JP2008169172A - Norcepharadione b derivative having inflammatory cytokine production-inhibiting action, food preparation, cosmetic, antiinflammatory agent comprising the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a norcepharadione B derivative which is weak in side effects and has an excellent inflammatory cytokine production-inhibiting action, and to provide a food preparation, a cosmetic, and an inflammatory agent comprising the same. <P>SOLUTION: This norcepharadione B derivative having the inflammatory cytokine production-inhibiting action is a derivative obtained by binding norcepharadione B to either of caprylic acid, laurylic acid, 14-methylpalmitic acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, alpha-lipoic acid, gamma-linolenic acid, stearic acid, and methylstearic acid, and is obtained by adding lipase for transesterification to the ground product of Houttuynia cordata leaves, heating the mixture and then extracting the product with a vegetable oil, or fermenting fishes and soybeans with Bacillus natto and then extracting the fermentation product with a vegetable oil. The food preparation or cosmetic comprises the norcepharadione B derivative, a Chrysanthemum morifolium flower extract-containing vegetable oil, and a pine leaf extract-containing vegetable oil. The inflammatory agent comprises the norcepharadione B derivative. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

The present invention relates to a norcepharadione B derivative having an inhibitory action on inflammatory cytokine production. The present invention also relates to food preparations, cosmetics and anti-inflammatory agents comprising the above-mentioned norcepharadione B derivative, chrysanthemum flower extract-containing vegetable oil, and pine needle extract-containing vegetable oil.

Inflammatory cytokines are several proteins produced by inflammatory cells such as macrophages, lymphocytes and monocytes during inflammation.

Inflammatory cytokines also induce inflammatory prostaglandins, which damage tissue cells and cause fever, swelling, redness, and pain throughout the body.

Inflammatory cytokines include interleukin-1 alpha, interleukin-1 beta, interleukin-6, interleukin-8, and tumor necrosis factor alpha (TNFalpha), which are proteins having a molecular weight of about 10,000 to 30,000. It is.

Among these, interleukin-1 alpha and interleukin-1 beta are released from monocytes and lymphocytes, which are inflammatory cells, and promote secretion of interleukin-6, interleukin-8 and TNFalpha. Leukine-6 is also involved in fever and tissue damage. TNF alpha is also referred to as cachectin, and is released during cachexia associated with cancer and the like, resulting in worsening of systemic symptoms (see, for example, Non-Patent Document 1).

The production of these inflammatory cytokines is induced intracellularly by bacterial or viral infection. The pathway includes a protein kinase C system and an intracellular signal transduction system via calcium. Furthermore, it has been reported that transcription factors kappa B (NF-kappa B) and NF-IL6, which are transcription factors in the nucleus, promote the transcription of messenger RNA of inflammatory cytokines (see, for example, Non-Patent Document 2).

A steroid hormone preparation has been developed as a substance that suppresses the production of inflammatory cytokines, and this steroid hormone preparation suppresses protein kinase C system and transcription factors of inflammatory cytokines in inflammatory cells, thereby suppressing the production of inflammatory cytokines. (For example, refer nonpatent literature 3).

However, steroid hormone preparations such as clobetasol propionate, diflorazone acetate, prezonidolone, and cortisone are known to have adverse immune effects, opportunistic infections, reduced adrenal function, steroid purpura, etc., and many side effects have been reported. (For example, see Non-Patent Document 4).

As a result of these side effects, steroid hormone preparations have the disadvantage that they cannot be used in large quantities and continuously.

On the other hand, licorice and herbs are known as natural anti-inflammatory agents. Licorice contains glycyrrhizic acid, and it has been reported that steroid-like action is involved in its function (see, for example, Non-Patent Document 5). However, its function is mild and it is water-soluble, so there is a drawback that the action does not last.

Naturally derived plant materials are used as pharmaceuticals, foods, cosmetics, etc. Among them, Dokudami is said to be ten drugs for Yamato herb, its scientific name is Houttunia cordadata, and the component isoquercitrin has a blood pressure lowering effect. It has been reported that decanoyl acetaldehyde has a bactericidal action and diuretic action, and a flavone component has a blood circulation improving action (for example, see Non-Patent Document 6). However, there are few reports on the identification of these alkaloid components and the characteristics of their anti-inflammatory effects.

The invention of a substance or anti-inflammatory agent that suppresses the production of inflammatory cytokines relates to an isolated nucleic acid molecule encoding a cytokine-suppressing anti-inflammatory drug binding protein having the amino acid sequence of the drug binding protein or a complementary chain molecule thereof (For example, refer to Patent Document 1).

There is also an invention of a human antibody that binds to human TNF alpha, which relates to an antibody that exerts an inhibitory action against inflammatory cytokines (see, for example, Patent Document 2).

Furthermore, in the invention of the protein complex forming agent, polyphenol is an active ingredient, and there is a protein complex forming agent effective as a gene complex, a cell adhesion inhibitor or an immunotolerant (see, for example, Patent Document 3). ). However, there is no invention related to norcepharadione B that suppresses inflammatory cytokine production.
Japanese Patent No. 3377529 JP-A-5-96 JP 2002-255811 A Hernandez-Rodrigues, J. et al. Rheumatology, 43, 294-301, 2004. Devaraj, S.M. Diabetes, 54, 85-91, 2005. Walsh, G.M. M.M. Et al. Endocrinol, 178, 37-43, 2003. Bruner, C.I. R. Et al., Dermatol. Online J, 9, 2, 2003. Sasaki, H .; Pathology, 70, 229-236, 2002-2003. Li, G. Z. Et al., Biol. Pharm. Bull, 28, 1864-1868, 2005.

Conventionally, there are steroids as substances that suppress inflammatory cytokines, but there are problems such as adrenal hypertrophy, opportunistic infections, and dermatitis. In addition, naturally-occurring substances have a problem that their actions are mild and water-soluble substances, and thus their actions are not sustainable.

Furthermore, natural alkaloids and polyphenols containing norcepharadione B have the problem of stability that their activity is easily lost by various oxidative stimuli and oxidants.

The present invention has been made paying attention to the problems existing in the prior art as described above. The object is to provide a norcepharadione B derivative having weak side effects and having an excellent inhibitory effect on the production of inflammatory cytokines.

Additive caprylic acid, lauric acid, eicosapentaenoic acid or docosahexaenoic acid and lipase for transesterification to ground pulverized leaves, warm, extract with vegetable oil, and have excellent side effects The object is to provide a norcepharadione B derivative having a production inhibitory action.

Provided is a norcepharadione B derivative having an excellent inhibitory action on inflammatory cytokine production, with less side effects obtained by extraction with edible fish, fermented natto and fermented fermented soybeans with vegetable oil There is.

Further, 1 weight of norcepharadione B derivative having an inhibitory action on inflammatory cytokine production contains 0.01 to 0.5 weight of vegetable oil containing chrysanthemum flower extract and 0.01 to 0.5 weight of vegetable oil containing pine leaf extract It is an object of the present invention to provide an excellent food preparation with weak side effects.

In addition, 1 to 1 weight of norcepharadione B derivative having inflammatory cytokine production inhibitory action, 0.05 to 0.8 weight of chrysanthemum flower extract-containing vegetable oil, 0.05 to 0.8 weight of vegetable oil containing pine needle extract The side effect which consists of a composition to contain is weak, and it is providing the outstanding cosmetics.

Another object of the present invention is to provide an excellent anti-inflammatory agent having a low side effect consisting of a norcepharadione B derivative having an inhibitory action on inflammatory cytokine production.

In order to achieve the above object, the invention according to claim 1 relates to a norcepharadione B derivative represented by the following formula (1) having an inhibitory action on inflammatory cytokine production.

X is any one selected from caprylic acid, lauric acid, 14-methylpalmitic acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, alpha-lipoic acid, gamma-linolenic acid, stearic acid, and methyl stearic acid. .

The invention according to claim 2 is obtained by adding caprylic acid and lipase for transesterification to a ground product of dokudami leaves, heating and extracting with vegetable oil, and the norcepharadione B derivative according to claim 1 Among them, it relates to a norcepharadione B derivative represented by the following formula (2) having an inhibitory action on inflammatory cytokine production, wherein X is caprylic acid.

The invention according to claim 3 is obtained by adding lauric acid and lipase for transesterification to a pulverized leaf of Dokudami, heating and extracting with vegetable oil, and the norcepharadione B derivative according to claim 1 Among them, it relates to a norcepharadione B derivative represented by the following formula (3) having an inhibitory action on inflammatory cytokine production, wherein X is lauric acid.

The invention according to claim 4 is obtained by adding eicosapentaenoic acid and lipase for transesterification to a ground product of dokudami leaves, heating, extracting with vegetable oil, and norcepharadione B according to claim 1 The present invention relates to a norcepharadione B derivative represented by the following formula (4) having an inhibitory action on inflammatory cytokine production, wherein X is eicosapentaenoic acid among the derivatives.

The invention according to claim 5 is obtained by adding docosahexaenoic acid and lipase for transesterification to a ground product of Dokudami leaves, heating, extracting with vegetable oil, and norcepharadione B derivative according to claim 1 Among them, it relates to a norcepharadione B derivative represented by the following formula (5) having an inhibitory action on inflammatory cytokine production, wherein X is docosahexaenoic acid.

The invention described in claim 6 has an inhibitory effect on the production of inflammatory cytokines according to claim 1, which is obtained by extracting a fermented product obtained by adding natto bacteria to edible fish, dokudami leaves and soybeans and fermenting them with vegetable oil. The present invention relates to a norcepharadione B derivative possessed.

The invention according to claim 7 is the weight of norcepharadione B derivative having an inhibitory action on inflammatory cytokine production according to claim 1 or claim 2 or claim 3 or claim 4 or claim 5 or claim 6. Furthermore, the present invention relates to a food preparation comprising a composition containing 0.01 to 0.5 weight of chrysanthemum flower extract-containing vegetable oil and 0.01 to 0.5 weight of pine leaf extract-containing vegetable oil.

The invention according to claim 8 is the weight of norcepharadione B derivative having an inhibitory action on the production of inflammatory cytokine according to claim 1 or claim 2 or claim 3 or claim 4 or claim 5 or claim 6. In addition, the present invention relates to a cosmetic comprising a composition containing 0.05 to 0.8 weight of chrysanthemum flower extract-containing vegetable oil and 0.05 to 0.8 weight of pine leaf extract-containing vegetable oil.

The invention according to claim 9 comprises the norcepharadione B derivative having an inhibitory action on inflammatory cytokine production according to claim 1 or claim 2 or claim 3 or claim 4 or claim 5 or claim 6. It relates to anti-inflammatory agents.

Since this invention is comprised as mentioned above, there exist the following effects.

According to the norcepharadione B derivative having an inhibitory action on inflammatory cytokine production according to claim 1, side effects are weak and an excellent anti-inflammatory action is exhibited.

According to a norcepharadione B derivative having an inhibitory action on inflammatory cytokine production, obtained by adding caprylic acid and lipase for transesterification to the ground product of dokudami leaf according to claim 2, heating and extracting with vegetable oil. Therefore, side effects are weak and an excellent anti-inflammatory effect is exhibited.

According to the norcepharadione B derivative having an inhibitory action on inflammatory cytokine production, obtained by adding lauric acid and lipase for transesterification to the ground pulverized product of Dokudami leaf according to claim 3, heating and extracting with vegetable oil. Therefore, side effects are weak and an excellent anti-inflammatory effect is exhibited.

A norcepharadione B derivative having an inhibitory action on inflammatory cytokine production obtained by adding eicosapentaenoic acid and lipase for transesterification to the pulverized leaf of Dokudami leaf according to claim 4, heating, and extracting with vegetable oil. According to this, side effects are weak and an excellent anti-inflammatory effect is exhibited.

According to the norcepharadione B derivative having an inhibitory action on inflammatory cytokine production, obtained by adding docosahexaenoic acid and lipase for transesterification to the ground pulverized product according to claim 5, heating and extracting with vegetable oil. Therefore, side effects are weak and an excellent anti-inflammatory effect is exhibited.

According to the norcepharadione B derivative having an inhibitory action on inflammatory cytokine production obtained by extracting a fermented product obtained by adding fermented natto to fermented fish, dokudami leaves and soybeans according to claim 6 and extracting the fermented product with vegetable oil. Side effects are weak, and an excellent anti-inflammatory effect is exhibited.

10. 1 to 0.5 weight of chrysanthemum flower extract-containing vegetable oil, 0.01 to 0.5 weight of chrysanthemum extract-containing vegetable oil 0.01 to 0. According to a food preparation comprising a composition containing 5% by weight, side effects are weak and an excellent anti-inflammatory action is exhibited.

9. A norcepharadione B derivative having an inhibitory action on inflammatory cytokine production according to claim 8, 0.05 to 0.8 weight of chrysanthemum flower extract-containing vegetable oil, 0.05 to 0.8 weight of pine leaf extract-containing vegetable oil. According to the cosmetic comprising the composition containing 8% by weight, the side effects are weak and an excellent wrinkle improving action is exhibited.

According to the anti-inflammatory agent comprising the norcepharadione B derivative having an inhibitory action on inflammatory cytokine production according to claim 9, the side effect is weak and an excellent anti-inflammatory action is exhibited.

Hereinafter, the best mode for carrying out the present invention will be described in detail.

First, the norcepharadione B derivative represented by the following formula (1) having an inhibitory action on inflammatory cytokine production will be described.

X is any one selected from caprylic acid, lauric acid, 14-methylpalmitic acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, alpha-lipoic acid, gamma-linolenic acid, stearic acid, and methyl stearic acid. .

