JP2008074801A - Hepatoprotector - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a hepatoprotector having antioxidation activity while protecting the liver to rapidly detox active and metabolize active oxygen species and to prevent its production and accumulation, especially a hepatoprotector which has a low adverse effect in comparison with a conventional medicine, comprises a naturally occurring substance and is especially orally administered. <P>SOLUTION: The hepatoprotector comprises an ellagitannin as an active ingredient. The ellagitannin is preferably at least one kind selected from Pedunculagin, Tellimagrandin I, Casuarictin, Tellimagrandin II, Rugsin C and Casuarinin. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a hepatoprotective agent that can suppress the production and accumulation of reactive oxygen species in the body, prevent liver damage, or prevent further deterioration of a disease state.

In recent years, active oxygen species present in the body, particularly in the human body, have attracted attention in relation to health. Reactive oxygen species are always produced at every site in the body that breathes oxygen, including superoxide anion (O ₂ ⁻ ), hydrogen peroxide, hydroxy radical (OH.), And singlet excited species ( ¹ O ₂ ). Take various forms. The reactive oxygen species may be taken into the living body from outside the living body in the form of food or the like. For example, lipid peroxides present in edible oils are a kind of reactive oxygen species. Reactive oxygen species are said to cause various diseases such as cell death, cancer, and arteriosclerosis when present in vivo. Therefore, reactive oxygen species are removed or detoxified by the action of enzymes such as superoxide dismutase (SOD) in vivo, but the SOD activity in the body decreases with aging, and various diseases caused by reactive oxygen species The possibility of is increased.

The liver has a wide variety of enzymes that are generally called detoxification organs. When harmful substances are present in the living body, they are detoxified or metabolized by the action of the liver and are discharged out of the body as oxygen and water.

  However, this detoxification and metabolism may produce reactive oxygen species, which damages the liver cell membrane and the like. In addition, with aging, detoxification and metabolic functions decrease, and active oxygen species accumulate in the body, which may cause hypertension, liver damage, etc. or worsen symptoms.

  Therefore, in order to maintain health and life, it is necessary to quickly detoxify or decompose active oxygen species while protecting the liver, and discharge it outside the living body.

  Medical or Kampo preparations currently used to protect the liver, when used alone or in combination, causes psychiatric disorders, rebound after discontinuation, interstitial pneumonia, and deaths that may be caused by it Therefore, there is a need for a hepatoprotective agent that contains a naturally occurring substance that can protect the liver and suppress the production and accumulation of reactive oxygen species in the body and has few side effects as an active ingredient. ing.

On the other hand, research on polyphenol components contained in walnuts has recently progressed. Its essence is ellagic acid and hydrolysable polyphenols [such as pedunculagin and tellimaglandin I], which have been reported to have strong antioxidant activity (Fukuda T, Ito H, Yoshida T, Antioxidative
polyphenols from walnut (Juglans regia L). Phytochemistry, 63, 795-801 (2003).). On the other hand, inhibitory activity against glucolytic enzymes contributing to diabetes prevention has also been reported (Fukuda T. et al.
Polyphenols from walnuts: Structures and functions.IFT 2006 Annual Meeting, Orland, Florida,
June 24-28, 2006).

  In addition, in the patent literature, an oxidative stress inhibitory action (Japanese Patent Laid-Open No. 2006-052184), a dullness improving action (Japanese Patent Laid-Open No. 2005-289913), a skin aging inhibitory action (Japanese Patent Laid-Open No. 2000-229836), and a histamine release inhibitory action (Japanese Patent Laid-Open No. 2005-289913) 179285), diabetic complication suppressing action (JP 2005-120031), urease inhibitory action (JP 2003-048844) and bladder function improving action (JP 2003-128566), etc., among these patent documents Some may be considered to be the effect of polyphenols contained in walnuts.

Walnuts are nuts grown all over the world, including the United States and China. Roasted vines are widely eaten, but oil that is squeezed from vines is also edible.
It has been clarified that the seed coat of walnut seed contains a high concentration of polyphenol, and hydrolyzable polyphenol such as ellagitannin is the main component. However, the hepatoprotective effect of walnut seed coat extract has not yet been found.

  Therefore, the present inventors examined the hepatoprotective action of hydrolyzed polyphenols obtained from seed coats of walnut seeds in a model of carbon tetrachloride-induced hepatocellular injury using rat primary cultured hepatocytes. The present inventors have found that ellagitannins obtained from seed seed coats exhibit particularly a hepatocellular injury inhibitory action and have completed the present invention.

  That is, an object of the present invention is to provide a hepatoprotective agent having antioxidant activity while protecting the liver in order to quickly detoxify and metabolize reactive oxygen species and prevent its production and accumulation, In particular, it is to provide a hepatoprotectant containing a naturally occurring substance with fewer side effects than conventional pharmaceuticals.

In order to solve the above problems, the hepatoprotective agent of the present invention is characterized by containing ellagitannin as an active ingredient.
The ellagitannin is preferably one in which a hexahydrodiphenoyl group is substituted on at least one of the 4th and 6th positions and the 2nd and 3rd positions of glucose.
Further, the ellagitannin is at least one selected from Pedunculagin, Tellimagrandin I, Casarictin, Tellimagrandin II, Rugsin C, and Casuarinin. Preferably there is.
In addition, the ellagitannins are preferably extracted from walnut seed coats and / or walnut seed coats.
Further, the walnut extract of the present invention is a walnut extract containing walnut seed coat and / or walnut seed coat, containing walnut-derived polyphenol, and as the walnut-derived polyphenol, It contains at least ellagitannin.
Further, as the above-mentioned ellagitannin, at least one selected from pedunculagin, telimaglandin I, casarictin, teramagrandin II, rugosin C, casarinin It is preferable to contain.
Furthermore, another hepatoprotective agent of the present invention is characterized by containing the walnut extract.
The hepatoprotective agent of the present invention and other inventions of the present invention can also be contained in foods, pet foods, cosmetics, quasi drugs or pharmaceuticals.

Hereinafter, the present invention will be described in more detail.
The hepatoprotective agent of the present invention is characterized by containing ellagitannin as an active ingredient.
Here, the above-mentioned ellagitannin has a hexahydrodiphenoyl (hereinafter also referred to simply as “HHDP group”) group in the molecule, and generates ellagic acid in addition to polyhydric alcohol by hydrolysis. A general term for tannins.
The type of ellagitannin is not particularly limited, but it is particularly preferred that at least one of glucose positions 4 and 6 and glucose positions 2 and 3 is substituted with an HHDP group. At this time, it is not particularly limited as long as the HHDP group is substituted for glucose. For example, a galloyl group or the like may be further substituted on a hydroxyl group of the glucose skeleton that is not substituted with the HHDP group. The above ellagitannins may be used alone or in combination of two or more.
Examples of such compounds include Pedunculagin, Tellimagrandin I, Casarictin, Tellimagrandin II, Rugsin C, Casuarinin and the like. It is not limited. These may be used alone or in combination of two or more.
At this time, Pedunculagin, Tellimagrandin I, Casarictin, Tellimagrandin II, Lugosin C, Casuarinin (hereinafter referred to as “Pedunculadin”) Is particularly preferred. This is because it has a better liver protective effect.

The pedunclazine is a compound represented by the following chemical formula (1).

Terimagranin I is a compound represented by the following chemical formula (2).

Further, casarrictin is a compound represented by the following chemical formula (3).

