JP6773363B2 - Organ fibrosis inhibitory composition - Google Patents

Description

The present invention relates to a composition for suppressing fibrosis of an organ.

Organ fibrosis refers to a state in which fibrous components such as collagen are excessively accumulated in various parts of the tissues constituting the organ, and organ fibrosis is a common pathological condition in organ failure. For example, when fibrosis occurs in the myocardium, abnormalities occur in the functioning of the heart, symptoms such as dyspnea and hypercardiac appear, and cirrhosis showing bone atrophy and degeneration in rheumatoid arthritis and fibrosis of the entire liver. Pathological conditions are also well known as examples of fibrotic connective tissue. It has been clarified that liver fibrosis is induced by viral infection, drug overdose, and excessive intake of sugars and lipids, and that as fibrosis progresses, it progresses to cirrhosis, liver cancer, and liver failure (non-patent). Documents 1 and 2).

J Clin Invest. 2005 Feb; 115 (2): 209-18 Jpn. J. Clin. Immunol. 2009; 32 (3): 160-67 The Japanese Society of Internal Medicine Magazine Vol. 103 Extra Edition, 2015

It is important to suppress liver fibrosis in order to prevent (progression) to cirrhosis and liver failure, but there is no specific and effective therapeutic agent for liver fibrosis (Non-Patent Document 3). .. In addition, there is no effective suppressing means for fibrosis of organs other than the liver.

Therefore, the present invention is a problem to be solved to provide an effective means for suppressing fibrosis of an organ.

As a result of intensive studies to solve the above problems, the present inventors have found that ingestion of turmeric extract significantly suppresses fibrosis of organs, and have completed the present invention. That is, the present invention includes the following inventions.
(1) An organ fibrosis-suppressing composition, which comprises a turmeric extract.
(2) The organ fibrosis inhibitory composition according to (1), wherein the turmeric extract contains a water-soluble turmeric extract.
(3) The organ fibrosis-suppressing composition according to (1) or (2), wherein the turmeric extract contains Bisacurone.
(4) The organ fibrosis inhibitory composition according to any one of (1) to (3), wherein the organ fibrosis is liver fibrosis.
(5) The organ fibrosis inhibitory composition according to (4), wherein the liver fibrosis is non-alcoholic liver fibrosis.

By ingesting the composition of the present invention, it is possible to suppress fibrosis of organs.
Since the composition of the present invention contains a turmeric extract, which is a component of food, as an active ingredient, it is considered to be highly safe for continuous ingestion or administration by humans or other animals.

FIG. 1 is a liver histological image of a control group stained with silius red, a 0.02% turmeric extract group, and a 0.08% turmeric extract group. FIG. 2 shows the liver fibrosis area ratio (sirius red positive area ratio) in the liver tissue of the control group, the 0.02% turmeric extract group, and the 0.08% turmeric extract group.

Hereinafter, the present invention will be described in detail.
The composition of the present invention is characterized by containing at least a turmeric extract.
The composition of the present invention may contain components other than the turmeric extract.
In one embodiment, the composition of the present invention comprises a turmeric extract.
The compositions of the present invention can be formulated with at least one other ingredient.

In the present invention, "containing" includes a mixed state or a coexisting state. The coexisting state means a state in which each is separated before use, but is in a coexisting combination state, and is mixed and used at the time of use.

<Turmeric extract>
In the present invention, the turmeric extract refers to an extract (turmeric extract) of a plant material derived from a plant belonging to the genus Turmeric of the family Zingiberaceae. The turmeric extract is not limited to the solvent extract obtained by extraction with an extraction solvent, but also includes the solvent extract further fractionally purified by column chromatography or the like. The turmeric extract used in the present invention is derived from an extract that has been subjected to an extraction operation (including a fraction purification operation when fractional purification is performed), a concentrate in which a solvent is partially removed from the extract, or an extract. It can be in the form of a dried product from which the solvent has been removed. The removal of the solvent from the extract can be carried out by volatilizing the solvent by heating and / or reducing the pressure. These heating and depressurizing methods are not particularly limited, and for example, conventionally known methods can be used.