In the first place, norcepharadione B is an alkaloid compound existing in nature that is biosynthesized by plants and microorganisms, and its safety has been confirmed. Its molecular weight is 307.3. The atomic composition of the chemical formula is 18 for C, 13 for H, 1 for N and 4 for O.

The term “norcepharadione B derivative” used herein refers to norcepharadione B, caprylic acid, lauric acid, 14-methylpalmitic acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, alpha-lipoic acid, gamma-linolenic acid, stearin It is a derivative in which any one selected from an acid and methyl stearic acid is bonded.

The norcepharadione B derivative is any of caprylic acid, lauric acid, 14-methylpalmitic acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, alpha-lipoic acid, gamma-linolenic acid, stearic acid, and methyl stearic acid. The carbon part farthest from the carboxylic acid group of the substance is covalently bonded.

In the first place, norcepharadione B is widely distributed in the stems and leaves of Dokudami, but there is a disadvantage that the structure of norcepharadione B is unstable, but the intended norcepharadione B derivative is structurally stable. Yes, it has excellent durability and safety.

The norcepharadione B derivative is caprylic acid, lauric acid, 14-methyl palmitic acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, alpha-lipoic acid, gamma-linolenic acid, stearic acid, methyl stearic acid. As a result of the binding of any one of them, the liposolubility thereof increases, and as a result, the structure of the norcepharadione B derivative is stabilized, and the anti-inflammatory action is more durable than norcepharadione B.

The norcepharadione B derivative suppresses the production of inflammatory cytokines such as interleukin-1 alpha, interleukin-8 and TNF alpha.

The norcepharadione B derivative passes through the cell membrane of inflammatory cells such as monocytes, macrophages and neutrophils, and suppresses the expression of protein kinase C, which plays a central role in inflammatory signals, thereby causing inflammatory cytokines. Suppresses the production of

The norcepharadione B derivative is caprylic acid, lauric acid, 14-methylpalmitic acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, alpha-lipoic acid, gamma-linolenic acid, stearic acid, which have high fat-soluble characteristics. Since any one selected from methyl stearic acid is bonded, it is more easily adapted to and absorbed by the cell membranes of the small intestine and skin than norcepharadione B.

When the above-mentioned norcepharadione B derivative is excessively ingested and absorbed, the excessive amount is decomposed by esterase in the blood, and capricelic acid, lauric acid, 14-methylpalmitic acid which is a component of norcepharadione B , Eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, alpha-lipoic acid, gamma-linolenic acid, stearic acid, methyl stearic acid. Since the safety of norcepharadione B and the respective fatty acids has been confirmed, the above-mentioned norcepharadione B derivative is also highly safe.

Among the above-mentioned norcepharadione B derivatives, when X is caprylic acid, a medium-chain saturated fatty acid residue of caprylic acid penetrates the cell membrane, is easily absorbed into the cell, is easy to act on the target protein kinase C, This is preferable because the inflammatory action is enhanced.

Among the above-mentioned norcepharadione B derivatives, when X is lauric acid, the saturated fatty acid residue of lauric acid penetrates into the cell membrane and is easily absorbed into the cell, easily acts on the target protein kinase C, and has an anti-inflammatory effect. Is preferred because it is enhanced.

Among the above-mentioned norcepharadione B derivatives, when X is 14-methylpalmitic acid, the saturated fatty acid residue of 14-methylpalmitic acid penetrates into the cell membrane and is easily absorbed into the cell, and thus becomes a target protein kinase C. It is preferable because it is easy to work and the anti-inflammatory action is enhanced.

Among the above-mentioned norcepharadione B derivatives, when X is eicosapentaenoic acid, an unsaturated fatty acid residue of eicosapentaenoic acid exhibits an inhibitory action on inflammatory prostaglandin production, so that an inflammatory prostaglandin produced from arachidonic acid This is preferable because the anti-inflammatory action is enhanced.

Among the above-mentioned norcepharadione B derivatives, when X is docosahexaenoic acid, unsaturated fatty acid residues of docosahexaenoic acid exhibit platelet aggregation suppression and arterial dilation effects, thereby improving blood flow and enhancing anti-inflammatory activity. This is preferable.

Among the above-mentioned norcepharadione B derivatives, when X is docosapentaenoic acid, the unsaturated fatty acid residue of docosapentaenoic acid exhibits the effect of capillary vasodilation. It is preferable because the substance is excreted and the anti-inflammatory action is enhanced.

Among the above-mentioned norcepharadione B derivatives, when X is gamma-linolenic acid, the unsaturated fatty acid residue of gamma-linolenic acid suppresses the reaction of inflammatory prostaglandins and the anti-inflammatory action is increased. preferable.

Among the above-mentioned norcepharadione B derivatives, when X is alpha-lipoic acid, the SH group of alpha-lipoic acid exhibits an anti-oxidant action, suppresses tissue damage to oxidative stress, and enhances the anti-inflammatory action. Is preferable.

When X is stearic acid among the above-mentioned norcepharadione B derivatives, the saturated fatty acid residue of stearic acid penetrates into the cell membrane and is easily absorbed into the cell, easily acts on the target protein kinase C, and has an anti-inflammatory effect. Is preferred because it is enhanced.

Among the above-mentioned norcepharadione B derivatives, when X is methyl stearic acid, a saturated fatty acid residue of methyl stearic acid penetrates into the cell membrane, is easily absorbed into the cell, and easily acts on the target protein kinase C. This is preferable because the inflammatory action is enhanced.

In addition, it is preferable to process, manufacture and extract the norcepharadione B derivative from dokudami leaf as a raw material because it is easy to obtain the raw material and is economical. When this derivative is extracted, supercritical extraction using an organic solvent such as ethanol, hexane, chloroform, benzene, ethyl acetate, or ether or liquefied carbon dioxide gas is used. In particular, the use of ethanol or hydrous ethanol used for edible processing is preferable because the range of use as food is increased.

Furthermore, it is preferable to purify the fatty acid used for the norcepharadione B derivative from plants, beans, and edible fish, or to use purified fats and oils. For example, these fatty acids are obtained from Fuji Oil, Nissin Oil, Nissui Pharmaceutical, Nissui Fisheries, Toyo Fisheries, and then biosynthesis using linking enzymes such as lipase and ester-linked enzymes, or chemically Can be synthesized.

In the case of a chemical synthesis reaction, it is heated together with a metal catalyst such as magnesium or aluminum. These raw materials are put in a reaction vessel and reacted with the organic solvent. It is preferable to obtain this reaction product as a crude product by removing the solvent because the cost required for purification can be reduced. In addition, it is more preferable to extract the produced derivative with vegetable oil because a highly lipophilic derivative can be efficiently obtained.

When a norcepharadione B derivative is obtained from these raw materials by a biochemical enzymatic reaction, an enzyme that causes an ester bond reaction, such as lipase AY “Amano” 30G, lipase G “Amano” 50, lipase from Amano Enzyme, is used. F-AP15, neurase F3G, etc. are used.

The desired norcepharadione B derivative can be obtained by extracting or purifying from a natural material. Natural materials include plants such as wolfberry leaves, seaweed, mushrooms, edible animals, edible fish, molluscs, insects, and crustaceans. In particular, the dokudami leaf, the head of edible fish, and the head of eel have a high content and are therefore easy to extract.

The produced norcepharadione B derivative is extracted with the above organic solvent or the following vegetable oil. Vegetable oils include palm oil, palm oil, soybean oil, olive oil, rapeseed oil, rice oil, germ oil, corn oil, safflower oil, linseed oil, almond oil, sesame oil, cacao oil, canola oil, grape seed oil, and sesame oil , Wheat germ oil, rice bran oil, safflower oil, perilla oil, tea oil, camellia oil, pumpkin seed oil, peanut oil, grape oil, hazelnut oil, cottonseed oil, peanut oil and other oils used in edible or cosmetics are used In addition, it is more preferable to use a vegetable oil containing a pine leaf extract, a kokushi extract, a green tea extract, a chrysanthemum extract or a bamboo leaf extract because the intended derivative is stably maintained.

Industrially, the heads of edible fish are removed during the processing of edible fish, are discarded as waste, and are not used. Extracting or refining the edible fish head or eel head as a raw material is preferable because it effectively uses waste and reduces the amount of waste.

It is preferable to obtain the above-mentioned norcepharadione B derivative by fermentation using microorganisms or yeasts because it has been confirmed to be safe for food and has abundant food experience. In this case, the microorganisms used are natto and lactic acid bacteria. There are bean yeast and Bacillus subtilis, and yeast includes beer yeast and alcoholic yeast, and natto is particularly preferable because of its excellent transesterification.

The fermentation is performed by adding fermented materials such as dokudami leaves, edible fish, heads and internal organs of edible fish, soybeans and milk, and the microorganisms or yeasts to the fermentation tank. After this fermentation, the desired norcepharadione B derivative can be obtained from the mixture of the microorganism or yeast and the fermentation liquor by extraction with the organic solvent or vegetable oil.

Of these, the leaves and stems of wolfberry are preferred because they have abundant food experience and can stably supply the intended norcepharadione B derivative. Furthermore, when the target norcepharadione B derivative is separated from the fermented product, the organic solvent or vegetable oil is used. In addition, collecting oil-soluble parts extracted and separated using organic solvents and vegetable oils containing pine leaf extract, kokushi extract, chrysanthemum extract, the substance is stabilized by excellent antioxidant power, High quality derivatives are preferred because they are separated.

When extracting from plants, leaves and stems with the scientific name Houttunia corda, green tea, ginger garlic, onion, garlic, soybeans, scallops, licorice, vermicelli, Hanai Kada, barley young leaves, kuzu flowers, red pepper, oysters, pears, chestnuts Cod, horseradish, bracken, rice, wheat, corn, radish, rape blossoms, cherry, pine, red oak, red-breasted, red-crowned whale, akebi, machazul, amadokororo, aloe, licorice, itidori, wild boar , Vulture, Ebisu, Oren, Psyllium, Okera, Okra, Hypericum, Onamomi, Ominae, Kakidooshi, Callauri, Karasubishaku, Kawaraketsumei, Kawaranadeshiko, Kanaoi, Kikuimo, Kiko, Cowpea, yellowfin, yellow-billed, goldworm, black-headed beetle, red-headed swordfish, crap, gardenia, white-horned beetle, red-footed beetle, red-billed beetle, Sartorii rose bucket, sanshuyu, janohi, silane, honeysuckle, seri, burdock, dandelion, dandelion, dandelion, dandelion, dandelion, dandelion Azalea, Tochinoki, Tochibaninjin, Nanten, Noibaru, Octopus, Yellowtail, Hawthorn, Hikikoshi, Hishi, Hitotsuba, Biwa, Fuki, Fukujuso, Fuji, Matatabi, Swordfish, Yamanoimo, Yukinoshita, Momogi, Leopard, Leopard , Stems, flowers or roots are preferred because they are readily available.

Among them, Doctomi to be used is a plant belonging to the genus Dokudami, and its scientific name is Houttynia corda, which is a perennial herb widely distributed in various parts of Japan and from the mainland of China to Southeast Asia. The dokudami used here may be any place of origin, and the leaves of the dokudami may be heart-shaped and dark green leaves, or leaves that are reddish and mottled. Moreover, what has a flower and a rhizome is also used for a flower and a rhizome.

Dokdami leaves, flowers and stems are preferred because they extract the desired norcepharadione B derivative.

Furthermore, when extracting the target norcepharadione B derivative from green tea, the leaves, stems or roots of Japanese green tea, powdered tea, and Chinese assam green tea are preferred because they are easily available. The green tea here is typically the scientific name Camellia sinensis and includes all green tea belonging to the genus Camellia.

For separation of the desired norcepharadione B derivative from the plant body, it is preferable to use a purification operation such as a separation resin. It is further preferable to extract the produced norcepharadione B derivative with the organic solvent or vegetable oil.

Purifying the target norcepharadione B derivative from the reaction product or composition is preferable from the viewpoint of reducing the amount of intake when ingested as a highly pure substance. When highly purified, a separation carrier or resin is utilized and purified. As the separation carrier or resin, porous polysaccharide, silicon oxide compound, polyacrylamide, polystyrene, polypropylene, styrene-vinylbenzene copolymer, etc. whose surface is coated as described later are used. Those having a particle size of 0.1 to 300 μm are preferable. The finer the particle size, the higher the accuracy of the separation, but the longer the separation time.

For example, a reverse phase carrier or a resin whose surface is coated with a hydrophobic compound is used for separation of a highly hydrophobic substance. Those coated with a cationic substance are suitable for the separation of anionically charged substances.

Also, those coated with an anionic substance are suitable for separating a cationically charged substance. When a specific antibody is coated, it is used as an affinity carrier or resin for separating only a specific substance.

The affinity carrier or resin is used for specific preparation of an antigen using an antigen-antibody reaction. A dispersible carrier or resin is used for isolation of substances such as silica gel (manufactured by Merck) if there is a difference in the distribution coefficient between the substances and the solvent for separation.

Among these, an adsorbent carrier or resin, a dispersible carrier or resin, a molecular sieve carrier or resin, and an ion exchange carrier or resin are preferable from the viewpoint of reducing production costs. Furthermore, the reverse phase carrier or resin and the dispersible carrier or resin are more preferable because the difference in the distribution coefficient with respect to the separation solvent is large.

When an organic solvent is used as the separation solvent, a carrier or resin having resistance to the organic solvent is used. Moreover, the carrier or resin utilized for pharmaceutical manufacture or food manufacture is preferable.

From these points, Diaion (Mitsubishi Chemical Corporation) and XAD-2 or XAD-4 (Rohm and Haas) are used as the adsorptive carrier, and Sephadex LH-20 (Amersham Pharmacia) is used as the molecular sieve carrier. Silica gel as the distribution carrier, IRA-410 (Rohm and Haas) as the ion exchange carrier, and DM1020T (Fuji Silysia) as the reverse phase carrier are more preferable. Of these, Diaion, Sephadex LH-20 and DM1020T are more preferred.