Furthermore, Terimagranin II is a compound represented by the following chemical formula (4).

Furthermore, lugosin C is a compound represented by the following chemical formula (5).

Casrinin is a compound represented by the following chemical formula (6).

The method for obtaining the ellagitannin is not particularly limited, but is preferably obtained by extracting polyphenols from walnut seed coats. This is because the walnut-derived polyphenol contains ellagitannin, and the ellagitannin particularly contains the pedunclazine and the like at a high concentration. At this time, it is not particularly limited as long as it contains walnut seed coat. For example, it may be extracted from seed coat peeled from walnut seed or extracted from seed coat covered with seed coat. May be. In particular, it is more preferable to extract from the seed coat peeled from the walnut seed. This is because a higher concentration of ellagitannins such as pedunclazine can be extracted.
In addition, the seeds or seed coats containing walnut seed coats may be extracted as they are, but it is more preferable to extract these pulverized products. This is because ellagitannins contained in the seed coat can be extracted at a higher concentration.
At this time, the extraction method is not particularly limited, and examples thereof include polar solvent extraction and supercritical extraction. Only one of these may be performed, or both of them may be performed.

  Here, when extracting by polar solvent extraction, the polar solvent to be used is not particularly limited. For example, water, methanol, ethanol, isopropanol, acetone, 1,3-butylene glycol, ethylene glycol, propylene glycol, glycerin, acetic acid, Examples include ethyl acetate, ether, hexane and the like. Of these, water, methanol, and ethanol are preferred. In particular, it is preferable to use a hydrous alcohol such as hydrous methanol or hydrous ethanol. It is because an active ingredient can be extracted efficiently. These may be used alone or in combination of two or more.

  When water is used as the extraction solvent, the extraction temperature is 20 to 100 ° C., preferably about 80 to 100 ° C. This is because if the extraction temperature is too low, it is difficult to extract active ingredients. The kind of water for extraction is not particularly limited, and tap water, distilled water, mineral water, alkaline ionized water and the like can be used.

  When hydrous alcohol is used as the extraction solvent, the alcohol concentration is preferably 30 to 90 wt%. This is because if the amount is less than about 30 wt% or exceeds 90 wt%, the extraction amount of the active ingredient tends to decrease. The extraction temperature is 20 to 95 ° C, preferably about 50 to 95 ° C. In addition, the water-containing ethanol extraction may be repeated at various concentrations in order to improve the content of the active ingredient.

  In addition, when extracting with a polar solvent, the extraction method is not particularly limited, and for example, any method such as continuous extraction, immersion extraction, countercurrent extraction, etc. can be employed, and any device can be used at room temperature or under reflux heating. Can be used. In addition, when extracting by the said method, only one of these may be performed and you may combine these methods.

As a specific method, an extraction raw material is put into a treatment tank filled with an extraction solvent, and an active ingredient is eluted while stirring. For example, when water or a hydrous alcohol is used as the extraction solvent, the extraction is performed for about 30 minutes to 5 hours using a polar solvent that is about 5 to 100 times the weight of the extraction raw material (weight ratio). The active ingredient is eluted in the solvent, and then filtered to remove the extraction residue to obtain an extract. Thereafter, the extract is subjected to treatments such as dilution, concentration, drying, and purification according to a conventional method to obtain a walnut extract, and this walnut extract is used as a hepatoprotectant.
Examples of the purification method include activated carbon treatment, resin adsorption treatment, ion exchange resin, liquid-liquid countercurrent distribution, and the like, but they are not used in large quantities when added to foods. It may be used unpurified.

  Furthermore, when performing extraction by supercritical extraction, the supercritical fluid used at this time is not particularly limited, and examples thereof include carbon dioxide and water. In addition, these may use only 1 type and may use 2 or more types together. Of these, carbon dioxide is particularly preferred. It is because an active ingredient can be extracted more easily. The extraction method at this time may be performed by a known method.

The walnut extract thus extracted contains walnut-derived polyphenol, and this polyphenol contains ellagitannin. Furthermore, as this ellagitannin, at least 1 sort (s) of each component, such as the said pedunclazine, is contained in high concentration.
The hepatoprotective agent of the present invention may be purified as it is by adding the walnut extract to a food or the like, or separating and concentrating each component such as the pedunclazine contained in the extract. It may be added to foods. At this time, only one component of the pedunclazine or the like may be separated and concentrated from the walnut extract, or a plurality of components may be separated and concentrated.
Moreover, the method of isolate | separating and concentrating components, such as said pedunclazine, from the said walnut extract is not specifically limited, For example, it can carry out by the column chromatography method, HPLC method, etc.

  The effect of inhibiting hepatocellular injury in the hepatoprotective agent of the present invention can be confirmed by using the evaluation method described below.

  By examining the inhibitory effect on rat hepatocyte damage induced by carbon tetrachloride, the inhibitory action on hepatocyte damage can be determined. The onset mechanism of carbon tetrachloride-induced liver injury is as follows. First, carbon tetrachloride is metabolized to trichloromethyl radicals by metabolic enzymes present in hepatocytes, and as a result of the radical chain reaction by these radicals, lipid peroxide and the like accumulate in the liver, causing serious damage to the cells. Develops. The inhibitory activity against hepatocellular injury can be evaluated by measuring the mitochondrial activity of the cells and using an MTT assay that can grasp the degree of cell growth.

  The effective amount of the hepatoprotective agent of the present invention when taken orally is 0.01 to 1 g, preferably 0.01 to 0.15 g, in terms of the total amount of hydrolyzed polyphenol per adult dose.

  The present invention provides a food containing the hepatoprotectant. This food may contain polyphenols as an active ingredient, for example in an amount of 10 to 1,000 mg, preferably 10 to 150 mg per adult dose. In the hepatoprotective agent of the present invention, the content of the active ingredient may vary depending on age and the like.

  The hepatoprotective agent of the present invention can be used as a material for various foods and drinks. Examples of food and drink include edible oil (salad oil), confectionery (gum, candy, caramel, chocolate, cookie, snack, jelly, gummy, tablet confection etc.), noodles (soba, udon, ramen etc.), dairy products ( Milk, ice cream, yogurt, etc.), seasonings (miso, soy sauce, etc.), soups, beverages (juice, coffee, tea, tea, carbonated drinks, sports drinks, etc.) and health foods (tablets , Capsules, etc.) and nutritional supplements (nutrient drinks, etc.). The hepatoprotective agent of the present invention may be appropriately blended with these foods and drinks.