Examples of the plant raw material include Curcuma longa (turmeric), Curcuma aromatica, Curcuma zedoraia, Curcuma phaeocalis, Curcuma kwangsiensis, Curcuma roots, Curcuma stalks, Curcuma stalks, etc. These rhizomes may be collected from the soil, and the appropriate part of the rhizome may be cut into the original shape, cut to an appropriate size or shape, or crushed. it can. These plant raw materials may be appropriately dried.

The method for extracting the turmeric extract from the plant material is not particularly limited, and a conventionally known method can be used. The extraction solvent is preferably at least one selected from the group consisting of water and a hydrophilic organic solvent. The at least one extraction solvent selected from the group consisting of water and a hydrophilic organic solvent may be any of water, a hydrophilic organic solvent, and a mixed solvent of water and a hydrophilic organic solvent. The hydrophilic organic solvent may be a mixed solvent of a plurality of types of hydrophilic organic solvents. "Water" also includes hot water. Examples of the hydrophilic organic solvent include at least one alcohol (may be a mixed solvent of a plurality of alcohols), and the alcohol is not particularly limited, but ethanol is preferable.

In the present invention, the mixing ratio of the mixed solvent of water and the hydrophilic organic solvent is not particularly limited, but for example, the weight ratio is preferably in the range of 90:10 to 10:90, more preferably in the range of 80:20 to 50:50. preferable. The temperature at the time of extraction is not particularly limited.

The water-soluble turmeric extract can be obtained by extracting from a turmeric plant raw material using at least one selected from the group consisting of water and a hydrophilic organic solvent as an extraction solvent. The extraction solvent for obtaining the water-soluble turmeric extract is preferably an extraction solvent containing water, and among the extraction solvents described in the present specification, water or a mixed solvent of water and a hydrophilic organic solvent is particularly used. More preferably. The water-soluble turmeric extract may be used alone or in combination with one or more other components in the present invention. Examples of other components include solvents, excipients, physiologically active components and the like, and may be hydrophobic components such as turmeric pigment described later. Prior to combination with other components, the water-soluble turmeric extract is soluble at room temperature (eg 20 ° C.) in at least one selected from the group consisting of water and hydrophilic organic solvents (particularly water). Specifically, at room temperature (for example, 20 ° C.), a concentration of 1% by weight or more in at least one selected from the group consisting of water and a hydrophilic organic solvent (particularly water) (the turmeric extract is dried). It is preferable to dissolve in physical conversion).

The water-soluble turmeric extract extracted using at least one selected from the group consisting of water and a hydrophilic organic solvent as the extraction solvent was extracted using a hydrophobic organic solvent such as ethyl acetate as the extraction solvent. It contains a more water-soluble compound as compared to the turmeric extract. Therefore, these extracts are clearly different from each other in the composition of the components contained.

In the present invention, as the turmeric extract, the turmeric rhizome extract obtained as described above can be used as it is, and the turmeric rhizome extract can be used as a solvent, excipient, physiologically active ingredient, etc. It can also be used in combination with other ingredients. For example, in an embodiment in which a turmeric extract containing a water-soluble turmeric extract is used as the turmeric extract, the water-soluble turmeric extract is a liquid product obtained by dissolving or suspending the water-soluble turmeric extract in an appropriate solvent. Various forms such as a composition combining a water-soluble turmeric extract and an excipient such as dextrin, and a composition combining a water-soluble turmeric extract and a turmeric pigment and an excipient described later can be used. it can.

The turmeric extract used in the present invention is preferably characterized by containing Bisacurone. The water-soluble turmeric extract is preferable because it contains water-soluble Bisacurone. Bisacurone is preferably contained in an amount of 0.15% by weight or more based on the total amount of the turmeric extract. The amount of Bisacurone in the turmeric extract is a high-performance liquid that is obtained by mixing the turmeric extract with ethyl acetate, distilling off ethyl acetate from the supernatant obtained by centrifugation under reduced pressure, and then dissolving the solution in acetonitrile as an analysis sample. It can be determined by subjecting to chromatography (HPLC).