The obtained extract is suspended in a solvent for swelling the carrier for separation or the resin before separation. The amount is preferably 1 to 50 times, more preferably 3 to 20 times the weight of the extract from the viewpoint of separation efficiency. The separation temperature is preferably 4 to 37 ° C., more preferably 10 to 25 ° C. from the viewpoint of the stability of the substance.

As the separation solvent, water or a lower alcohol containing water, a hydrophilic solvent, or a lipophilic solvent is used. As the lower alcohol, methanol, ethanol, propanol and butanol are used, and among these, ethanol is preferable because it is also used during edible processing.

When Sephadex LH-20 is used, a lower alcohol is preferable as the separation solvent. When silica gel is used, the separation solvent is preferably chloroform, methanol, acetic acid or a mixture thereof. When Diaion and DM1020T are used, the separation solvent is preferably a lower alcohol such as methanol or ethanol or a mixed solution of lower alcohol and water.

After collecting the separated fractions, it is preferable to remove the solvent by drying or vacuum drying to obtain the desired norcepharadione B derivative as a powder or concentrated liquid because the influence of the solvent can be excluded. The norcepharadione B derivative is obtained as a liquid or powder. The obtained norcepharadione B derivative is used in medicines, food preparations, cosmetics, hygiene tools, immersed fibers, plastics, clothing, anti-inflammatory agents against inflammation caused by contaminants, and the like.

Examples of pharmaceuticals include skin, systemic or local anti-inflammatory agents, antiallergic agents, hay fever improving agents, antiobesity agents, lipolytic agents, wrinkle removing agents, fatty liver inhibitors, hyperlipidemia improving agents, anti-arteriosclerosis Used for agents. It is also used as a veterinary medicine such as fish and livestock, or an anti-inflammatory agent for pets, and since the material used is naturally derived, it is highly safe and more preferable. Furthermore, since it exhibits a preventive and suppressive action against the onset of cancer and mutation caused by inflammation, it is also used as a carcinogenesis preventive or cancer suppressant.

Anti-inflammatory, rhinitis prevention, hay fever prevention, dermatitis prevention, muscle pain and muscle fatigue prevention, metabolic syndrome prevention, fatigue recovery, nourishing tonic, liver function maintenance etc. Is done. In addition, this food preparation is more preferable because it is naturally derived for pets and for the growth of fish and livestock.

This cosmetic has anti-inflammatory effects by suppressing the production of inflammatory cytokines, and also exhibits vascular dilation and lymphatic dilation of the skin, so wrinkles and sagging caused by inflammation such as sunburn. It is effective for the suppression or prevention of the production. In particular, it exerts anti-inflammatory action against inflammation caused by sunburn, and removes the cause of wrinkles and sagging. In addition, this cosmetic exhibits an excellent therapeutic or preventive action against atopic dermatitis in which a large amount of inflammatory cytokines are produced.

As sanitary tools, it is used for gauze, masks, pollen countermeasure masks, sanitary products for suppressing inflammation, and clothing for atopic patients. It is also used as an indoor air improver that induces inflammation, plastic materials and clothes used in toilets, deodorants, improvers for sick house disease, fibers, and clothes. Further, it is also used as a mask, filter, and fuel additive for protecting against environmental substances causing inflammation, for example, protecting the body from harmful substances such as dioxin, asbestos, PCB, hydrogen sulfide, and nitrogen oxides. In particular, since it exhibits an inhibitory action against smoking and harmful substances contained in tobacco, it is also used in tobacco filters.

Next, among the norcepharadione B derivatives represented by the above formula (1) obtained by adding caprylic acid and lipase for transesterification to the ground pulverized leaf, heating and extracting with vegetable oil, X The norcepharadione B derivative represented by the following formula (2) having an inhibitory action on the production of inflammatory cytokines in which is caprylic acid will be described.

Here, the norcepharadione B derivative is the above-mentioned norcepharadione B derivative, which is a derivative in which carbon farthest from the carboxylic acid of caprylic acid is covalently bonded to norcepharadione B.

The norcepharadione B derivative suppresses the production of inflammatory cytokines such as interleukin-1 alpha, interleukin-8 and TNF alpha.

The norcepharadione B derivative passes through the cell membrane of inflammatory cells such as monocytes, macrophages, and neutrophils, moves into the nucleus and acts on transcription factors such as NF-kappa B and NF-IL6, and transcription. The factor suppresses the gene level expression of inflammatory cytokines and suppresses the production of inflammatory cytokines. Further, in the above-mentioned norcepharadione B derivative, the saturated fatty acid residue of caprylic acid penetrates into the cell membrane, is easily absorbed into the cell, easily acts on the target protein kinase C, and the anti-inflammatory action is enhanced. preferable.

The norcepharadione B derivative is obtained by adding caprylic acid and lipase for transesterification to a ground product of dokudami leaves, heating and extracting with vegetable oil.

All leaves that grow on the plant body of Dokudami are used as Dokudami leaves. Dokudami is an edible plant belonging to the genus Dokudami, and grows naturally in Japan, Asia, and all over the world, which has the scientific name Houttunia cordadata. It is also described in Yamato Honso and has been used for folk medicines and medicinal dishes for a long time.

It is also used as a dokudami extract as a cosmetic ingredient. The dokudami used here is used in Japan, Korea, China, Taiwan and other Asian countries, North America, South America, Oceania, Africa, and any cultivated dokudami. Chinese products are preferred because they can track the use history of pesticides, are stable in quality, and inexpensive.

The dokudami leaves can be either fresh or dried.

It is preferable that the collected Dokudami leaves are washed with tap water.

The dokudami leaves are crushed. A pulverizer is used for pulverization. For example, a free mill, super free mill, sample mill, goblin, super clean mill, micros manufactured by Nara Machinery Co., Ltd., a small vacuum dryer manufactured by Toyo Riko as a vacuum dryer, stock A compact decompression heat transfer dryer DPTH-40 manufactured by Matsui Co., Ltd., clean dry VD-7, VD-20 manufactured by AKM Kyushu Technos Co., Ltd., etc. are used.

Caprylic acid used here is obtained from coconut oil, soybean oil, rapeseed oil, cottonseed oil, corn oil, safflower oil, sesame oil, rice oil, sunflower oil, olive oil, Ryoshoku, Nisshin Oil, Fuji Oil Co., Ltd., etc. Those extracted and purified from plants such as palm and soybean are preferred because they have few impurities.

The transesterification lipase used here is, for example, a lipozyme or novozyme 435 manufactured by Novozyme, a lipase PL or lipase QLM manufactured by Meisho Sangyo, or a lipase AY “Amano” manufactured by Amano Enzyme. High quality products such as 30G, lipase G “Amano” 50, lipase F-AP15, and neurase F3G are used, and these are preferable because their safety has been confirmed.

To the clean stainless steel cylinder, etc., the pulverized product of dokudami leaves, caprylic acid and lipase for transesterification are added and heated. Here, it is preferable to add tap water as a solvent from the viewpoint of smoothing the reaction.

The amount of caprylic acid is preferably 0.02 to 0.5 weight, and the amount of lipase for transesterification is preferably 0.0001 to 0.04 weight with respect to 1 weight of the ground pulverized product.

As said heating temperature, 10-37 degreeC is preferable and 13-33 degreeC is more preferable.

The heating time is preferably 1 to 36 hours, and more preferably 3 to 24 hours.

The heating is preferably performed while stirring, and a rate of 40 to 140 times per minute is preferable.

It is cooled after being warmed. The cooling method is preferably natural cooling or water cooling.

The reactants are separated by vegetable oil. The reactant is soluble in vegetable oil because of its high oil solubility. Vegetable oils include palm oil, palm oil, soybean oil, olive oil, rapeseed oil, rice oil, germ oil, corn oil, safflower oil, linseed oil, almond oil, sesame oil, cacao oil, canola oil, grape seed oil, and sesame oil Oils used in edible or cosmetic products such as wheat germ oil, rice bran oil, safflower oil, perilla oil, tea oil, camellia oil, pumpkin seed oil, peanut oil, grape oil, hazelnut oil, cottonseed oil, peanut oil are used In addition, it is more preferable to use a vegetable oil containing a pine leaf extract, a kokushi extract, a green tea extract, a chrysanthemum extract or a bamboo leaf extract because the intended derivative is stably maintained.

In particular, the above-mentioned pine leaf extract-containing vegetable oil is a vegetable oil having an excellent antioxidative action and containing an oil-soluble polyphenol extracted by adding a vegetable oil to a pulverized product of pine leaves. Can be separated.

The pine leaves used for the pine leaf extract-containing vegetable oil may be any of Japanese, Chinese and Taiwanese.

Pine leaves cultivated without using pesticides are preferred because they can avoid the danger of pesticides.

The vegetable oil to be added is preferably 0.4 to 3 weights with respect to 1 weight of the pulverized leaf of added wolfberry.

The isolated norcepharadione B derivative is absorbed into the body, and then the excess amount is decomposed by esterase and further metabolized in the liver. Therefore, safety is high and there are few side effects.

Separating and purifying the desired norcepharadione B derivative from the reaction product is preferable from the viewpoint of obtaining a highly pure substance. As a purification method, it is preferable to use a purification operation such as an organic solvent for separation or a resin. As the organic solvent, ethanol, hexane, chloroform, benzene, ethyl acetate, ether and the like are used, and among these, ethanol for food processing or hydrous ethanol is more preferable because it is easy to handle.

As the separation carrier or resin, porous polysaccharide, silicon oxide compound, polyacrylamide, polystyrene, polypropylene, styrene-vinylbenzene copolymer, etc., whose surface is coated, are used. It is preferable to separate and purify with an appropriate separation solvent and remove the solvent to obtain the desired norcepharadione B derivative.

The norcepharadione B derivative thus obtained is obtained as a liquid or powder. The obtained norcepharadione B derivative is used for pharmaceuticals, food preparations or cosmetics. As pharmaceuticals, they are used as anti-inflammatory agents, anti-obesity agents, lipolytic agents, wrinkle removing agents, fatty liver inhibitors, hyperlipidemia improving agents, anti-arteriosclerotic agents, anti-allergic agents and the like.

The food preparation is used for anti-inflammatory, rhinitis prevention, hay fever prevention, dermatitis prevention, muscle pain and muscle fatigue prevention, improvement of metabolic syndrome, fatigue recovery, nutrition tonic, maintenance of liver function, etc. The

This cosmetic product exhibits anti-inflammatory effects by suppressing the production of inflammatory cytokines, and also exhibits vasodilatory effects on the skin and limba tube dilation, so it suppresses wrinkles and sagging caused by inflammation such as sunburn. Or it is effective for prevention of production. In particular, it exerts anti-inflammatory action against inflammation caused by sunburn, and removes the cause of wrinkles and sagging. Furthermore, this cosmetic exhibits an excellent therapeutic or preventive action against atopic dermatitis in which inflammatory cytokines are produced in large quantities.

Next, among the norcepharadione B derivatives represented by the above formula (1) obtained by adding lauric acid and lipase for transesterification to ground pulverized leaves, heating and extracting with vegetable oil, X A norcepharadione B derivative represented by the following formula (3) having an inhibitory action on the production of inflammatory cytokines in which is lauric acid will be described.

Here, the norcepharadione B derivative is the above-mentioned norcepharadione B derivative, which is a derivative in which the carbon farthest from the carboxylic acid of lauric acid is covalently bonded to norcepharadione B.

The norcepharadione B derivative suppresses the production of inflammatory cytokines such as interleukin-1 alpha, interleukin-8 and TNF alpha.

The norcepharadione B derivative passes through the cell membrane of inflammatory cells such as monocytes, macrophages, and neutrophils, moves into the nucleus and acts on transcription factors such as NF-kappa B and NF-IL6, and transcription. The factor suppresses the gene level expression of inflammatory cytokines and suppresses the production of inflammatory cytokines.

Further, in the above-mentioned norcepharadione B derivative, the saturated fatty acid residue of lauric acid penetrates into the cell membrane, is easily absorbed into the cell, easily acts on the target protein kinase C, and the anti-inflammatory action is enhanced. preferable.

The norcepharadione B derivative is obtained by adding lauric acid and transesterification lipase to a ground product of Dokudami leaves, heating and extracting with vegetable oil.

All leaves that grow on the plant body of Dokudami are used as Dokudami leaves. Dokudami is an edible plant belonging to the genus Dokudami, and grows naturally in Japan, Asia, and all over the world, which has the scientific name Houttunia cordadata. It is also described in Yamato Honso and has been used for folk medicines and medicinal dishes for a long time.

It is also used as a dokudami extract as a cosmetic ingredient. The dokudami used here is used in Japan, Korea, China, Taiwan and other Asian countries, North America, South America, Oceania, Africa, and any cultivated dokudami. Chinese products are preferred because they can track the use history of pesticides, are stable in quality, and inexpensive.

The dokudami leaves can be either fresh or dried.

It is preferable that the collected Dokudami leaves are washed with tap water.

The dokudami leaves are crushed. For pulverization, a pulverizer is used. For example, a free mill, super free mill, sample mill, goblin, super clean mill, micros manufactured by Nara Machinery Co., Ltd. as a pulverizer, and a small vacuum manufactured by Toyo Riko as a vacuum dryer. A dryer, a small vacuum heat transfer type dryer DPTH-40 manufactured by Matsui Co., Ltd., clean dry VD-7, VD-20 manufactured by AKM Kyushu Technos Co., Ltd., etc. are used.