These foods and drinks can be blended with various ingredients depending on the type, for example, glucose, fructose, sucrose, maltose, sorbitol, stevioside, corn syrup, lactose, citric acid, tartaric acid, malic acid, succinic acid. Acid, lactic acid, L-ascorbic acid, dl-α-tocopherol, sodium erythorbate, glycerin, propylene glycol, glycerin fatty acid ester, polyglycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, gum arabic, Food materials such as carrageenan, casein, gelatin, pectin, agar, vitamin Bs, nicotinic acid amide, calcium pantothenate, amino acids, calcium salts, pigments, fragrances and preservatives can be used. In addition, this liver protective agent with health maintenance functions includes other antioxidants and health food ingredients such as antioxidants, reduced ascorbic acid (vitamin C), vitamin E, and reduced glutatin. , Tocotrienol, vitamin A derivative, lycopene, β-cryptoxanthin, astaxanthin, zeaxanthin, fucoxanthin, uric acid, ubiquinone, coenzyme Q10, folic acid, garlic extract, allicin, sezamin, lignans, catechin, isoflavone, chalcone, tannins, flavonoids , Coumarin, isocoumarins, blueberry extract, arbutin, tannin, anthocyanin, apple polyphenol, grape seed extract, ellagic acid, kojic acid, surge extract health food material, V. (vitamin) A, V.B1, V.B2 , V.B6, V.B12, VC, VD, VE, VP, Choline Niacin, pantothenic acid, calcium folate, EPA, oligosaccharide, dietary fiber, squalene, soy lecithin, taurine, donariella, protein, octacosanol, DHA, egg yolk lecithin, linoleic acid, lactoferrin, magnesium, zinc, chromium, selenium, potassium, heme Iron, oyster meat extract, chitosan, chitin oligosaccharide, collagen, chondroitin, turmeric, swordfish extract, suppon, licorice, kukoshi, keihi, hawthorn, ginger, ganoderma, plantain, chamomile, chamomile, dandelion, hibiscus, honey, boren, Royal jelly, lime, lavender, rosehip, rosemary, sage, bifidobacteria, faecalis, lacris, wheat germ oil, sesame oil, perilla oil, soybean oil, medium chain fatty acid, agaricus, ginkgo biloba extract Turmeric, chondroitin, brown rice germ extract, litchi, onion, DHA, EPA, DPA, cocoon tea, cordyceps, garlic, bee, papaya, puer, propolis, mussels tree, jabushitake, royal jelly, saw palmetto, hyaluronic acid, collagen, Gabba, harp seal oil, shark cartilage, glucosamine, lecithin, phosphatidylserine, paddy carrot, mulberry leaves, soy extract, echinacea, sorghum, barley extract, olive leaf, olive fruit, gymnema, banaba, salasia, garcinia, chitosan , St. John's wort, jujube, carrot, passion flower, broccoli, placenta, pearl barley, grape seeds, peanut seed coat, bilberry, black cohosh, maria thistle, laurel, sage, rosemary, luffa, black vinegar, bitter gourdー, maca, safflower, flax, oolong tea, flower spine, caffeine, capsaicin, xylooligosaccharide, glucosamine, buckwheat, citrus, dietary fiber, protein, prunes, spirulina, barley young leaves, nucleic acid, yeast, shiitake, plum meat, amino acids, Deep sea bream extract, noni, oyster meat, suppon, champignon, plantain, acerola, pineapple, banana, peach, apricot, melon, strawberry, raspberry, orange, fucoidan, mesimacob, cranberry, chondroitin sulfate, zinc, iron, ceramide, silk Peptide, Glycine, Niacin, Chest Tree, Ceramide, L-Cysteine, L-Carnitine, Red Wine Leaf, Millet, Horsetail, Biotin, Centella Asiatica, Hascup, Pycnogenol, Fuki, Rhubarb, Clove, Rosemary, Catechin, Puff -Al, citric acid, brewer's yeast, merirot, black zinger, ginger, gadget, nattokinase, becouge, tocotrienol, lactoferrin, cinnamon, buckwheat, cocoa, yuzu seed extract, perilla seed extract, litchi seed extract, evening primrose extract, black rice extract , Α-lipoic acid, GABA, fresh coffee bean extract, Japanese bursa extract, kiwi seed extract, Unshu mandarin orange extract, red ginger extract, astaxanthin, leek seed extract, linden extract) and the like.

  As a specific production method, in the case of a walnut extract, the liver protective agent of the present invention is spray-dried or freeze-dried together with powdered dextrin, and this is easily converted into a powder, granule, tablet, or solution. Instant foods). Further, if necessary, it can be mixed with a binder such as gum arabic to form a powder or granules, and added to a solid food. The hydrolyzable polyphenol can be added to the beverage as it is or after being dispersed and dissolved in, for example, water, ethanol, glycerin or a mixture thereof.

Further, the hepatoprotective agent of the present invention can be contained in mammalian animal feed. The animal feed can be contained in the same manner as the food and drink. The animal feed is not particularly limited. For example, it is used for domestic animals such as cattle and pigs, companion animals such as dogs, cats and hamsters (animals kept as pets). can do.
For example, flour, meat, etc. can be used as companion animal feed. At this time, examples of the flour include wheat flour, rice flour, rye flour, corn flour, millet flour, bubble flour, corn flour, and soybean flour, and these flours may be used in combination of two or more. By using flour, nutrients such as carbohydrates can be supplied to companion animals. Among the above flours, it is most preferable to use flour, and as flour, strong flour, medium flour, thin flour can be used alone or in combination, and even when such flour and other flour are used in combination Good. Furthermore, in order to adjust the elasticity of the animal feed after the heat treatment, wheat flour, wheat gluten, soybean protein and the like may be combined. In addition, the network structure derived from gluten contained in wheat flour can constitute a puffed tissue structure when heat-treated, which contributes to improving the texture.

  The meat used in the present invention is not particularly limited, and chicken, pork, beef, mutton, goat meat, salmon meat, turkey meat, horse meat, etc. can be used, but chicken is preferably used in terms of flavor. The The above meat is obtained by slaughtering and demolishing livestock in the usual way. In addition, since the deterioration of the quality of a product with intermediate moisture or low moisture is mainly caused by oxidation of fat, the meat used is preferably lean meat with little fat content or fat removed. In addition, the coexistence of meat can improve the palatability of companion animals as well as strengthening high quality animal proteins.

The companion animal feed can be prepared by various methods. As a preferred method, a kneaded raw material mixture (hereinafter referred to as “dough”) containing flour (preferably wheat flour) and meat is prepared and molded. Thereafter, a heat treatment method can be exemplified. The composition of flour and meat in the dough is not particularly limited, but is usually about 5 to 60% flour, preferably about 10 to 50%, about 5 to 80% meat, preferably about 20 to 50%, and the required amount. It is adjusted to consist of water. Moreover, when using Aw regulator, the said Aw regulator is added so that it may become about 5-30%, Preferably it is about 10-20%. In addition, what is necessary is just to adjust the usage-amount of water suitably according to usage-amounts, such as flour, meat, and Aw regulator, so that dough can be knead | mixed and shape | molded.
The method for preparing the dough is not particularly limited, but preferably the meat is first ground with a silent cutter, chopper, or the like. At this time, it is preferable to chop the chopped meat so that bubbles are sufficiently contained therein. Then, the flour-containing dough can be prepared by adding flour, water and, if necessary, an Aw adjusting agent to the finely ground meat and sufficiently kneading to contain bubbles. In preparing the dough, a foaming agent may be added. It is preferable to use a foaming agent, particularly when flour other than wheat flour is used as the flour. By adding the foaming agent, fine bubbles can be uniformly contained in the dough. Various foaming agents can be used as the foaming agent, but it is preferable to use a soy protein foaming agent and / or an enzyme-decomposed soybean protein foaming agent from the viewpoint of the stability of air bubbles.