In the present invention, bisaclone is a compound classified into bisabolan-type sesquiterpenes, and means a compound having the following planar structural formula or a salt thereof. Bisacurone has an asymmetric carbon at the position marked with * in the planar structural formula, and therefore there are several types of optical isomers. Bisacurone in the present specification is a concept that includes any of these optical isomers. is there.

The turmeric extract used in the present invention preferably has a curcumin content of 0.5% by weight or less, and more preferably does not contain curcumin.

<Organ fibrosis inhibitory composition>
"Organ fibrosis" refers to a state in which fibrous components such as collagen are excessively accumulated in various parts of tissues constituting the organ, and organ fibrosis is a common pathological condition in organ failure. For example, liver fibrosis is caused by viral infections, drug overdose, and carbohydrate and lipid overdose. "Non-alcoholic liver fibrosis" refers to liver fibrosis caused by fat, in addition to alcohol. Examples of organs for which suppression of organ fibrosis is desired include liver, heart, lung, kidney, pancreas, stomach, intestinal tract (small intestine, large intestine, colon, etc.), blood vessels, bone marrow, muscle, skin, eyes, and the like. The organ fibrosis inhibitory composition of the present invention is preferably selected from liver, heart, lung, kidney, pancreas, stomach, intestinal tract (small intestine, large intestine, colon, etc.), blood vessel, bone marrow, muscle, skin and eye. It is a composition for suppressing fibrosis in the above-mentioned organs.

Liver fibrosis can be observed in liver tissue by staining collagen by means such as silius red staining.

In the present invention, the "organ fibrosis suppressing composition" refers to a composition used for suppressing the fibrosis of an organ. The organ fibrosis-suppressing composition of the present invention is a composition to be ingested or administered by an arbitrary route, preferably a composition for oral or nasal ingestion or administration, and more preferably oral ingestion or administration. It can be any embodiment of a pharmaceutical product (for humans or non-human animals), foods and drinks, feeds, food additives, health foods, supplements, feed additives and the like. The animals targeted by the organ fibrosis-suppressing composition of the present invention are mammals such as humans, mice, rats, rabbits, dogs, cats, cows, and horses, and humans are particularly preferable.

The organ fibrosis-suppressing composition of the present invention may be the turmeric extract itself, or may be in the form of a combination of the turmeric extract and at least one other component.

The content of the turmeric extract in the organ fibrosis inhibitory composition of the present invention is, preferably, per day for one human, particularly one adult, per daily intake or dose of the organ fibrosis inhibitory composition of the present invention. The non-alcoholic liver contains turmeric extract as bisacron, for example, 40 μg to 24,000 μg, preferably 180 μg to 8,000 μg, and more preferably 250 μg to 3,300 μg per ingestion or dose of turmeric. It is preferable because it can effectively suppress organ fibrosis such as fibrosis. In the organ fibrosis-suppressing composition of the present invention, for a target animal, particularly a human being, particularly an adult, the turmeric extract is, for example, 0.7 μg / kg body weight / day to 400 μg / kg body weight / day, preferably 3 μg / day as Bisacurone. It is contained so as to be administered or ingested in an amount of kg body weight / day to 133 μg / kg body weight / day, more preferably 4 μg / kg body weight / day to 55 μg / kg body weight / day. Here, the "daily intake or dose" is, in the case of oral or nasal, preferably oral, ingestion or administration, typically 0 as the amount of the organ fibrosis inhibitory composition of the present invention. .1 g to 500 g. The organ fibrosis inhibitory composition of the present invention may be continuously ingested or administered, or may be ingested or administered when necessary.

<Formulation>
As described above, the organ fibrosis-suppressing composition of the present invention can contain a turmeric extract and one or more other components. The other ingredients are not particularly limited, but are preferably oral or nasal, such as pharmaceuticals (for humans or non-human animals), foods and drinks, feeds, food additives, health foods, supplements, feed additives, etc. It is an acceptable ingredient for ingestion or administration. Examples of other components include fructose-glucose liquid sugar, dextrin, acidulant, vitamins, thickener, turmeric pigment, inositol, flavor, cyclic oligosaccharide, sweetener, mineral, antioxidant, emulsifier and the like, which will be described later. Other components mentioned with respect to specific examples of the various compositions to be made.