Lauric acid used here is obtained from coconut oil, soybean oil, rapeseed oil, cottonseed oil, corn oil, safflower oil, sesame oil, rice oil, sunflower oil, olive oil, etc., such as Ryoshoku, Nisshin Oil and Fuji Oil Co., Ltd. Those extracted and purified from plants such as palm and soybean are preferred because they have few impurities.

The transesterification lipase used here is, for example, a lipozyme or novozyme 435 manufactured by Novozyme, a lipase PL or lipase QLM manufactured by Meisho Sangyo, or a lipase AY “Amano” manufactured by Amano Enzyme. High quality products such as 30G, lipase G “Amano” 50, lipase F-AP15, and neurase F3G are used, and these are preferable because their safety has been confirmed.

To the clean stainless steel cylinder, etc., the pulverized material of the dokudami leaf, lauric acid and lipase for transesterification are added and heated. Here, it is preferable to add tap water as a solvent from the viewpoint of smoothing the reaction.

The amount of lauric acid is preferably 0.02 to 0.5 weight and the amount of lipase for transesterification is preferably 0.0001 to 0.04 weight with respect to 1 weight of the pulverized product of Dokudami leaf to be added.

As said temperature of heating, 10-30 degreeC is preferable and 13-27 degreeC is more preferable.

The heating time is preferably 1 to 24 hours, more preferably 2 to 14 hours.

The heating is preferably performed while stirring, and a rate of 8 to 120 times per minute is preferable.

It is cooled after being warmed. The cooling method is preferably natural cooling or water cooling.

The reactants are separated by vegetable oil. The reactant is soluble in vegetable oil because of its high oil solubility. Vegetable oils include palm oil, palm oil, soybean oil, olive oil, rapeseed oil, rice oil, germ oil, corn oil, safflower oil, linseed oil, almond oil, sesame oil, cacao oil, canola oil, grape seed oil, and sesame oil , Wheat germ oil, rice bran oil, safflower oil, perilla oil, tea oil, camellia oil, pumpkin seed oil, peanut oil, grape oil, hazelnut oil, cottonseed oil, peanut oil and other oils used in edible or cosmetics are used Moreover, it is preferable to use a vegetable oil containing a pine leaf extract, a kokushi extract, a green tea extract, a chrysanthemum extract or a bamboo leaf extract because the target derivative is stably maintained.

In particular, the above-mentioned pine leaf extract-containing vegetable oil is a vegetable oil having an excellent antioxidative action and containing an oil-soluble polyphenol extracted by adding a vegetable oil to a pulverized product of pine leaves. Can be separated.

The pine leaves used for the pine leaf extract-containing vegetable oil may be any of Japanese, Chinese and Taiwanese.

Pine leaves cultivated without using pesticides are preferred because they can avoid the danger of pesticides.

The vegetable oil to be added is preferably 0.4 to 3 weights with respect to 1 weight of the pulverized leaf of added wolfberry.

The isolated norcepharadione B derivative is absorbed into the body, and then the excess amount is decomposed by esterase and further metabolized in the liver. Therefore, safety is high and there are few side effects.

Separating and purifying the desired norcepharadione B derivative from the reaction product is preferable from the viewpoint that the intake can be reduced as a highly pure substance. As a purification method, it is preferable to use a purification operation such as an organic solvent for separation or a resin. As the organic solvent, ethanol, hexane, chloroform, benzene, ethyl acetate, ether and the like are used, and among these, ethanol for food processing or hydrous ethanol is more preferable because it is easy to handle.

As the separation resin, porous polysaccharides, silicon oxide compounds, polyacrylamide, polystyrene, polypropylene, styrene-vinylbenzene copolymers, etc. whose surfaces are coated are used. It is preferable to separate and purify with an appropriate separation solvent and remove the solvent to obtain the desired norcepharadione B derivative.

The norcepharadione B derivative thus obtained is obtained as a liquid or powder. The obtained norcepharadione B derivative is used for pharmaceuticals, food preparations or cosmetics. As pharmaceuticals, they are used as anti-inflammatory agents, anti-obesity agents, lipolytic agents, wrinkle removing agents, fatty liver inhibitors, hyperlipidemia improving agents, anti-arteriosclerotic agents, anti-allergic agents and the like.

The food preparation is used for anti-inflammatory, rhinitis prevention, hay fever prevention, dermatitis prevention, muscle pain and muscle fatigue prevention, improvement of metabolic syndrome, fatigue recovery, nutrition tonic, maintenance of liver function, etc. The

This cosmetic product exhibits anti-inflammatory effects by suppressing the production of inflammatory cytokines, and also exhibits vasodilatory effects on the skin and limba tube dilation, so it suppresses wrinkles and sagging caused by inflammation such as sunburn. Or it is effective for prevention of production. In particular, it exerts anti-inflammatory action against inflammation caused by sunburn, and removes the cause of wrinkles and sagging.

Furthermore, this cosmetic exhibits an excellent therapeutic or preventive action against atopic dermatitis in which inflammatory cytokines are produced in large quantities.

Next, among the norcepharadione B derivatives represented by the above formula (1) obtained by adding eicosapentaenoic acid and lipase for transesterification to the pulverized leaves of Dokudami, heating, and extracting with vegetable oil, The norcepharadione B derivative represented by the following formula (4) having an inhibitory action on inflammatory cytokine production in which X is eicosapentaenoic acid will be described.

The norcepharadione B derivative mentioned here is the above-mentioned norcepharadione B derivative, which is a derivative in which the carbon farthest from the carboxylic acid of eicosapentaenoic acid is covalently bonded to norcepharadione B.

The norcepharadione B derivative suppresses the production of inflammatory cytokines such as interleukin-1 alpha, interleukin-8 and TNF alpha.

The norcepharadione B derivative passes through the cell membrane of inflammatory cells such as monocytes, macrophages, and neutrophils, moves into the nucleus and acts on transcription factors such as NF-kappa B and NF-IL6, and transcription. The factor suppresses the gene level expression of inflammatory cytokines and suppresses the production of inflammatory cytokines. In addition, in the above-mentioned norcepharadione B derivative, the saturated fatty acid residue of eicosapentaenoic acid penetrates into the cell membrane, is easily absorbed into the cell, is likely to act on the target protein kinase C, and has an enhanced anti-inflammatory effect. To preferred.

The norcepharadione B derivative is obtained by adding eicosapentaenoic acid and lipase for transesterification to a ground product of dokudami leaves, heating, and extracting with vegetable oil.

All leaves that grow on the plant body of Dokudami are used as Dokudami leaves. Dokudami is an edible plant belonging to the genus Dokudami, and grows naturally in Japan, Asia, and all over the world, which has the scientific name Houttunia cordadata. It is also described in Yamato Honso and has been used for folk medicines and medicinal dishes for a long time.

It is also used as a dokudami extract as a cosmetic ingredient. The dokudami used here is used in Japan, Korea, China, Taiwan and other Asian countries, North America, South America, Oceania, Africa, and any cultivated dokudami. Chinese products are preferred because they can track the use history of pesticides, are stable in quality, and inexpensive.

The dokudami leaves can be either fresh or dried.

It is preferable that the collected Dokudami leaves are washed with tap water.

The dokudami leaves are crushed. For pulverization, free mill, super free mill, sample mill, goblin, super clean mill, micros, manufactured by Nara Machinery Co., Ltd. as a pulverizer, a small vacuum dryer manufactured by Toyo Riko as a vacuum dryer, manufactured by Matsui Co., Ltd. A small decompression heat transfer type dryer DPTH-40, clean dry VD-7, VD-20, etc. manufactured by AKM Kyushu Technos Co., Ltd. are used.

The eicosapentaenoic acid used here is preferably derived from fish and extracted from fish oil and purified, since it has few impurities. Eicosapentaenoic acid manufactured by Nippon Suisan is preferred because of its stable quality.

The transesterification lipase used here is, for example, a lipozyme or novozyme 435 manufactured by Novozyme, a lipase PL or lipase QLM manufactured by Meisho Sangyo, or a lipase AY “Amano” manufactured by Amano Enzyme. High quality products such as 30G, lipase G “Amano” 50, lipase F-AP15, and neurase F3G are used, and these are preferable because their safety has been confirmed.

To the clean stainless steel cylinder, etc., the above pulverized product of dokudami leaf, eicosapentaenoic acid and lipase for transesterification are added and heated. Here, it is preferable to add tap water as a solvent from the viewpoint of smoothing the reaction.

The amount of eicosapentaenoic acid is preferably 0.02 to 0.5 weight, and the amount of lipase for transesterification is preferably 0.0001 to 0.04 weight with respect to 1 weight of the pulverized product of Dokudami leaf to be added.

As said temperature of heating, 10-30 degreeC is preferable and 13-27 degreeC is more preferable.

The heating time is preferably 1 to 24 hours, more preferably 2 to 14 hours.

The heating is preferably performed while stirring, and a rate of 8 to 120 times per minute is preferable.

It is cooled after being warmed. The cooling method is preferably natural cooling or water cooling.

The reactants are separated by vegetable oil. The reactant is soluble in vegetable oil because of its high oil solubility. Vegetable oils include palm oil, palm oil, soybean oil, olive oil, rapeseed oil, rice oil, germ oil, corn oil, safflower oil, linseed oil, almond oil, sesame oil, cacao oil, canola oil, grape seed oil, and sesame oil Oils used in edible or cosmetic products such as wheat germ oil, rice bran oil, safflower oil, perilla oil, tea oil, camellia oil, pumpkin seed oil, peanut oil, grape oil, hazelnut oil, cottonseed oil, peanut oil are used In addition, it is more preferable to use a vegetable oil containing a pine leaf extract, a kokushi extract, a green tea extract, a chrysanthemum extract or a bamboo leaf extract because the intended derivative is stably maintained.

In particular, the above-mentioned pine leaf extract-containing vegetable oil is a vegetable oil having an excellent antioxidative action and containing an oil-soluble polyphenol extracted by adding a vegetable oil to a pulverized product of pine leaves. Can be separated.

The pine leaves used for the pine leaf extract-containing vegetable oil may be any of Japanese, Chinese and Taiwanese.

Pine leaves cultivated without using pesticides are preferred because they can avoid the danger of pesticides.

The vegetable oil to be added is preferably 0.4 to 3 weights with respect to 1 weight of the pulverized leaf of added wolfberry.

The isolated norcepharadione B derivative is absorbed into the body, and then the excess amount is decomposed by esterase and further metabolized in the liver. Therefore, safety is high and there are few side effects.

Separating and purifying the desired norcepharadione B derivative from the reaction product is preferable from the viewpoint that the intake can be reduced as a highly pure substance. As a purification method, it is preferable to use a purification operation such as an organic solvent for separation or a resin. As the organic solvent, ethanol, hexane, chloroform, benzene, ethyl acetate, ether and the like are used, and among these, ethanol for food processing or hydrous ethanol is more preferable because it is easy to handle.

As the separation resin, porous polysaccharides, silicon oxide compounds, polyacrylamide, polystyrene, polypropylene, styrene-vinylbenzene copolymers, etc. whose surfaces are coated are used. It is preferable to separate and purify with an appropriate separation solvent and remove the solvent to obtain the desired norcepharadione B derivative.

The norcepharadione B derivative thus obtained is obtained as a liquid or powder. The obtained norcepharadione B derivative is used for pharmaceuticals, food preparations or cosmetics. As pharmaceuticals, they are used as anti-inflammatory agents, anti-obesity agents, lipolytic agents, wrinkle removing agents, fatty liver inhibitors, hyperlipidemia improving agents, anti-arteriosclerotic agents, anti-allergic agents and the like.

The food preparation is used for anti-inflammatory, rhinitis prevention, hay fever prevention, dermatitis prevention, muscle pain and muscle fatigue prevention, improvement of metabolic syndrome, fatigue recovery, nutrition tonic, maintenance of liver function, etc. The

This cosmetic product exhibits anti-inflammatory effects by suppressing the production of inflammatory cytokines, and also exhibits vasodilatory effects on the skin and limba tube dilation, so it suppresses wrinkles and sagging caused by inflammation such as sunburn. Or it is effective for prevention of production. In particular, it exerts anti-inflammatory action against inflammation caused by sunburn, and removes the cause of wrinkles and sagging.

Furthermore, this cosmetic exhibits an excellent therapeutic or preventive action against atopic dermatitis in which inflammatory cytokines are produced in large quantities.

Next, docosahexaenoic acid and lipase for transesterification are added to ground pulverized leaves of Dokudami, heated and extracted with vegetable oil. Among the norcepharadione B derivatives represented by the above formula (1), X The norcepharadione B derivative represented by the following formula (5) having an inhibitory action on the production of inflammatory cytokines, in which is docosahexaenoic acid will be described.

The term “norcepharadione B derivative” as used herein refers to the aforementioned norcepharadione B derivative, which is a derivative in which the carbon farthest from the carboxylic acid of docosahexaenoic acid is covalently bonded to norcepharadione B.

The norcepharadione B derivative suppresses the production of inflammatory cytokines such as interleukin-1 alpha, interleukin-8 and TNF alpha.

The norcepharadione B derivative passes through the cell membrane of inflammatory cells such as monocytes, macrophages, and neutrophils, moves into the nucleus and acts on transcription factors such as NF-kappa B and NF-IL6, and transcription. The factor suppresses the gene level expression of inflammatory cytokines and suppresses the production of inflammatory cytokines. Further, in the above-mentioned norcepharadione B derivative, the saturated fatty acid residue of docosahexaenoic acid penetrates into the cell membrane, is easily absorbed into the cell, easily acts on the target protein kinase C, and the anti-inflammatory action is enhanced. preferable.

The norcepharadione B derivative is obtained by adding docosahexaenoic acid and lipase for transesterification to a ground product of Dokudami leaves, heating and extracting with vegetable oil.