The dough prepared in this manner is molded and heat-treated, whereby the companion animal feed of the present invention is obtained. The dough may be formed into an appropriate shape according to the ease of eating when the companion animal eats the companion animal feed of the present invention, the handling of the owner, etc., for example, plate shape, stick shape, Examples include a disk shape, a donut shape, and a heart shape. Also, from doughs prepared from the same formulation, dye them with pigments of different colors, or mix vegetables or fruits to prepare multiple doughs with different appearances, and combine them in a multilayer or concentric form You can also
The heating means for the molded dough is not particularly limited, and examples thereof include oven heating and microwave heating. These heating methods are known, and heat treatment may be performed according to a conventional method. The water content of the feed after the heat treatment is usually about 20 to 40%. By the above heat treatment, the dough swells due to the evaporation of water and the expansion of bubbles, and the water evaporates in a short time, so Aw is lowered and the storage stability is improved. Moreover, when wheat flour is used as the flour, the mesh structure derived from gluten contained in the wheat flour is fixed by heat treatment, and the texture is improved. In the case of oven heating, there is an advantage that a unique color tone (amber color) and aroma can be generated in the feed. On the other hand, in the case of microwave heating, it can be heated from inside the dough. There is an advantage that it can be uniformly expanded and a feed having uniform air bubbles can be obtained. In the above heat treatment, it is preferable to adjust so that the Aw of the obtained feed is in the range of 0.6 to 0.9. As described above, the storage stability of the feed can be remarkably improved by adjusting Aw to this range.

The above-mentioned companion animal feed thus obtained is a feed having a bread-like property and has a soft texture and moderate flexibility and elasticity, so that it is a companion with weak teeth such as a young dog, an old dog or a cat. Suitable as animal feed, snacks, etc. Of course, it can be used as a feed or a snack for healthy adult dogs and cats. The animal feed is produced by storing an appropriate amount in a packaging container and sealing it. As the packaging container, it is preferable to use an oxygen gas-impermeable packaging material. Examples of the packaging form include vacuum packaging, inert gas filling packaging, and the like, but it is preferable to carry out inert gas filling packaging together with an oxygen scavenger (for example, Ageless ^TM ). According to such a packaging form, it is possible to prevent quality deterioration and microorganism growth due to oxygen during the storage period.

The companion animal feed is, for example, an additive conventionally used by those skilled in the art for meat or dough to be used (for example, sodium chloride, polymerized phosphate, antioxidants such as sodium erythorbate, plant Protein, skim milk powder, sodium caseinate, egg white, gluten, shellfish powder, bone meal, vitamins, minerals, trace elements, seasonings, flavors, pigments, preservatives, pH adjusters, etc.) and / or vegetables and fruits added You can also Alternatively, the dough may be formed into a plate shape, heat-treated, and then cut into a stick shape, a disk shape, a donut shape, a heart shape, or the like to prepare a feed. Furthermore, various vitamins, minerals, etc. can be mix | blended with the meat or dough to be used, and it can also be made to match | combine with the NRC nutrition standard of a dog or a cat.

  The hepatoprotective agent of the present invention may be used as a raw material for drugs (including pharmaceuticals and quasi drugs). It can be produced by appropriately blending the hepatoprotective agent of the present invention with a raw material for a pharmaceutical preparation. Examples of the pharmaceutical raw material that can be blended in the hepatoprotective agent of the present invention include excipients (glucose, lactose, sucrose, sodium chloride, starch, calcium carbonate, kaolin, crystalline cellulose, cocoa butter, hydrogenated vegetable oil, kaolin, talc, etc. ), Binder (distilled water, physiological saline, ethanol water, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.), disintegrant (sodium alginate, agar, sodium bicarbonate) , Calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, gum arabic powder, gelatin, ethanol, etc.), disintegration inhibitors (sucrose, stearin, cocoa butter, hydrogenated oil, etc.), absorption enhancers (quaternary) Ammonium base, sodium lauryl sulfate, etc.) Agents (glycerin, starch, lactose, kaolin, bentonite, silicic acid, etc.), lubricants (purified talc, stearates, polyethylene glycol, and the like) and the like.

  The administration method of the hepatoprotectant according to the present invention can generally be administered orally in the form of tablets, pills, soft / hard capsules, fine granules, powders, granules and the like. The water-soluble preparation can be administered orally as a liquid. Furthermore, parenteral administration may be used. When administered as a parenteral agent, the hepatoprotective agent of the present invention is dispersed in an appropriate solubilizing agent such as ethanol or water, and then in a dosage form such as a poultice, lotion, ointment, tincture or cream. Can be applied. The water-soluble preparation of the present hepatoprotective agent can be used as it is or in the form of a poultice, lotion, ointment, tincture, cream, etc. with a dispersant, suspension, stabilizer, etc. added. Can be applied.

  The dose may vary depending on the administration method, medical condition, age of the patient, etc., but for adults, it can be generally administered in an amount of about 5 to 200 mg as an active ingredient per day and usually about 0.5 to 100 mg for children.

  The compounding ratio when using the hepatoprotective agent of the present invention as a drug can be appropriately changed depending on the dosage form, but is usually about 0.01 to 10 wt% when administered orally or by mucosal absorption, In the case of parenteral administration, it should be about 0.01 to 20 wt%. Since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient, or the dose may need to be administered beyond the range. In addition to the hepatoprotective agent, the pharmaceutical composition may include other known compounds commonly used in the pharmaceutical field and compounds necessary for molding into a form suitable for oral administration. Examples of such compounds include lactose, starch, hydroxypropyl cellulose, kaolin, talc, calcium carbonate and the like.

  The hepatoprotective agent of the present invention is preferably taken about 3 times a day during meals.

Even if the hepatoprotective agent of the present invention is used as a skin external preparation (including cosmetics, pharmaceuticals and quasi drugs), it can be expected to have a hepatoprotective effect.
Examples of the external preparation for skin to which the hepatoprotective agent of the present invention can be formulated include, for example, emulsion, soap, face wash, bath preparation, cream, emulsion, lotion, eau de cologne, shaving cream, shaving lotion, makeup Oil, sunscreen / sunscreen lotion, funny powder, foundation, perfume, pack, nail cream, enamel, enamel remover, eyebrow, blusher, eye cream, eye shadow, mascara, eyeliner, lipstick, lip balm, shampoo, rinse, Examples include hair dyes, dispersions, and cleaning materials.
Examples of the form of a pharmaceutical or quasi-drug that can contain the hepatoprotective agent of the present invention include ointments, creams, and liquids for external use.

In addition to the liver protective agent according to the present invention, the external preparation for skin of the above-described form includes ingredients, oils, higher alcohols, and other ingredients blended in skin external preparations such as cosmetics and quasi-drugs, as long as the liver protective action is not impaired Fatty acids, ultraviolet absorbers, powders, pigments, surfactants, polyhydric alcohols / sugars, polymers, physiologically active ingredients, solvents, antioxidants, fragrances, preservatives, and the like can be blended.
Examples are listed below, but the present invention is not limited to these examples.

