or collagenase (collagenage) IV, a pharmaceutical composition for treating liver disease.
  7. 인진, 지유 및 울금 추출물을 유효성분으로 포함하는 간질환 예방 및 개선용 건강기능성식품.Health functional food for the prevention and improvement of liver disease, which contains ginjin, fat milk and turmeric extract as active ingredients.
  8. 간질환이 유발된 개체에 인진, 지유 및 울금 추출물과 B형 간염의 항바이러스제를 병용 투여하는 단계를 포함하는, 간질환 치료 방법.A method of treating liver disease, comprising co-administering an antiviral agent of hepatitis B with hejingin, fat milk and turmeric extract to a subject having a liver disease.
  9. 제8항에 있어서,The method of claim 8,
    상기 B형 간염의 항바이러스제는 엔테카비어(entecavir), 테노포비어(tenofovir), 라미부딘(lamibudine), 아데포비어(adefovir) 및 클레부딘(clebudine)에서 선택되는 1종 이상인 것을 특징으로 하는, 간질환 치료 방법.The antiviral agent of hepatitis B is characterized in that at least one selected from entecavir (tencavir), tenofovir (tenofovir), lamivudine (lamibudine), adefovir (clefodine) and clebudine, liver disease treatment method.
  10. 제8항에 있어서,The method of claim 8,
    상기 간질환은 지방간, 간염 또는 간경화로부터 선택되는 어느 하나인 것을 특징으로 하는, 간질환 치료 방법.The liver disease is characterized in that any one selected from fatty liver, hepatitis or cirrhosis, liver disease treatment method.
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