All leaves that grow on the plant body of Dokudami are used as Dokudami leaves. Dokudami is an edible plant belonging to the genus Dokudami, and grows naturally in Japan, Asia, and all over the world, which has the scientific name Houttunia cordadata. It is also described in Yamato Honso and has been used for folk medicines and medicinal dishes for a long time.

It is also used as a dokudami extract as a cosmetic ingredient. The dokudami used here is used in Japan, Korea, China, Taiwan and other Asian countries, North America, South America, Oceania, Africa, and any cultivated dokudami. Chinese products are preferred because they can track the use history of pesticides, are stable in quality, and inexpensive.

The dokudami leaves can be either fresh or dried.

It is preferable that the collected Dokudami leaves are washed with tap water.

The dokudami leaves are crushed. A pulverizer is used for pulverization, for example, a free mill, super free mill, sample mill, goblin, super clean mill, micros, manufactured by Nara Machinery Co., Ltd., a small vacuum dryer manufactured by Toyo Riko as a vacuum dryer, A compact decompression heat transfer dryer DPTH-40 manufactured by Matsui Co., Ltd., clean dry VD-7, VD-20 manufactured by AKM Kyushu Technos Co., Ltd., etc. are used.

The docosahexaenoic acid used here is preferably derived from fish and extracted from fish oil and purified, since it has few impurities. Docosahexaenoic acid manufactured by Nippon Suisan is preferred because of its stable quality.

The transesterification lipase used here is, for example, a lipozyme or novozyme 435 manufactured by Novozyme, a lipase PL or lipase QLM manufactured by Meisho Sangyo, or a lipase AY “Amano” manufactured by Amano Enzyme. High quality products such as 30G, lipase G “Amano” 50, lipase F-AP15, and neurase F3G are used, and these are preferable because their safety has been confirmed.

To the clean stainless steel cylinder, etc., the above pulverized leaves of docami, docosahexaenoic acid and lipase for transesterification are added and heated. Here, it is preferable to add tap water as a solvent from the viewpoint of smoothing the reaction.

The amount of docosahexaenoic acid is preferably 0.02 to 0.5 weight, and the amount of lipase for transesterification is preferably 0.0001 to 0.04 weight with respect to 1 weight of the pulverized product of Dokudami leaf to be added.

As said temperature of heating, 10-30 degreeC is preferable and 13-27 degreeC is more preferable.

The heating time is preferably 1 to 24 hours, more preferably 2 to 14 hours.

The heating is preferably performed while stirring, and a rate of 8 to 120 times per minute is preferable.

It is cooled after being warmed. The cooling method is preferably natural cooling or water cooling.

Since the reactant is highly oil-soluble, it dissolves in vegetable oil and is separated by vegetable oil using its properties. Vegetable oils include palm oil, palm oil, soybean oil, olive oil, rapeseed oil, rice oil, germ oil, corn oil, safflower oil, linseed oil, almond oil, sesame oil, cacao oil, canola oil, grape seed oil, and sesame oil Oils used in edible or cosmetic products such as wheat germ oil, rice bran oil, safflower oil, perilla oil, tea oil, camellia oil, pumpkin seed oil, peanut oil, grape oil, hazelnut oil, cottonseed oil, peanut oil are used In addition, it is more preferable to use a vegetable oil containing a pine leaf extract, a kokushi extract, a green tea extract, a chrysanthemum extract or a bamboo leaf extract because the intended derivative is stably maintained.

In particular, the above-mentioned pine leaf extract-containing vegetable oil is a vegetable oil having an excellent antioxidative action and containing an oil-soluble polyphenol extracted by adding a vegetable oil to a pulverized product of pine leaves. Can be separated.

The pine leaves used for the pine leaf extract-containing vegetable oil may be any of Japanese, Chinese and Taiwanese.

Pine leaves cultivated without using pesticides are preferred because they can avoid the danger of pesticides.

The vegetable oil to be added is preferably 0.4 to 3 weights with respect to 1 weight of the pulverized leaf of added wolfberry.

The isolated norcepharadione B derivative is absorbed into the body, and then the excess amount is decomposed by esterase and further metabolized in the liver. Therefore, safety is high and there are few side effects.

Separating and purifying the desired norcepharadione B derivative from the reaction product is preferable from the viewpoint that the intake can be reduced as a highly pure substance. As a purification method, it is preferable to use a purification operation such as an organic solvent for separation or a resin. As the organic solvent, ethanol, hexane, chloroform, benzene, ethyl acetate, ether and the like are used, and among these, ethanol for food processing or hydrous ethanol is more preferable because it is easy to handle.

As the separation carrier or resin, porous polysaccharide, silicon oxide compound, polyacrylamide, polystyrene, polypropylene, styrene-vinylbenzene copolymer, etc., whose surface is coated, are used. It is preferable to separate and purify with an appropriate separation solvent and remove the solvent to obtain the desired norcepharadione B derivative.

The norcepharadione B derivative thus obtained is obtained as a liquid or powder. The obtained norcepharadione B derivative is used for pharmaceuticals, food preparations or cosmetics. As pharmaceuticals, they are used as anti-inflammatory agents, anti-obesity agents, lipolytic agents, wrinkle removing agents, fatty liver inhibitors, hyperlipidemia improving agents, anti-arteriosclerotic agents, anti-allergic agents and the like.

The food preparation is used for anti-inflammatory, rhinitis prevention, hay fever prevention, dermatitis prevention, muscle pain and muscle fatigue prevention, improvement of metabolic syndrome, fatigue recovery, nutrition tonic, maintenance of liver function, etc. The

This cosmetic product exhibits anti-inflammatory effects by suppressing the production of inflammatory cytokines, and also exhibits vasodilatory effects on the skin and limba tube dilation, so it suppresses wrinkles and sagging caused by inflammation such as sunburn. Or it is effective for prevention of production. In particular, it exerts anti-inflammatory action against inflammation caused by sunburn, and removes the cause of wrinkles and sagging.

Furthermore, this cosmetic exhibits an excellent therapeutic or preventive action against atopic dermatitis in which inflammatory cytokines are produced in large quantities.

Next, a norcepharadione B derivative having an inhibitory action on inflammatory cytokine production obtained by extracting a fermented product obtained by adding natto bacteria to fermented fish, dokudami leaves and soybeans and fermenting them with vegetable oil will be described.

The norcepharadione B derivative having an inhibitory action on inflammatory cytokine production here is the above-mentioned norcepharadione B derivative.

That is, norcepharadione B, caprylic acid, lauric acid, palmitic acid, 14-methyl palmitic acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, alpha-lipoic acid, gamma-linolenic acid, stearic acid, methyl stearic acid A derivative in which any one selected from is bound.

This norcepharadione B derivative includes caprylic acid, lauric acid, palmitic acid, 14-methyl palmitic acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, alpha-lipoic acid, gamma-linolenic acid, stearic acid, methyl stearic acid The carbon part furthest away from the carboxylic acid group of any of these substances is covalently bonded.

Norcepharadione B derivatives mentioned here are caprylic acid, lauric acid, palmitic acid, 14-methyl palmitic acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, alpha-lipoic acid, gamma-linolenic acid, stearic acid, methyl When stearic acid is bonded, the structure of norcepharadione B is stabilized.

The norcepharadione B derivative suppresses the production of inflammatory cytokines such as interleukin-1 alpha, interleukin-8 and TNF alpha.

The norcepharadione B derivative passes through the cell membrane of inflammatory cells such as monocytes, macrophages and neutrophils, and suppresses the expression of protein kinase C, which plays a central role in inflammatory signals, thereby causing inflammatory cytokines. Suppresses the production of

The norcepharadione B derivative has caprilic acid, lauric acid, palmitic acid, 14-methylpalmitic acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, alpha-lipoic acid, gamma-linolenic acid, which has high fat-soluble characteristics. Furthermore, since any one selected from stearic acid and methyl stearic acid is bonded, it has a feature that it is easily adapted to the cell membrane of the small intestine and skin and is easily absorbed.

When the above-mentioned norcepharadione B derivative is excessively ingested and absorbed, the excess amount is decomposed by the esterase in blood, and norcepharadione B and its respective caprylic acid, lauric acid, palmitic acid, 14-methylpalmitin Acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, alpha-lipoic acid, gamma-linolenic acid, stearic acid, methyl stearic acid, each of which has been confirmed to be safe. Norcepharadione B derivatives are also highly safe.

Among the above norcepharadione B derivatives, when X is caprylic acid, the saturated fatty acid residue of caprylic acid penetrates into the cell membrane, is easily absorbed into the cell, easily acts on the target protein kinase C, and has an anti-inflammatory action. Is preferred because it is enhanced.

Among the above-mentioned norcepharadione B derivatives, when X is lauric acid, the saturated fatty acid residue of lauric acid penetrates into the cell membrane and is easily absorbed into the cell, easily acts on the target protein kinase C, and has an anti-inflammatory effect. Is preferred because it is enhanced.

Among the above-mentioned norcepharadione B derivatives, when X is eicosapentaenoic acid, an unsaturated fatty acid residue of eicosapentaenoic acid exhibits inflammatory prostaglandin production inhibitory action, so that inflammatory prostaglandin produced from arachidonic acid This is preferable because the anti-inflammatory action is enhanced.

Among the above-mentioned norcepharadione B derivatives, when X is docosahexaenoic acid, unsaturated fatty acid residues of docosahexaenoic acid exhibit platelet aggregation suppression and arterial dilation effects, thereby improving blood flow and enhancing anti-inflammatory activity. This is preferable.

Among the above-mentioned norcepharadione B derivatives, when X is docosapentaenoic acid, the unsaturated fatty acid residue of docosapentaenoic acid exhibits the effect of capillary vasodilation. It is preferable because the substance is excreted and the anti-inflammatory action is enhanced.

Among the above-mentioned norcepharadione B derivatives, when X is gamma-linolenic acid, the unsaturated fatty acid residue of gamma-linolenic acid suppresses the reaction of inflammatory prostaglandins and the anti-inflammatory action is increased. preferable.

Among the above-mentioned norcepharadione B derivatives, when X is alpha-lipoic acid, the SH group of alpha-lipoic acid exhibits an anti-oxidant action, which prevents tissue damage against oxidative stress and enhances the anti-inflammatory action. Is preferable.

When X is stearic acid among the above-mentioned norcepharadione B derivatives, the saturated fatty acid residue of stearic acid penetrates into the cell membrane and is easily absorbed into the cell, easily acts on the target protein kinase C, and has an anti-inflammatory effect. Is preferred because it is enhanced.

Among the above-mentioned norcepharadione B derivatives, when X is methyl stearic acid, a saturated fatty acid residue of methyl stearic acid penetrates into the cell membrane, is easily absorbed into the cell, and easily acts on the target protein kinase C. This is preferable because the inflammatory action is enhanced.

The norcepharadione B derivative is obtained by extracting a fermented product obtained by adding natto bacteria to edible fish, dokudami leaves, and soybeans and fermenting them with vegetable oil. As used herein, edible fish refers to fish used for food, and among them, eels have abundant food experience.

Eel head and internal organs have dietary experience, caprylic acid, lauric acid, palmitic acid, 14-methyl palmitic acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, alpha-lipoic acid, gamma-linolenic acid, stearic acid It is preferable because it contains methyl stearic acid.

In the fishery, eel heads and internal organs are discarded in the processing process, which is preferable because waste can be used effectively.

Of these, eels grown and grown on the shores of Lake Hamana are preferred. Moreover, it is preferable to dismantle after slaughtering at a dismantling site, cut the head and internal organs, and collect.

It is preferable to cut the collected eel head and internal organs with a knife and pulverize them with DM-6 manufactured by Nakayama Institute of Technology.

The term “Dokudami leaf” as used herein refers to all the leaves that grow on the Dokudami, and is a leaf of Dokudami grown or grown in Japan, Asia, or other countries.

Of these, the leaf of dokudami contains a large amount of the desired norcepharadione B, which is preferable because it is extracted, and is discarded as natural waste, which can reduce waste and prevent environmental pollution. To preferred.

It is preferable that the dokudami leaves are pulverized by a pulverizer such as DM-6 manufactured by Nakayama Institute of Technology.

Soybean here can be used from any origin, such as from Japan, China, the United States, or Russia, and is preferably pulverized by a pulverizer such as DM-6 manufactured by Nakayama Technical Research Laboratory.

The natto bacteria here are a kind of Bacillus subtilis used for the processing of natto and food. Natto bacteria manufactured by Natto Motopo are preferred because they are suitable for fermentation.

As for each addition amount regarding the said fermentation, 0.03-0.3 weight is preferable for dokudami leaf, 0.1-3 weight is preferable for soybeans, and 0.001-0.001 for natto bacteria with respect to 1 weight of edible fish. 0.03 weight is preferred.

The fermentation is carried out in a clean culture tank, and it is preferable to mix the materials with tap water.

Moreover, this fermentation is heated at 30-40 degreeC, and fermentation is performed for 24 to 96 hours. After fermentation, in order to carry out the extraction efficiently, it is diluted with tap water.

Since the said fermented material has the property to melt | dissolve in vegetable oil from oil solubility being high, it isolate | separates with vegetable oil. Vegetable oils include palm oil, palm oil, soybean oil, olive oil, rapeseed oil, rice oil, germ oil, corn oil, safflower oil, linseed oil, almond oil, sesame oil, cacao oil, canola oil, grape seed oil, and sesame oil Oils used in edible or cosmetic products such as wheat germ oil, rice bran oil, safflower oil, perilla oil, tea oil, camellia oil, pumpkin seed oil, peanut oil, grape oil, hazelnut oil, cottonseed oil, peanut oil are used In addition, it is more preferable to use a vegetable oil containing a pine leaf extract, a kokushi extract, a green tea extract, a chrysanthemum extract or a bamboo leaf extract because the intended derivative is stably maintained.