(1) Examples of oil components Ester-based oil phase components: glyceryl tri-2-ethylhexanoate, cetyl 2-ethylhexanoate, isopropyl myristate, butyl myristate, isopropyl palmitate, ethyl stearate, octyl palmitate, isostearic acid Isocetyl, butyl stearate, butyl myristate, ethyl linoleate, isopropyl linoleate, ethyl oleate, isocetyl myristate, isostearyl myristate, isostearyl palmitate, octyldodecyl myristate, isocetyl isostearate, diethyl sebacate, adipine Diisopropyl acid, isoaralkyl neopentanoate, glyceryl tri (capryl / caprate), trimethylolpropane tri-2-ethylhexanoate, trimethylol triisostearate Propane, pentaerythritol tetra-2-ethylhexanoate, cetyl caprylate, decyl laurate, hexyl laurate, decyl myristate, myristyl myristate, cetyl myristate, stearyl stearate, decyl oleate, cetyl ricinoleate, isolaurate Stearyl, isotridecyl myristate, isocetyl myristate, isostearyl myristate, isocetyl palmitate, isostearyl palmitate, octyl stearate, isocetyl stearate, isodecyl oleate, octyldodecyl linoleate, octyldodecyl isoleate, isopropyl isostearate Cetostearyl 2-ethylhexanoate, stearyl 2-ethylhexanoate, hexyl isostearate, ethyleneglycol dioctanoate , Ethylene glycol dioleate, propylene glycol dicaprate, propylene glycol di (capryl / capric acid), propylene glycol dicaprylate, neopentyl glycol dicaprate, neopentyl glycol dioctanoate, glyceryl tricaprylate, glyceryl triundecylate, triisopalmitine Glyceryl acid, glyceryl triisostearate, octyldodecyl neopentanoate, isostearyl octanoate, octyl isononanoate, hexyl decyl neodecanoate, octyldodecyl neodecanoate, isocetyl isostearate, isostearyl isostearate, octyldecyl isostearate, polyglycerin oleic acid Ester, polyglycerol isostearate, dipropyl carbonate, charcoal Dialkyl (C12-18), triisocetyl citrate, triisoaralkyl citrate, triisooctyl citrate, lauryl lactate, myristyl lactate, cetyl lactate, octyl decyl lactate, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, Trioctyl citrate, diisostearyl malate, 2-ethylhexyl hydroxystearate, di-2-ethylhexyl succinate, diisobutyl adipate, diisopropyl sebacate, dioctyl sebacate, cholesteryl stearate, cholesteryl isostearate, cholesteryl hydroxystearate, olein Cholesteryl acid, dihydrocholesteryl oleate, phytosteryl isostearate, phytosteryl oleate, 12-stearoyl hydroxystearate Cetyl, 12-stearoyl-hydroxystearic acid stearyl 12-stearoyl-hydroxystearic acid isostearate, and the like.
Hydrocarbon oil phase components: squalane, liquid paraffin, α-olefin oligomer, isoparaffin, ceresin, paraffin, liquid isoparaffin, polybutene, microcrystalline wax, petrolatum and the like.
Animal and vegetable oils and their hydrogenated oils, and naturally occurring waxes: beef tallow, hydrogenated beef tallow, lard, hydrogenated tallow, horse oil, hydrogenated horse oil, mink oil, orange luffy oil, fish oil, hydrogenated fish oil, egg yolk oil and other animal oils and Its hardened oil, avocado oil, almond oil, olive oil, cacao butter, kiwi seed oil, apricot oil, kukui nut oil, sesame oil, wheat germ oil, rice germ oil, rice bran oil, safflower oil, shea butter, soybean oil, evening primrose oil , Perilla oil, tea seed oil, camellia oil, corn oil, rapeseed oil, hydrogenated rapeseed oil, palm kernel oil, hydrogenated palm kernel oil, palm oil, hydrogenated palm oil, peanut oil, hydrogenated peanut oil, castor oil, hydrogenated castor oil , Vegetable oils such as sunflower oil, grape seed oil, jojoba oil, hardened jojoba oil, macadamia nut oil, medhome oil, cottonseed oil, hardened cottonseed oil, coconut oil, hardened coconut oil and its hardened , Beeswax, high acid value beeswax, lanolin, reduced lanolin, hydrogenated lanolin, liquid lanolin, carnauba wax and montan wax.
Silicone oil phase components: dimethylpolysiloxane, methylphenylpolysiloxane, methylcyclopolysiloxane, octamethylpolysiloxane, decamethylpolysiloxane, dodecamethylcyclosiloxane, methylhydrogenpolysiloxane, polyether-modified organopolysiloxane, dimethyl Siloxane / methylcetyloxysiloxane copolymer, dimethylsiloxane / methylstearoxysiloxane copolymer, alkyl-modified organopolysiloxane, terminal-modified organopolysiloxane, amino-modified silicone oil, amino-modified organopolysiloxane, dimethiconol, silicone gel, acrylic Examples include silicone, trimethylsiloxysilicic acid, and silicone RTV rubber.
Fluorine oil phase components: perfluoropolyether, fluorine-modified organopolysiloxane, fluorinated pitch, fluorocarbon, fluoroalcohol, fluoroalkyl / polyoxyalkylene co-modified organopolysiloxane, and the like.

(2) Examples of higher alcohols Lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, behenyl alcohol, 2-ethylhexanol, hexadecyl alcohol, octyldodecanol and the like can be mentioned.

(3) Examples of fatty acids Caprylic acid, capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, arachidonic acid, behenic acid , Erucic acid, 2-ethylhexanoic acid and the like.

(4) Examples of UV absorbers Paraaminobenzoic acid, amyl paraaminobenzoate, ethyldihydroxypropyl paraaminobenzoate, glyceryl paraaminobenzoate, ethyl paraaminobenzoate, octyl paraaminobenzoate, octyldimethyl paraaminobenzoate, ethylene glycol salicylate, salicylic acid Octyl, triethanolamine salicylate, phenyl salicylate, butylphenyl salicylate, benzyl salicylate, homomenthyl salicylate, benzyl cinnamate, octyl paramethoxycinnamate, 2-ethylhexyl paramethoxycinnamate, mono 2-diparamethoxycinnamate Glyceryl ethylhexanoate, isopropyl paramethoxycinnamate, diethanolamine salt of paramethoxyhydrocinnamic acid, diisopropyl diisopropylcinnamic acid Stealth mixture, urocanic acid, ethyl urocanate, hydroxymethoxybenzophenone, hydroxymethoxybenzophenone sulfonic acid and its salts, dihydroxymethoxybenzophenone, dihydroxymethoxybenzophenone sodium disulfonate, dihydroxybenzophenone, dihydroxydimethoxybenzophenone, hydroxyoctoxybenzophenone, tetrahydroxybenzophenone, Butylmethoxydibenzoylmethane, 2,4,6-trianilino-p- (carbo-2-ethylhexyl-1-oxy) -1,3,5-triazine, 2- (2-hydroxy-5-methylphenyl) benzotriazole , Methyl-O-aminobenzoate, 2-ethylhexyl-2-cyano-3, 3-diphenyl acrylate, phenylbenzimidazole sulfate, 3- (4-methylbenzylidene) can Examples include full, isopropyldibenzoylmethane, 4- (3,4-dimethoxyphenylmethylene) -2, 5-dioxo-1-imidazolidinepropionate 2-ethylhexyl, and the like, polymer derivatives, silane derivatives, and the like.