In particular, the above-mentioned pine leaf extract-containing vegetable oil is a vegetable oil having an excellent antioxidative action and containing an oil-soluble polyphenol extracted by adding a vegetable oil to a pulverized product of pine leaves. Can be separated.

The pine leaves used for the pine leaf extract-containing vegetable oil may be any of Japanese, Chinese and Taiwanese.

Pine leaves cultivated without using pesticides are preferred because they can avoid the danger of pesticides.

The addition amount of vegetable oil is 0.02-2 weight with respect to 1 weight of said fermented material. In this case, extraction by stirring is preferable, the stirring temperature is preferably 10 to 30 ° C., and the stirring time is preferably 0.5 to 3 hours.

After the stirring, it is preferable to collect the pine leaf extract-containing vegetable oil separated in the upper layer and remove the water. In order to remove moisture, a dryer such as TGD-250LF2 manufactured by Toyo Giken is used.

After the separated norcepharadione B derivative is absorbed into the body, the excess amount is decomposed by digestive enzymes such as esterase and further metabolized in the liver, so that it is highly safe and has few side effects.

Separating and purifying the desired norcepharadione B derivative from the reaction product is preferable from the viewpoint that the intake can be reduced as a highly pure substance. As a purification method, it is preferable to use a purification operation such as an organic solvent for separation or a resin. As the organic solvent, ethanol, hexane, chloroform, benzene, ethyl acetate, ether and the like are used, and among these, ethanol for food processing or hydrous ethanol is more preferable because it is easy to handle.

As the separation carrier or resin, porous polysaccharide, silicon oxide compound, polyacrylamide, polystyrene, polypropylene, styrene-vinylbenzene copolymer, etc., whose surface is coated, are used. It is preferable to separate and purify with an appropriate separation solvent and remove the solvent to obtain the desired norcepharadione B derivative.

The norcepharadione B derivative thus obtained is obtained as a liquid or powder. The obtained norcepharadione B derivative is used for pharmaceuticals, food preparations or cosmetics. As pharmaceuticals, they are used as anti-inflammatory agents, anti-obesity agents, lipolytic agents, wrinkle removing agents, fatty liver inhibitors, hyperlipidemia improving agents, anti-arteriosclerotic agents, anti-allergic agents and the like.

The food preparation is used for anti-inflammatory, rhinitis prevention, hay fever prevention, dermatitis prevention, muscle pain and muscle fatigue prevention, improvement of metabolic syndrome, fatigue recovery, nutrition tonic, maintenance of liver function, etc. The

This cosmetic product exhibits anti-inflammatory effects by suppressing the production of inflammatory cytokines, and also exhibits vasodilatory effects on the skin and limba tube dilation, so it suppresses wrinkles and sagging caused by inflammation such as sunburn. Or it is effective for prevention of production. In particular, it exerts anti-inflammatory action against inflammation caused by sunburn, and removes the cause of wrinkles and sagging.

Furthermore, this cosmetic exhibits an excellent therapeutic or preventive action against atopic dermatitis in which inflammatory cytokines are produced in large quantities.

Next, to 1 weight of the norcepharadione B derivative having an inhibitory action on inflammatory cytokine production, 0.01 to 0.5 weight of chrysanthemum flower extract-containing vegetable oil, 0.01 to 0.5 weight of pine leaf extract-containing vegetable oil A food preparation comprising a composition containing weight will be described.

The norcepharadione B derivative having an inhibitory action on inflammatory cytokine production here may be any of a crude product, a fermented product, a mixture, a synthesized product, and a highly purified substance extracted and purified. Norcepharadione B derivative means that caprylic acid, lauric acid, palmitic acid, 14-methylpalmitic acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, alpha-lipoic acid at the X position of norcepharadione B Any one selected from gamma-linolenic acid, stearic acid, and methyl stearic acid is a derivative having a covalent bond.

The norcepharadione B derivative herein is a derivative that suppresses the production of inflammatory cytokines such as interleukin-1 alpha, interleukin-8, and TNF alpha.

Furthermore, the norcepharadione B derivative mentioned here passes through the cell membrane of inflammatory cells such as monocytes, macrophages, and neutrophils, moves into the nucleus, and acts on transcription factors such as NF-kappa B and NF-IL6. A transcription factor is a derivative that suppresses gene level expression of inflammatory cytokines and suppresses production of inflammatory cytokines.

Here, the chrysanthemum flower extract-containing vegetable oil is a vegetable oil comprising a chrysanthemum flower extract containing polyphenols, and is obtained by extracting a chrysanthemum flower or a fermented chrysanthemum flower with a vegetable oil.

The vegetable oils used in the chrysanthemum flower extract-containing vegetable oil include palm oil, palm oil, soybean oil, olive oil, rapeseed oil, rice oil, germ oil, corn oil, safflower oil, linseed oil, almond oil, sesame oil, cacao oil, Edible oil such as canola oil, grape seed oil, sesame oil, wheat germ oil, rice bran oil, safflower oil, perilla oil, tea oil, camellia oil, pumpkin seed oil, peanut oil, grape oil, hazelnut oil, cottonseed oil, peanut oil Or the oil used for cosmetics is used.

Chrysanthemum flower extract-containing vegetable oil manufactured by Toyo Fermentation Co., Ltd. is preferable because of its high quality and low impurities.

The pine leaf extract-containing vegetable oil is obtained by pulverizing Japanese, Chinese and Asian pine, red pine, black pine and other French pine pine leaves with a pulverizer and extracting them with vegetable oil.

Processed raw material of pine leaves with cellulase such as Onozuka R-10, Y-NC manufactured by Yakult Pharmaceutical Co., Ltd., Cellulase A “Amano” 3 and Cellulase T “Amano” 4 manufactured by Amano Enzyme Co., Ltd. This is preferable because the extraction efficiency is improved. A pine leaf extract-containing vegetable oil manufactured by Toyo Fermentation Co., Ltd. is preferable because of its high quality and low impurities.

The added chrysanthemum flower extract-containing vegetable oil is 0.01-0.5 wt. Per 1 wt. Of the norcepharadione B derivative having an inhibitory action on inflammatory cytokine production. 01-0.5 weight, which gives a composition.

If the weight of the chrysanthemum flower extract-containing vegetable oil is less than 0.01 weight relative to 1 weight of the norcepharadione B derivative, the intended composition may not be sufficiently obtained.

If the weight of the chrysanthemum flower extract-containing vegetable oil is more than 0.5 weight relative to 1 weight of the norcepharadione B derivative, the solubility of the norcepharadione B derivative is lowered and may be precipitated.

When the weight of the pine leaf extract-containing vegetable oil is less than 0.01 weight relative to 1 weight of the norcepharadione B derivative, the target composition may not be sufficiently obtained.

When the weight of the pine leaf extract-containing vegetable oil is more than 0.5 weight relative to 1 weight of the norcepharadione B derivative, the solubility of the norcepharadione B derivative is lowered and may be precipitated.

In order to obtain the said composition, it is preferable to heat after mixing. As heating conditions, the temperature is 30 to 45 ° C., and the heating time is 6 to 40 hours.

When the heating temperature is lower than 30 ° C, there is a possibility that sufficient mixing does not occur. When the heating temperature is higher than 45 ° C., the reaction product generated by oxidation may turn brown. When the heating time is less than 6 hours, a sufficient product may not be obtained. If the heating time exceeds 40 hours, the product produced by oxidation may turn brown.

This composition is preferable because the above-mentioned norcepharadione B derivative is released gradually little by little and becomes a continuous composition.

Moreover, by comprising in this way, a norcepharadione B derivative is stably maintained by the antioxidant power of a chrysanthemum flower extract containing vegetable oil, and the decomposition | disassembly by oxidation is suppressed. In particular, double bonds of unsaturated fatty acids are protected from oxidation and maintain the structure.

Further, the composition is processed together with other raw materials to form a food preparation. In this case, by adding to various food materials or beverage materials, for example, it can be made into a food preparation in the form of powder, tablet, liquid (drink, etc.), capsule or the like. Moreover, you may add a base material, an excipient | filler, an additive, a subsidiary material, a bulking agent, etc. suitably.

The food preparation is taken orally in several divided doses per day. The daily intake is preferably 0.2 to 10 g, more preferably 0.3 to 6 g, and even more preferably 0.5 to 4 g. If the daily intake is less than 0.2 g, sufficient anti-inflammatory action may not be exhibited. If the daily intake exceeds 10 g, the cost may increase. In addition to the above, it can be used in the form of rice cake, rice crackers, cookies, beverages and the like.

The food preparation referred to here is a health functional food, health supplement food, general food, hospital food used in a hospital, animal feed, pet supplement, or pet food.

This food preparation is used for anti-inflammatory, rhinitis prevention, hay fever prevention, dermatitis prevention, prevention of muscle pain and fatigue, improvement of metabolic syndrome, fatigue recovery, nutrition tonic, maintenance of liver function, etc. .

Next, to 1 weight of the norcepharadione B derivative having an inhibitory action on inflammatory cytokine production, 0.05 to 0.8 weight of chrysanthemum flower extract-containing vegetable oil, 0.05 to 0.8 weight of pine leaf extract-containing vegetable oil A cosmetic comprising a composition containing weight will be described.

The norcepharadione B derivative having an inhibitory action on inflammatory cytokine production here may be any of a crude product, a fermented product, a mixture, a synthesized product, and a highly purified substance extracted and purified. The norcepharadione B derivative means that caprylic acid, lauric acid, palmitic acid, 14-methyl palmitic acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, alpha-lipoic acid, gamma-linolenic acid, Any one selected from stearic acid and methyl stearic acid is a covalently bonded derivative.

The norcepharadione B derivative herein is a derivative that suppresses the production of inflammatory cytokines such as interleukin-1 alpha, interleukin-8, and TNF alpha.

Furthermore, the norcepharadione B derivative mentioned here passes through the cell membrane of inflammatory cells such as monocytes, macrophages, and neutrophils, moves into the nucleus, and acts on transcription factors such as NF-kappa B and NF-IL6. A transcription factor is a derivative that suppresses gene level expression of inflammatory cytokines and suppresses production of inflammatory cytokines.

Here, the chrysanthemum flower extract-containing vegetable oil is a vegetable oil comprising a chrysanthemum flower extract containing polyphenols, and is obtained by extracting a chrysanthemum flower or a fermented chrysanthemum flower with a vegetable oil.

The vegetable oils used in the chrysanthemum flower extract-containing vegetable oil include palm oil, palm oil, soybean oil, olive oil, rapeseed oil, rice oil, germ oil, corn oil, safflower oil, linseed oil, almond oil, sesame oil, cacao oil, Edible oil such as canola oil, grape seed oil, sesame oil, wheat germ oil, rice bran oil, safflower oil, perilla oil, tea oil, camellia oil, pumpkin seed oil, peanut oil, grape oil, hazelnut oil, cottonseed oil, peanut oil Or the oil used for cosmetics is used.

Chrysanthemum flower extract-containing vegetable oil manufactured by Toyo Fermentation Co., Ltd. is preferable because of its high quality and low impurities.

The pine leaf extract-containing vegetable oil is obtained by pulverizing Japanese, Chinese and Asian pine, red pine, black pine and other French pine pine leaves with a pulverizer and extracting them with vegetable oil.

Processed raw material of pine leaves with cellulase such as Onozuka R-10, Y-NC manufactured by Yakult Pharmaceutical Co., Ltd., Cellulase A “Amano” 3 and Cellulase T “Amano” 4 manufactured by Amano Enzyme Co., Ltd. This is preferable because the extraction efficiency is improved. A pine leaf extract-containing vegetable oil manufactured by Toyo Fermentation Co., Ltd. is preferable because of its high quality and low impurities.

The amount of vegetable oil containing chrysanthemum flower extract added is 0.05 to 0.8% by weight, and the amount of vegetable oil containing pine needle extract is 0. It is 05-0.8 weight, and a composition is obtained by this.

If the weight of the chrysanthemum flower extract-containing vegetable oil is less than 0.05 weight per 1 weight of the norcepharadione B derivative, the target composition may not be sufficiently obtained.

When the weight of the chrysanthemum flower extract-containing vegetable oil is more than 0.8 weight relative to 1 weight of the norcepharadione B derivative, the solubility of the norcepharadione B derivative is lowered and may be precipitated.

When the weight of the pine leaf extract-containing vegetable oil is less than 0.05 weight per 1 weight of the norcepharadione B derivative, the target composition may not be sufficiently obtained.

When the weight of the pine leaf extract-containing vegetable oil is more than 0.8 weight with respect to 1 weight of the norcepharadione B derivative, the solubility of the norcepharadione B derivative is lowered and may be precipitated.

In order to obtain the said composition, it is preferable to heat after mixing. As heating conditions, the temperature is 30 to 45 ° C., and the heating time is 6 to 40 hours.

When the heating temperature is lower than 30 ° C, there is a possibility that sufficient reaction does not occur. When the heating temperature is higher than 45 ° C., the reaction product generated by oxidation may turn brown. When the heating time is less than 6 hours, a sufficient product may not be obtained.

If the heating time exceeds 40 hours, the product produced by oxidation may turn brown.

This composition is preferable because the above-mentioned norcepharadione B derivative is released gradually little by little and becomes a continuous composition.

Moreover, by comprising in this way, a norcepharadione B derivative is stably maintained by the antioxidant power of a chrysanthemum flower extract containing vegetable oil, and the decomposition | disassembly by oxidation is suppressed. In particular, double bonds of unsaturated fatty acids are protected from oxidation and maintain the structure.