(5) Examples of powders and pigments Red 104, Red 201, Yellow 4, Blue 1, Black 401 and other dyes, Yellow 4 AL lake, Yellow 203 BA lake and other lake dyes, nylon powder , Silk powder, urethane powder, Teflon (registered trademark) powder, silicone powder, polymethyl methacrylate powder, cellulose powder, starch, silicone elastomer spherical powder, polyethylene powder, yellow iron oxide, red iron oxide, black Colored pigments such as iron oxide, chromium oxide, carbon black, ultramarine and bitumen, white pigments such as zinc oxide, titanium oxide and cerium oxide, extender pigments such as talc, mica, sericite, kaolin and barium sulfate plate, titanium mica Pearl pigments such as barium sulfate, calcium carbonate, magnesium carbonate, aluminum silicate, metal salts such as magnesium silicate, Inorganic powders such as Rica and alumina, metal soaps such as aluminum stearate, magnesium stearate, zinc palmitate, zinc myristate, magnesium myristate, zinc laurate, zinc undecylenate, bentonite, smectite, boron nitride, etc. It is done. There are no particular restrictions on the shape of these powders (spherical, rod-like, needle-like, plate-like, irregular shape, flake-like, spindle-like, etc.) and particle diameter. These powders are conventionally known surface treatments such as fluorine compound treatment, silicone treatment, silicone resin treatment, pendant treatment, silane coupling agent treatment, titanium coupling agent treatment, oil agent treatment, N-acylated lysine treatment, The surface treatment may or may not be performed in advance by polyacrylic acid treatment, metal soap treatment, amino acid treatment, lecithin treatment, inorganic compound treatment, plasma treatment, mechanochemical treatment or the like.

(6) Examples of surfactants Anionic surfactants: fatty acid soap, α-acyl sulfonate, alkyl sulfonate, alkyl allyl sulfonate, alkyl naphthalene sulfonate, alkyl sulfate, POE alkyl ether sulfate , Alkylamide sulfate, alkyl phosphate, POE alkyl phosphate, alkylamide phosphate, alkyloylalkyl taurine salt, N-acyl amino acid salt, POE alkyl ether carboxylate, alkyl sulfosuccinate, alkyl sulfoacetic acid Sodium, acylated hydrolyzed collagen peptide salt, perfluoroalkyl phosphate, etc. are mentioned.
Cationic surfactant: alkyltrimethylammonium chloride, stearyltrimethylammonium chloride, stearyltrimethylammonium bromide, cetostearyltrimethylammonium chloride, distearyldimethylammonium chloride, stearyldimethylbenzylammonium chloride, behenyltrimethylammonium bromide, benzalkonium chloride , Behenic acid amidopropyldimethylhydroxypropylammonium chloride, stearic acid diethylaminoethylamide, stearic acid dimethylaminopropylamide, lanolin derivative quaternary ammonium salts, and the like.
Amphoteric surfactants: carboxybetaine type, amide betaine type, sulfobetaine type, hydroxysulfobetaine type, amide sulfobetaine type, phosphobetaine type, aminocarboxylate type, imidazoline derivative type, amidoamine type and the like.
Nonionic surfactant: propylene glycol fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, POE sorbitan fatty acid ester, POE sorbitol fatty acid ester, POE glycerin fatty acid ester, POE alkyl ether, POE fatty acid ester, POE cured castor Oil, POE castor oil, POE / POP copolymer, POE / POP alkyl ether, polyether-modified silicone lauric acid alkanolamide, alkylamine oxide, hydrogenated soybean phospholipid, and the like.
Natural surfactant: lecithin, saponin, sugar surfactant and the like.

(7) Examples of polyhydric alcohols and sugars Ethylene glycol, diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, glycerin, diglycerin, polyglycerin, 3-methyl-1,3-butanediol, 1, 3 -Butylene glycol, sorbitol, mannitol, raffinose, erythritol, glucose, sucrose, fructose, xylitol, lactose, maltose, maltitol, trehalose, alkylated trehalose, mixed isomerized sugar, sulfated trehalose, pullulan and the like. These chemically modified compounds can also be used.

(8) Examples of polymers Acrylic ester / methacrylic acid ester copolymer (plus size, manufactured by Kyoyo Chemical), vinyl acetate / crotonic acid copolymer (resin 28-1310, manufactured by NSC), vinyl acetate / croton Acid / vinyl neodecanate copolymer (28-2930, manufactured by NSC), methyl vinyl ether maleic acid half ester (Gantrez ES, manufactured by ISP), T-butyl acrylate / ethyl acrylate / methacrylic acid copolymer (rubymer) , BASF), vinyl pyrrolidone / vinyl acetate / vinyl propionate copolymer (Rubicol VAP, BASF), vinyl acetate / crotonic acid copolymer (Rubiset CA, BASF), vinyl acetate / croton Acid / vinyl pyrrolidone copolymer (Rubiset CAP, manufactured by BASF), vinyl pyrrolidone / acrylate copolymer (Rubiflex, BA SF), acrylate / acrylamide copolymer (Ultrahold, BASF), vinyl acetate / butyl maleate / isobornyl acrylate copolymer (Advantage, ISP), carboxy vinyl polymer (Carbopol, BF Goodrich), anionic polymer compounds such as acrylic acid / alkyl methacrylate copolymers (Pemulene, BF Goodrich) and acetic acid amphoteric compounds of dialkylaminoethyl methacrylate polymers (Yukaformer, Mitsubishi Chemical) Amphoteric polymer compounds such as octyl acrylate acrylate / hydroxypropyl acrylate / butyl aminoethyl methacrylate copolymer (AMPHOMER, NSC), quaternized vinylpyrrolidone / dimethylaminoethyl methacrylate (GAFQUAT, ISP) , Methyl vinyl imidazolium chloride Cationic polymer compounds such as vinyl / vinylpyrrolidone copolymer (rubicoat, manufactured by BASF), polyvinylpyrrolidone (rubiscol K, manufactured by BASF), vinylpyrrolidone / vinyl acetate copolymer (rubiscol VA, manufactured by BASF) ), Nonionic polymer compounds such as vinylpyrrolidone / dimethylaminoethyl methacrylate copolymer (copolymer 937, manufactured by ISP), vinylcaprolactam / vinylpyrrolidone / dimethylaminoethyl methacrylate copolymer (copolymer VC713, manufactured by ISP), etc. There is. Cellulose or derivatives thereof, keratin and collagen or derivatives thereof, calcium alginate, pullulan, agar, gelatin, tamarind seed polysaccharide, xanthan gum, carrageenan, high methoxyl pectin, low methoxyl pectin, guar gum, gum arabic, crystalline cellulose, arabino Naturally derived polymer compounds such as galactan, gum karaya, gum tragacanth, alginic acid, albumin, casein, curdlan, gellan gum and dextran can also be suitably used.