Furthermore, the composition is processed together with other raw materials as a cosmetic. Thereafter, it can be used together with oils, surfactants, vitamins, ultraviolet absorbers, thickeners, moisturizers, auxiliary materials and the like in accordance with conventional methods.

It can be in the form of lotion, cream, ointment, lotion, milky lotion, pack, oil, soap, face wash, fragrance, audi cologne, bath preparation, shampoo, rinse and the like. The form of the cosmetic preparation is arbitrary, and can be used as a solution, cream, paste, gel, gel, solid, or powder.

As a cosmetic, it is applied to the skin several times a day. The daily coating amount is preferably 0.01 to 10 g, more preferably 0.05 to 3 g, and further preferably 0.1 to 2 g. When the daily application amount is less than 0.01 g, the treatment or prevention effect of wrinkles and sagging may not be exhibited. When the application amount per day exceeds 10 g, the cost may increase.

The cosmetics referred to here are basic cosmetics, whitening cosmetics, hair cleansing agents, treatment agents, dyeing agents, hair restorers, hair nourishing agents, body wash, quasi-drugs, which are cosmetics used for humans. In addition, it is a skin improvement agent used for animals, a shampoo for pets, and a body wash.

This cosmetic product exhibits anti-inflammatory effects by suppressing the production of inflammatory cytokines, and also exhibits vasodilatory effects on the skin and limba tube dilation, so it suppresses wrinkles and sagging caused by inflammation such as sunburn. Or it is effective for prevention of production.

In particular, it exerts anti-inflammatory action against inflammation caused by sunburn, and removes the cause of wrinkles and sagging.

Furthermore, this cosmetic exhibits an excellent therapeutic or preventive action against atopic dermatitis in which inflammatory cytokines are produced in large quantities.

Next, the anti-inflammatory agent comprising the norcepharadione B derivative having an inhibitory action on inflammatory cytokine production will be described.

The norcepharadione B derivative having an inhibitory action on inflammatory cytokine production here may be any of a crude product, a fermented product, a mixture, a synthesized product, and a highly purified substance extracted and purified. The norcepharadione B derivative means that caprylic acid, lauric acid, palmitic acid, 14-methyl palmitic acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, alpha-lipoic acid, gamma-linolenic acid, Any one selected from stearic acid and methyl stearic acid is a covalently bonded derivative.

The norcepharadione B derivative herein is a derivative that suppresses the production of inflammatory cytokines such as interleukin-1 alpha, interleukin-8, and TNF alpha.

Furthermore, the norcepharadione B derivative mentioned here passes through the cell membrane of inflammatory cells such as monocytes, macrophages, and neutrophils, moves into the nucleus, and acts on transcription factors such as NF-kappa B and NF-IL6. A transcription factor is a derivative that suppresses gene level expression of inflammatory cytokines and suppresses production of inflammatory cytokines.

When used as a pharmaceutical, since it is necessary to remove the influence of impurities, it is preferable to use the norcepharadione B derivative having the structure described above, which is synthesized by an enzymatic reaction and has little solvent residue.

It is used as a pharmaceutical orally or parenterally, and as a quasi-drug, it is used by blending with tablets, capsules, drinks, soaps, toothpastes and the like.

Examples of oral preparations include tablets, capsules, powders, syrups, and drinks. When mixed with the above-mentioned tablets and capsules, it can be used together with a binder, excipient, swelling agent, lubricant, sweetener, flavoring agent and the like. The tablets can also be coated with shellac or sugar.

Moreover, in the case of the said capsule, liquid carriers, such as fats and oils, can be further contained in said material. In the case of the above syrup and drink, sweeteners, preservatives, pigment flavoring agents and the like can be contained.

Examples of parenteral preparations include injections in addition to external preparations such as ointments, creams, and liquids. As the base material of the external preparation used here, petrolatum, paraffin, fats and oils, lanolin, macro gold and the like are used, and an ointment, a cream and the like can be obtained by a usual method.

Injections include liquids, and other lyophilization agents. This is used aseptically dissolved in distilled water for injection or physiological saline at the time of use.

The anti-inflammatory agent here is a pharmaceutical product or quasi-drug preparation for the purpose of treating or preventing skin, systemic or local inflammation.

Systemic inflammation includes fever, redness, and edema. Pneumonia, encephalitis, pharyngitis, bronchitis, keratitis, enteritis, gastritis, duodenal inflammation, colitis, hepatitis, nephritis, cystitis , Pancreatitis, neuritis, myositis, arteritis, dermatitis, atopic dermatitis, dermatitis due to sunburn, etc. Especially, it is used as an external preparation for dermatitis due to sunburn.

The effect is exerted by an action mechanism that suppresses the production of inflammatory cytokines against inflammation of these whole body and local organs.

In addition, it can be used as a veterinary medicine for the treatment of inflammation and dermatitis in livestock and pets.

Hereinafter, the embodiment will be specifically described with reference to examples and test examples. In addition, the following description is an example and can be implemented changing a form.

First, the norcepharadione B derivative obtained by fermentation will be described.

70 eels (scientific name: Angulara japonica) grown and grown on the shores of Lake Hamana were used as raw materials. The grown eels were slaughtered at a demolition site and then disassembled, and the head and internal organs were cut and collected. The body part was edible and the head and internal organs were collected.

The collected head and internal organs of 1.3 kg were cut with a knife and pulverized with DM-6 manufactured by Nakayama Technical Research Institute.

This was placed in a clean culture tank and 3.2 L of tap water was added. After washing 1.6 kg of dokudami leaves collected in Shizuoka Prefecture cultivated without agricultural chemicals with tap water, they are dried with a dryer (GZQ3 type, manufactured by Nishimura Kikai Co., Ltd.) and cut with scissors. The product was pulverized with DM-6. 150 g of this pulverized product was added to the above cylinder. To this, Chinese soybean was washed with water, heated to 36 ° C. for 36 minutes, and then 1.5 kg of soybean ground material was added.

To this, 15 g of natto bacteria manufactured by Natto Motopo was added. Fermentation was continued for 46 hours at 35 ° C. with stirring.

3.3 L of tap water was added to the tank after the fermentation. This was made into a fermented product.

0.9 kg of Ajinomoto soybean oil was added to the fermented product, and the mixture was stirred for 1 hour and mixed.

This was allowed to stand, and the oil-soluble portion separated by soybean oil separated into the upper layer was collected as a liquid. In order to remove moisture, it was subjected to TGD-250LF2 manufactured by Toyo Giken, and the target norcepharadione B derivative was obtained as an oily substance. This was used as the sample of Example 1.

The preparation of norcepharadione B derivative covalently bound with caprylic acid is described below.

1 kg of Shizuoka-grown dokudami leaves grown without pesticides were purchased, washed thoroughly with tap water, and dried with a dryer.

1 kg of this dokudami leaf was subjected to a pulverizer (manufactured by Sanriki Seisakusho Co., Ltd., a three-powered universal pulverizer) and pulverized to obtain a pulverized green tea.

1 kg of ground pulverized leaves was placed in a clean cylinder and 9 L of tap water was added. To this, 250 g of caprylic acid purchased from Ryoshoku was added and stirred.

To this was added 10 g of lipase AY “Amano” 30G manufactured by Amano Enzyme, and the mixture was heated to 28 ° C. and stirred at a rate of 70 times / minute for 13 hours to obtain a heated solution.

After cooling the cylinder containing the warming solution with tap water, 0.9 kg of Ajinomoto soybean oil was added, and the oil portion was collected.

This oil part was dried with a vacuum dryer (manufactured by AKM Kyushu Technos, Clean Dry) to obtain norcepharadione B derivative bound with caprylic acid as an oily liquid. This was also used as the sample of Example 2.

The preparation of norcepharadione B derivative to which lauric acid is bound is described below.

3 kg of leaves from Shizuoka grown without chemicals were collected, washed thoroughly with tap water, and dried with a dryer (GZQ3 type, manufactured by Nishimura Kikai Co., Ltd.). This was used as the leaf of the raw dokudami.

2 kg of this dokudami leaf was subjected to a pulverizer (manufactured by Sanriki Seisakusho Co., Ltd., a three-purpose universal pulverizer) and pulverized to obtain a pulverized product of dokudami leaf.

1 kg of pulverized leaves of Dokudami leaf was put in a clean cylinder and 10 L of tap water was added. To this, 200 g of lauric acid purchased from Ryoshoku was added and stirred.

To this was added 17 g of lipase AY “Amano” 30G manufactured by Amano Enzyme, and the mixture was heated to 29 ° C. and stirred at a rate of 66 times / min for 14 hours to obtain a heated solution.

After cooling the cylinder containing the warming liquid with tap water, 1 kg of RIKEN vitamin palm oil was added, and the oil portion was collected.

This was dried by a vacuum dryer (manufactured by AKM Kyushu Technos, Clean Dry) to obtain norcepharadione B derivative combined with lauric acid as an oily liquid. This was also used as the sample of Example 3.

Hereinafter, preparation of norcepharadione B derivative to which eicosapentaenoic acid is bound will be described.

3 kg of Chinese dokudami leaves grown without pesticides were collected, washed thoroughly with tap water, and dried with a dryer. This was used as the leaf of the raw dokudami. 2.2 kg of this dokudami leaf was subjected to a pulverizer (manufactured by Sanriki Seisakusho Co., Ltd., a three-purpose universal pulverizer) and pulverized to obtain a pulverized product of dokudami leaf.

1.2 kg of ground water of dokudami leaf was put into a clean cylinder and 12 L of tap water was added. To this, 330 g of Eicosapentaenoic acid manufactured by Nippon Suisan was added and stirred.

To this was added 12 g of lipase AY “Amano” 30G manufactured by Amano Enzyme, and the mixture was heated to 25 ° C. and stirred at a rate of 64 times / min for 13 hours to obtain a heated solution.

After cooling the cylinder containing the warming liquid with tap water, 1 kg of RIKEN vitamin palm oil was added, and the oil portion was collected.

This was dried by a vacuum dryer (manufactured by AKM Kyushu Technos, Clean Dry) to obtain norcepharadione B derivative bound with eicosapentaenoic acid as an oily liquid. This was also used as the sample of Example 4.

Hereinafter, preparation of norcepharadione B derivative to which docosahexaenoic acid is bound will be described.

3 kg of Chinese dokudami leaves cultivated without pesticides were collected, thoroughly washed with tap water, and dried with a dryer (GZQ3 type, manufactured by Nishimura Kikai). This was used as the leaf of the raw dokudami.

The 2.5 kg of this dokudami leaf was subjected to a pulverizer (manufactured by Sanriki Seisakusho Co., Ltd., a three-purpose universal pulverizer) and pulverized to obtain a pulverized product of dokudami leaf.

1.1 kg of pulverized leaves of Dokudami leaves were put into a clean cylinder and 10 L of tap water was added. To this, 350 g of docosahexaenoic acid manufactured by Nissui Pharmaceutical was added and stirred.

To this was added 11 g of lipase AY “Amano” 30G manufactured by Amano Enzyme, and the mixture was heated to 25 ° C. and stirred at a rate of 69 times / minute for 12 hours to obtain a heated solution.

After cooling the cylinder containing the warming liquid with tap water, 1 kg of pine leaf extract-containing coconut oil manufactured by Toyo Fermentation Co., Ltd. was added, and the oil portion was collected.

This was dried with a vacuum dryer (manufactured by AKM Kyushu Technos, Clean Dry) to obtain norcepharadione B derivative bound with docosahexaenoic acid as an oily liquid. This was also used as the sample of Example 5.

Hereinafter, a purified product of the norcepharadione B derivative will be described.

20 g of norcepharadione B derivative obtained in Example 4 was suspended in 500 mL of ethanol and applied to a column packed with 750 g of Diaion made by Mitsubishi Chemical. This was washed with 900 mL of 10% ethanol-containing water. Further, after washing with 900 mL of 30% ethanol-containing water, elution was performed with 900 mL of 75% ethanol-containing water, and a fraction of 90% ethanol-containing water was collected.

This was subjected to a vacuum dryer to distill off ethanol and water, and then 8 g of an oily purified product of norcepharadione B derivative was obtained by a freeze dryer manufactured by Nippon FD. This was used as the sample of Example 6.

Below, the identification test of a norcepharadione B derivative is demonstrated.
(Test Example 1)

Each norcepharadione B derivative obtained in Example 1, Example 2, Example 3, Example 4, Example 5, Example 5 and Example 6 obtained as described above was dissolved in purified ethanol, and mass spectrometry was performed. The analysis was performed with a high performance liquid chromatography equipped with an instrument (HPLC, Shimadzu Corporation), and further analyzed with a nuclear magnetic resonance apparatus (NMR, Bruker, AC-250).

As a result, from the sample of Example 1, norcepharadione B as a norcepharadione B derivative was changed to caprylic acid, lauric acid, palmitic acid, 14-methylpalmitic acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, A norcepharadione B derivative bound with alpha-lipoic acid, gamma-linolenic acid, stearic acid, methyl stearic acid was identified.

Further, from the sample of Example 2, a norcepharadione B derivative in which caprylic acid was bound to norcepharadione B was identified. The carbon farthest from the carboxylic acid of caprylic acid was covalently bonded.

Further, from the sample of Example 3, a norcepharadione B derivative in which lauric acid was bonded to norcepharadione B was identified. The carbon farthest from the carboxylic acid of lauric acid was covalently bonded.

Further, from the specimens of Example 4 and Example 6, a norcepharadione B derivative in which eicosapentaenoic acid was bound to norcepharadione B was identified. The carbon farthest from the carboxylic acid of eicosapentaenoic acid was covalently bonded.