(9) Examples of physiologically active ingredients Examples of physiologically active ingredients include substances that impart some physiological activity to the skin when applied to the skin. For example, whitening ingredients, immunostimulants, anti-aging agents, UV protection agents, slimming agents, tanning agents, antioxidants, hair growth agents, hair restorers, moisturizers, blood circulation promoters, antibacterial agents, bactericides, desiccants, A cooling sensation agent, a warming sensation agent, vitamins, an amino acid, a wound healing promoter, an irritation relaxation agent, an analgesic agent, a cell activator, an enzyme component, etc. are mentioned. Examples of these suitable ingredients include, for example, ashitaba extract, avocado extract, amateur extract, altea extract, arnica extract, aloe extract, apricot extract, apricot kernel extract, ginkgo biloba extract, fennel extract, turmeric extract, oolong tea extract, ages Extract, Echinacea leaf extract, Ogon extract, Oat extract, Oen extract, Barley extract, Hypericum extract, Oyster extract, Dutch mustard extract, Orange extract, Seawater dried product, Seaweed extract, Hydrolyzed elastin, Hydrolyzed wheat powder, Hydrolyzed silk , Chamomile extract, Carrot extract, Kawara mugwort extract, Licorice extract, Calcade extract, Oyster extract, Kina extract, Cucumber extract, Guanosine, Gardenia extract, Kumazasa extract, Clarae Kiss, walnut extract, grapefruit extract, clematis extract, chlorella extract, mulberry extract, gentian extract, tea extract, yeast extract, burdock extract, fermented rice bran extract, rice germ oil, comfrey extract, collagen, bilberry extract, saicin extract, psycho extract Extract Kizuta extract, hawthorn extract, elderberry extract, yarrow extract, mint extract, sage extract, mallow extract, senki Sue extract, assembly extract, soybean extract, tiso extract, thyme extract, tea extract, clove extract, chigaya extract, chimpi extract, touki extract, toshinsen extract, tonin extract, spruce extract, dokudami extract, tomato extract, natto extract, carrot extract, garlic extract, Novara extract, hibiscus extract, bacmond extract, parsley extract, honey, hamamelis extract, parietalia extract, toad extract, bisabolol, loquat extract, dandelion extract, burdock extract, bukuro extract, butcher bloom extract, grape extract, propolis, loofah extract, Safflower extract, peppermint extract, bodaige extract, button extract, hop extract, pine extract, marronnier extract, mizubasho Kiss, Mukuroji extract, Melissa extract, Peach extract, Cornflower extract, Eucalyptus extract, Yukinoshita extract, Yokuinin extract, Artemisia extract, Lavender extract, Apple extract, Lettuce extract, Lemon extract, Lotus root extract, Rose extract, Rosemary extract, Roman chamomile extract And royal jelly extract.
Biopolymers such as deoxyribonucleic acid, mucopolysaccharide, sodium hyaluronate, sodium chondroitin sulfate, collagen, elastin, chitin, chitosan, hydrolyzed eggshell membranes, amino acids, hydrolyzed peptides, sodium lactate, urea, sodium pyrrolidonecarboxylate , Moisturizing ingredients such as betaine, whey, trimethylglycine, oily ingredients such as sphingolipid, ceramide, phytosphingosine, cholesterol, cholesterol derivatives, phospholipids, ε-aminocaproic acid, glycyrrhizic acid, β-glycyrrhetinic acid, lysozyme chloride, guaiazulene, Immunostimulants such as hydrocortisone, vitamin A, vitamin B2, vitamin B6, vitamin C, vitamin D, vitamin E, calcium pantothenate, biotin, nicotinamide, vitamin C ester Vitamins, active ingredients such as allantoin, diisopropylamine dichloroacetate, 4-aminomethylcyclohexanecarboxylic acid, antioxidants such as tocopherol, carotenoid, flavonoid, tannin, lignan, saponin, α-hydroxy acid, β-hydroxy acid, etc. Cell activators, blood circulation promoters such as γ-oryzanol and vitamin E derivatives, wound healing agents such as retinol and retinol derivatives, arbutin, kojic acid, placenta extract, sulfur, ellagic acid, linoleic acid, tranexamic acid, glutathione, etc. Whitening agent, cephalanthin, licorice extract, red pepper tincture, hinokitiol, garlic iodide extract, pyridoxine hydrochloride, DL-α-tocopherol, DL-α-tocopherol acetate, nicotinic acid, nicotinic acid derivative, calcium pantothenate, D-pan Tothenyl alcohol, acetyl pantothenyl ethyl ether, biotin, allantoin, isopropylmethylphenol, estradiol, ethinyl estradiol, capronium chloride, benzalkonium chloride, diphenhydramine hydrochloride, takanal, camphor, salicylic acid, nonyl acid vanillylamide, nonanoic acid vanillylamide, pyroctone Olamine, glyceryl pentadecanoate, L-menthol, mononitroguaiacol, resorcin, γ-aminobutyric acid, benzethonium chloride, mexiletine hydrochloride, auxin, female hormone, cantalis tincture, cyclosporine, zinc pyrithione, hydrocortisone, minoxidil, monostearic acid Examples include hair growth agents such as polyoxyethylene sorbitan, mint oil, and Sasanishiki extract.

(10) Examples of antioxidants: sodium bisulfite, sodium sulfite, erythorbic acid, sodium erythorbate, dilauryl thiodipropionate, tocopherol, tolyl biguanide, nordihydroguaiaretic acid, parahydroxyanisole, butylhydroxyanisole, dibutylhydroxy Examples include plant extracts having an antioxidant effect such as toluene, ascorbyl stearate, ascorbyl palmitate, octyl gallate, propyl gallate, carotenoid, flavonoid, tannin, lignan, saponin, apple extract and clove extract.

(11) Examples of solvents Purified water, ethanol, lower alcohol, ethers, LPG, fluorocarbon, N-methylpyrrolidone, fluoroalcohol, volatile linear silicone, next-generation chlorofluorocarbon and the like.

The following preparation examples and examples illustrate the invention in more detail.
In the following preparation examples, first, a walnut extract is prepared from a ground or seed coat pulverized product containing walnut seed coat, and this is purified using a resin column and HPLC to obtain a polyphenol derived from walnut (such as the above-mentioned pedunclazine). Each component) was obtained. In the following Example 1, the liver protective action of each component obtained in Preparation Example 1 was examined.

Preparation Example 1
70% ethanol (15 L) was added to seeds or seed coats (10 kg) containing dried walnut seed coats from China and extracted at room temperature for 24 hours. After filtering the obtained extract, water-containing ethanol was distilled off at 50 ° C. or lower to obtain a walnut extract. The obtained walnut extract was suspended in water and partitioned with ethyl acetate and n-butanol, and n-butanol was distilled off to obtain an n-butanol fraction. The n-butanol fraction (20 g) was passed through Diaion HP-20 and eluted with water and 10, 20, 40% ethanol as needed. After concentrating each elution fraction, the 10% elution part (0.95 g) was eluted with 10-50% aqueous methanol using a Toyopearl HW-40 column, then further eluted with methanol, and further (methanol: water Elution with a solvent prepared at a weight ratio of: acetone = (7: 1: 2) gave pedunclazine (253.9 mg).
The 20% elution part (4.6 g) was eluted with 20-70% aqueous methanol using a Toyopearl HW-40 column, then with methanol, and further (methanol: water: acetone) = (7: 1: 2) Further elute with the solvent prepared in step 1, followed by HPLC (develocil C30-UG-5 (Nomura Chemical), 10 mM phosphate-10 mM potassium phosphate-acetonitrile (42.5: 42.5: 15) or 10 mM phosphate-10 mM phosphate) Fractionated with potassium-ethanol-ethyl acetate (42.5: 42.5: 10: 5), casarictin (163.5 mg), terimagranin I (585.8 mg), terimagranin II (7.6 mg), lugosin C (37.1 mg) Casrinin (176.9 mg) was obtained, and the obtained components were identified by comparing NMR data with a standard substance.

Example 1: Inhibition activity of carbon tetrachloride-induced rat hepatocyte injury The hepatoprotective action of each component obtained in Preparation Example 1 was examined using a hepatocyte injury model induced by carbon tetrachloride.

In other words, hepatocytes obtained from rats by collagenase perfusion (4 × 10 ⁴
cells / 100 mL) was precultured (4 hours), and then replaced with a medium containing 5 mM carbon tetrachloride and sample. After culturing for 40 hours, cell damage was measured by MTT assay.
The measurement results are shown in Table 1.

  All results in Table 1 are expressed as mean ± standard error (n = 8). From the results in Table 1 above, it can be seen that the hepatoprotective agent of the present invention suppresses hepatocyte damage in vitro.

As described above, hepatic damage caused by carbon tetrachloride is metabolized into trichloromethyl radicals by the metabolic enzymes present in the liver, and the chain reaction caused by this radical causes the liver to be metabolized into the liver. It is believed to be a disorder induced by the accumulation of lipid peroxide. Therefore, in order to suppress the liver damage induced by carbon tetrachloride, it is necessary to eliminate the trichloromethyl radical and to eliminate the excessively produced active oxygen. From the results of Example 1 described above, the hepatoprotective agent of the present invention is considered to be based on the action of both of them.
Thereby, it was confirmed that each component extracted from the seed coat of walnut has a hepatoprotective action.

  In addition, the said Example does not limit this invention, Of course, it applies within the range which does not deviate from the summary of this invention. For example, in the present embodiment, only one component each obtained from seed or seed coat containing walnut seed coat has been described, but a mixture of these ingredients may be used.

Formulation Examples Formulation examples of the hepatoprotective agent of the present invention are given below, but the following formulation examples do not limit the present invention.
Formulation Example 1: Chewing gum
53.0wt% sugar
Gum base 20.0
Glucose 10.0
Minamata 16.0
Fragrance 0.5
Liver protectant 0.5
100.0wt%

Formulation Example 2: Gummy
Reduced water tank 40.0wt%
Granulated sugar 20.0
Glucose 20.0
Gelatin 4.7
Water 9.68
Kiwi juice 4.0
Kiwi flavor 0.6
Dye 0.02
Hepatoprotectant 1.0
100.0wt%

Formulation Example 3: Candy
50.0 wt% sugar
Minamata 33.0
Water 14.4
Organic acid 2.0
Fragrance 0.2
Hepatoprotectant 0.4
100.0wt%

Formulation Example 4: Yogurt (hard / soft)
Milk 41.5wt%
Nonfat dry milk 5.8
Sugar 8.0
Agar 0.15
Gelatin 0.1
Lactic acid bacteria 0.005
Hepatoprotectant 0.4
Perfume
Water residue
100.0wt%

Formulation Example 5: Soft drink
Fructose glucose liquid sugar 30.0wt%
Emulsifier 0.5
Hepatoprotectant 0.05
Perfume
Purified water residue
100.0wt%

Formulation Example 6: Soft capsule
Rice germ oil 87.0wt%
Emulsifier 12.0
Hepatoprotectant 1.0
100.0wt%

Formulation Example 7: Tablet
Lactose 54.0wt%
Crystalline cellulose 30.0
Starch degradation product 10.0
Glycerin fatty acid ester 5.0
Hepatoprotectant 1.0
100.0wt%

Formulation Example 8: Oral granules (pharmaceuticals)
Hepatoprotectant 1.0wt%
Lactose 30.0
Cornstarch 60.0
Crystalline cellulose 8.0
Polyvinylpyrrolidone 1.0
100.0wt%

Formulation Example 9: Tablet
76.4 wt% sugar
Glucose 19.0
Sucrose fatty acid ester 0.2
Liver protectant 0.5
Purified water 3.9
100.0wt%

Formulation Example 10: Cosmetic cream
Squalane 20.0wt%
Beeswax 5.0
Refined jojoba oil 5.0
Glycerin 5.0
Glycerol monostearate 2.0
Polyoxyethylene (20) sorbitan-
Monostearate 2.0
Hepatoprotectant 2.0
Preservative appropriate amount
Perfume
Purified water residue
100.0wt%

Formulation Example 11: Lotion
Ethanol 5.0wt%
Glycerin 2.0
1,3-butylene glycol 2.0
Polyethylene oleyl ether 0.5
Sodium citrate 0.1
Citric acid 0.1
Hepatoprotectant 0.1
Purified water residue
100.0wt%

Formulation Example 12: Body gel
Macadamia nut oil 2.0wt%
Octyldodecyl myristate 10.0
Methylphenylpolysiloxane 5.0
Behenyl alcohol 3.0
Stearic acid 3.0
Batyl alcohol 1.0
Glyceryl monostearate 1.0
Tetraoleic acid polyoxyethylene sorbit 2.0
Hydrogenated soybean phospholipid 1.0
Ceramide 0.1
Retinol palmitate 0.1
Preservative appropriate amount
Centella extract 1.0
Hepatoprotectant 1.0
1,3-butylene glycol 5.0
Purified water residue
100.0wt%

Formulation Example 13: Latex
Squalane 4.0wt%
Vaseline 2.5
Cetanol 2.0
Glycerin 2.0
Lipophilic glyceryl monostearate 1.0
Stearic acid 1.0
L-Arginine 1.0
Liver protectant 0.5
Potassium hydroxide 0.1
Perfume
Purified water residue
100.0wt%

Formulation Example 14: Bath agent (liquid)
Propylene glycol 50.0wt%
Ethanol 20.0
Sodium sulfate 5.0
Liver protectant 0.5
Lanolin 0.5
Avocado oil 0.5
Dye 1.5
Fragrance 22.0
100.0wt%

As described above, the hepatoprotective agent of the present invention can prevent oxidative damage in the body, prevent liver damage based on the toxicity of active oxygen, and alleviate the worsening of the pathological condition when taken daily. it can. The hepatoprotective agent of the present invention contains a walnut extract extracted from a natural plant belonging to the genus Walnut family, in particular, a walnut seed coat and / or a walnut seed coat. Compared to drugs, it has fewer side effects and is safer for the human body. By containing the hepatoprotective agent of the present invention in a pharmaceutical composition or food, it can be taken orally more easily in daily life. Moreover, this invention can be utilized as a skin external preparation and can provide the hepatoprotectant which can be ingested from skin. Furthermore, by having a liver protecting action, it is possible to effectively prevent spots and the like due to liver damage.

Claims (15)

  A hepatoprotectant containing ellagitannin as an active ingredient.   The hepatoprotection according to claim 1, wherein the ellagitannin is one in which a hexahydrodiphenoyl group is substituted at at least one of the 4th and 6th positions and the 2nd and 3rd positions of glucose. Agent.   The ellagitannin is at least one selected from Pedunculagin, Tellimagrandin I, Casarictin, Tellimagrandin II, Rugsin C, and Casuarinin. The hepatoprotective agent according to claim 1 or 2, wherein:   The hepatoprotective agent according to any one of claims 1 to 3, wherein the ellagitannins are extracted from walnut seed coats and / or walnut seed coats. Walnut extract extracted from walnut seed coat and / or walnut seed coat,
A walnut extract characterized by containing walnut-derived polyphenol and at least ellagitannin as the walnut-derived polyphenol.   The ellagitannin contains at least one selected from Pedunculagin, Tellimagrandin I, Casarictin, Tellimagrandin II, Rugsin C, and Casuarinin. Walnut extract characterized by that.   The pharmaceutical containing the hepatoprotectant of any one of Claims 1-4.   A skin external preparation containing the hepatoprotective agent according to any one of claims 1 to 4.   Food-drinks containing the hepatoprotectant of any one of Claims 1-4.   The feed for mammals containing the hepatoprotective agent of any one of Claims 1-4. A hepatoprotectant comprising the walnut extract according to claim 5 or 6 as an active ingredient.   The pharmaceutical containing the walnut extract of Claim 5 or Claim 6.   The skin external preparation containing the walnut extract of Claim 5 or Claim 6.   Food-drinks containing the walnut extract of Claim 5 or Claim 6.   Mammal animal feed comprising the walnut extract according to claim 5 or 6.