Further, from the sample of Example 5, a norcepharadione B derivative in which docosahexaenoic acid was bound to norcepharadione B was identified. The carbon farthest from the carboxylic acid of docosahexaenoic acid was covalently bonded.

Below, the suppression test of the inflammatory cytokine production of a norcepharadione B derivative is demonstrated.

(Test Example 2)
In the test, heparinized blood was collected from 5 males aged 28 to 66 and 7 females aged 21 to 77 who were infected with skim pollinosis, and monocytes were cultured by MEM (Nissui Pharmaceutical). .

1000 monocytes were seeded in a culture dish having a diameter of 35 mm and cultured at 37 ° C. for 24 hours under 5% carbon dioxide gas.

To this, 10 ng of cedar pollen (manufactured by Funamishi) and the specimens obtained in Examples 1 to 6 were dissolved in dimethyl sulfoxide, and 1 ng of each was added, followed by 48 hours after the addition. The culture supernatant was collected, and the amounts of interleukin-1 alpha, interleukin-6 and TNF alpha as inflammatory cytokines were quantified by an absorbance method using an ELISA kit (manufactured by Amgen).

As a solvent control, dimethyl sulfoxide was used instead of the specimen.

In addition, clobetasol propionate, which is a steroid agent, was used as a positive control.

As a result, in the case of the amount of interleukin-1 alpha, assuming that the amount of the solvent control was 100%, 55% in Example 1, 53% in Example 2, 51% in Example 3, It was 49% in Example 4, 33% in Example 5, and 22% in Example 6. In addition, the clobetasol propionate was 60%.

Therefore, it was concluded that all of the samples of Examples 1 to 6 suppressed the production of interleukin-1 alpha with respect to cedar pollen.

In the case of the amount of interleukin-6, when the amount of the solvent control is 100%, the added amount of 1 ng is 72% in Example 1, 71% in Example 2, 73% in Example 3, and Example. It was 66% in Example 4, 63% in Example 5, and 61% in Example 6. In addition, clobetasol propionate was 75%.

Therefore, it was concluded that all of the samples of Examples 1 to 6 suppressed the production of interleukin-6 against cedar pollen.

Further, in the case of the amount of TNF alpha, when the amount of the solvent control is 100%, the added amount of 1 ng is 60% in Example 1, 63% in Example 2, 52% in Example 3, and in Example 4. It was 46%, 51% in Example 5, and 32% in Example 6. In addition, clobetasol propionate was 78%.

Therefore, it was concluded that all of the samples of Examples 1 to 6 suppressed the production of TNF alpha against cedar pollen.

As a result, the samples of Examples 1 to 6 were considered to suppress the production of inflammatory cytokines to the same extent or more than clobetasol propionate.

Below, manufacture of the foodstuff formulation containing a norcepharadione B derivative is described.

100 g of norcepharadione B derivative obtained in Example 1 above was placed in a food processing mixer (Tsukasa, pow mixer, single type) and 40 g of chrysanthemum flower extract-containing vegetable oil manufactured by Toyo Fermentation Co., Ltd. was added. . To this, 40 g of pine leaf extract-containing soybean oil manufactured by Toyo Fermentation Co., Ltd. was added, and this was heated at 37 ° C. for 24 hours with cooling, to obtain about 176 g of a composition.

To 130 g of this composition, 330 g of edible cellulose, 1.2 g of ascorbic acid and 10 g of edible fragrance were added to a food processing mixer (Tsukasa, Pow mixer, W type) and mixed. This was pulverized by a conventional method, dried, and then filled into porcine-derived gelatin hard capsules as 250 mg per capsule to obtain a food preparation. This was used as the sample of Example 7.

The anti-inflammatory action using food preparations will be described below.
(Test Example 3)

Nine males presenting scabs and worms due to house dust mites aged 22-72 years old, 10 capsules of the food preparation obtained in Example 7 once a day, that is, 2.5 g per day for 28 days every day Feeded. The reactivity of house dust mites was observed before feeding and on the 28th day of feeding. Furthermore, blood was collected before feeding and on the 28th day of feeding, and the IgE amount was measured by an immunoantibody method.

As a result, after feeding, the number of mite and catfish due to house dust mites was 31% on average compared to before feeding, and a clear decrease in reactivity was observed.

Furthermore, the blood IgE amount was 45% on average compared to before feeding, and a decrease in the IgE amount was observed. In addition, no abnormalities were observed in physical condition or health after eating.

100 g of norcepharadione B derivative obtained in Example 2 was put into a cosmetic processing mixer (manufactured by Kotobuki Kogyo Co., Ltd., Paule Container Mixer), and 50 g of chrysanthemum flower extract-containing vegetable oil manufactured by Toyo Fermentation Co., Ltd. was added. To this, 50 g of pine leaf extract-containing soybean oil manufactured by Toyo Fermentation Co., Ltd. was added, and this was heated at 37 ° C. for 30 hours with stirring to obtain about 190 g of a composition.

This composition was put into the mixer, and beeswax (manufactured by API) 100 g, petrolatum 300 g and squalane (manufactured by Nippon Suisan) 1 g were added and mixed to obtain a cream as a cosmetic preparation. This was used as the sample of Example 8. At the same time, a base-only cream excluding the norcepharadione B derivative obtained in Example 2 was prepared.

(Test Example 4)
Using the cream obtained in Example 8, a wrinkle improvement test for ultraviolet rays was conducted on 12 women aged 20 to 66 years. That is, 12 cases were divided into two groups, and 1 g of cream containing the norcepharadione B derivative of Example 8 was applied to the face for 14 days. At the same time, a group using a cream containing only the base material was set.

The woman was exposed to ultraviolet rays for 1 hour every day with an ultraviolet irradiation device for sunburn (Neotan 888, manufactured by Emrock). Before use and after 14 days of use, skin skin temperature and skin area per unit area using skin elasticity, skin surface horny layer moisture measuring device (IBBS, SKICON 200) using keratin moisture, elasticity meter (Cutometer) The wrinkle length was measured.

Furthermore, sweat and sebum were collected, and the amount of TNF alpha, which is an inflammatory cytokine, was measured by an immunoenzymatic method (manufactured by Amgen).

As a result, a skin temperature decrease of 0.33 ° C. was observed as an average value in the use example of the cream containing the norcepharadione B derivative as compared with the cream using only the base material. In addition, the skin surface angle layer water content increased to 168% in the use example of the cream containing the norcepharadione B derivative as compared with the use of the cream of the base material alone. Further, the elasticity of the elasticity meter was increased to 188% in the usage example of the cream containing the norcepharadione B derivative as compared with the cream using only the base material.

The length of the wrinkle was 48% in the use example of the cream containing the norcepharadione B derivative as compared with the use of the cream containing only the base material, and a reduction in wrinkle was clearly observed.

In addition, the amount of TNF alpha in sweat and sebum was reduced to an average of 56% in the use case of the cream containing the norcepharadione B derivative compared to the use of the base-only cream.

Furthermore, no side effects were observed in the cream containing the norcepharadione B derivative, and the usability was also good.

Therefore, the cream of Example 8 was confirmed to have the effect of suppressing cytokine production due to ultraviolet rays and improving wrinkles, and having high safety.

Below, the anti-inflammatory agent which consists of a norcephalradione B derivative is described.

In a clean stainless steel dissolution tank, 50 g of norcepharadione B derivative obtained in Example 2 above, 150 g of lanolin, 120 g of macro gold, 20 g of beeswax, and 30 g of ozokerite were added and dissolved at 38 ° C. for 1 hour. This was supplied to a kneader and mixed. This was dissolved again in a dissolution tank, heated, and deaerated with a deaerator to obtain the desired anti-inflammatory agent as an ointment.

As a control, a control sample using lanolin instead of the norcepharadione B derivative obtained in Example 2 was prepared, and used as a control sample in the test.
(Test Example 5)

Ten males presenting scabs and worms due to house dust mites aged 22-64 years old were given 1 g of the anti-inflammatory agent obtained in Example 9 once a day for 14 days to the outside of the nasal cavity, around the nasal cavity and around the oral cavity. Applied.

The reactivity of house dust mites was observed before application and on the 14th day of application. Further, blood was collected before application and on the 14th day of application, and the amount of TNF alpha and IgE were measured by an immunoantibody method.

As a result, after application, the number of scabs and catfish due to house dust mites was 35% on average compared to before application, and in both cases, a decrease in reactivity to pollen was observed. The average amount of TNF alpha in the blood was 39% compared to that before application, and a decrease in the amount of TNF alpha, an inflammatory cytokine, was observed.

The blood IgE level was 41% compared to the value before application, and a decrease in the IgE level was observed. In addition, no abnormalities were observed in the physical condition, health condition, and laboratory test values after application.

Therefore, the anti-inflammatory agent comprising the norcepharadione B derivative of Example 9 reduced the amount of inflammatory cytokines and IgE against hay fever, exhibited an anti-inflammatory effect, and was confirmed to be safe.

On the other hand, when a control sample using lanolin was used in place of the norcepharadione B derivative, the number of expression of scabs and honeyworms by cedar pollen was 101% on average compared to before application, and the reaction to pollen There was no change in sex.

In addition, the amount of TNF alpha in blood after using a control sample using lanolin is 99% on average compared to before application, and the amount of TNF alpha, which is an inflammatory cytokine, does not change compared to before use. It was.

Furthermore, the amount of IgE in blood after use of a control sample using lanolin was 103% on average, and no change was observed compared to before use.

The norcepharadione B derivative having an inhibitory action on the production of inflammatory cytokines according to the present invention exhibits an excellent function with weak side effects for the purpose of preventing and improving systemic and local inflammation, dermatitis, pneumonia, bronchitis, It can improve the quality of life of patients suffering from various inflammations such as hepatitis or semi-healthy people and can be applied to the medical field.

In addition, the food preparation comprising the norcepharadione B derivative having an inhibitory action on the production of inflammatory cytokine according to the present invention improves or develops inflammation such as hay fever, house dust mite, sick house syndrome, cold, allergy, dermatitis, etc. It helps prevent and improve the quality of people's lives.

Furthermore, cosmetics comprising norcepharadione B derivatives that have an inhibitory action on the production of inflammatory cytokines have an effect of improving or preventing inflammation such as wrinkles and dullness due to sunburn, inflammation of the skin and atopy, and improve the quality of life of the people. It is to improve.

In addition, according to the anti-inflammatory agent comprising a norcepharadione B derivative having an inhibitory action on the production of inflammatory cytokines, it is possible to improve or prevent inflammation such as dermatitis, hepatitis, encephalitis, pneumonia, cold, pancreatitis, hay fever and allergy. Contribute and improve people's lives. This anti-inflammatory agent has few side effects and contributes to the activation of the medical and pharmaceutical industries by exhibiting an excellent anti-inflammatory action.

The head and internal organs of dokudami and edible fish are treated as waste. The present invention reduces waste from the point of effectively using these wastes, can prevent environmental destruction due to soil and marine eutrophication due to waste, and is expected to effectively use fishery and agricultural resources, Furthermore, it contributes to the development of fisheries and agriculture.

Claims (9)

A norcepharadione B derivative represented by the following formula (1) having an inhibitory action on inflammatory cytokine production.

X is any one selected from caprylic acid, lauric acid, 14-methylpalmitic acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, alpha-lipoic acid, gamma-linolenic acid, stearic acid, and methyl stearic acid. . 2. Inflammation obtained by adding caprylic acid and lipase for transesterification to ground pulverized leaves, heating and extracting with vegetable oil, wherein X is caprylic acid among the norcepharadione B derivatives according to claim 1 A norcepharadione B derivative represented by the following formula (2) having a suppressive action on sex cytokine production.

Inflammation obtained by adding lauric acid and lipase for transesterification to ground pulverized leaves, heating and extracting with vegetable oil, wherein X is lauric acid among the norcepharadione B derivatives according to claim 1 A norcepharadione B derivative represented by the following formula (3) having a suppressive action on sex cytokine production.

2. A product obtained by adding eicosapentaenoic acid and lipase for transesterification to a pulverized leaf of dokudami, heating and extracting with vegetable oil, wherein X is eicosapentaenoic acid among the norcepharadione B derivatives according to claim 1. A norcepharadione B derivative represented by the following formula (4) having a certain inflammatory cytokine production inhibitory action.

Inflammation obtained by adding docosahexaenoic acid and lipase for transesterification to pulverized leaves of Dokudami, heating and extracting with vegetable oil, wherein X is docosahexaenoic acid among the norcepharadione B derivatives according to claim 1 A norcepharadione B derivative represented by the following formula (5) having a suppressive action on sex cytokine production.

The norcepharadione B derivative having an inhibitory action on inflammatory cytokine production according to claim 1, obtained by extracting a fermented product obtained by adding fermented natto to fermented fish, dokudami leaves and soybean and fermenting them with vegetable oil. Claim 1 or Claim 2 or Claim 3 or Claim 4 or Claim 5 or Claim 6 Norsepharadione B derivative having inhibitory action on inflammatory cytokine production, 1 weight of chrysanthemum flower extract-containing vegetable oil 0 A food preparation comprising a composition comprising 0.01 to 0.5 wt., Pine needle extract-containing vegetable oil 0.01 to 0.5 wt. Claim 1 or Claim 2 or Claim 3 or Claim 4 or Claim 5 or Claim 6 Norsepharadione B derivative having inhibitory action on inflammatory cytokine production, 1 weight of chrysanthemum flower extract-containing vegetable oil 0 A cosmetic comprising a composition containing 0.05 to 0.8 weight of pine needle extract-containing vegetable oil 0.05 to 0.8 weight. An anti-inflammatory agent comprising the norcepharadione B derivative having an inhibitory action on inflammatory cytokine production according to claim 1, claim 2, claim 3, claim 4, claim 5, or claim 6.