Examples of the acidulant include citric acid, malic acid, gluconic acid, tartaric acid, and salts thereof.

Examples of vitamins include niacin, vitamin B1, vitamin B6, vitamin C, vitamin E and the like.

Examples of the thickener include thickening polysaccharides such as gellan gum, xanthan gum, pectin, and guar gum.

The turmeric pigment is obtained by extracting from the rhizome portion of turmeric with warm ethanol, hot fat or propylene glycol, or room temperature to hot hexane or acetone, and it is preferable that it mainly contains curcumin. .. The amount of turmeric pigment in the composition is about 3 mg to 50 mg, more preferably about 5 mg to 40 mg, particularly preferably about 3 mg to 50 mg of curcumin per ingestion or dose, preferably one oral ingestion or dose. It is preferable to add an amount of turmeric pigment in an amount of 6 mg to 30 mg.

Examples of minerals include magnesium, calcium, sodium and potassium.
Examples of the antioxidant include vitamin C, enzyme-treated rutin and the like.
Examples of the sweetener include sugars such as fructose, glucose and liquid sugar, and high-sweetness sweeteners such as honey, sucralose, acesulfame potassium, thaumatin and aspartame.

The composition of the present invention comprising a turmeric extract and at least one other component is preferably a composition formulated for oral or nasal ingestion or administration, more preferably oral ingestion or oral administration. A composition formulated for administration. Here, the compositions formulated for oral or nasal ingestion or administration are in various forms such as pharmaceuticals (for humans or animals), foods and drinks, feeds, food additives, health foods, supplements, feed additives and the like. Can be.

The shape of the organ fibrosis suppressing composition of the present invention is not particularly limited, and may be any property such as liquid, fluid, gel, semi-solid, or solid.

When the organ fibrosis-suppressing composition of the present invention is used as a pharmaceutical product, a pharmaceutical composition containing a turmeric extract and at least one pharmaceutically acceptable other component such as a pharmaceutical additive. It is preferably formulated in the form. The pharmaceutical composition may be in the form of an oral solid preparation such as a capsule, a tablet (including a coated tablet such as a sugar-coated tablet or an enteric coated tablet or a multi-layer tablet), a powder or a granule, or an oral liquid preparation. It may be in the form of a parenteral preparation such as an injection, a drip, or a suppository. These preparations can be produced by a method known per se.

Formulation additives commonly used in solid preparations such as capsules, tablets, powders or granules include, for example, excipients (eg, lactose, sucrose, glucose, starch, crystalline cellulose, etc.), binders ( For example, starch paste solution, hydroxypropyl cellulose solution, carmellose solution, gum arabic solution, gelatin solution, sodium alginate solution, etc.), disintegrant (for example, starch, carmellose sodium, calcium carbonate, etc.), lubricant (for example, stear). Magnesium acid, talc, stearic acid, calcium stearate, etc.), surfactants (eg, polysolvate 80, polyoxyethylene hydrogenated castor oil, etc.), thickeners (eg, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, etc.) ), Etc., but are not limited to these. Tablets or granules are coated with a coating agent (for example, gelatin, sucrose, gum arabic, carnauba wax, cellulose acetate, methacrylic acid copolymer, hydroxypropyl cellulose phthalate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose, etc.). You may. The capsule may be a microcapsule, a soft capsule, or the like, in addition to a hard capsule. The solid preparation can be produced by a conventionally known method.

Liquid formulations include, for example, sugars (eg, sucrose, sorbitol, fructose, etc.), glycols (eg, polyethylene glycol, propylene glycol, etc.), dispersions or thickeners (eg, gelatin, gum arabic, hydroxyethyl cellulose, hydroxypropyl). Cellulose, polyvinyl alcohol, polyethylene glycol, etc.), emulsifiers (eg, glycerin fatty acid ester, sucrose fatty acid ester, etc.), solubilizers (eg, gum arabic, polysorbitol 80, etc.), pH adjusters (eg, citric acid, citric acid, etc.) (Trisodium, etc.), preservatives (for example, paraoxybenzoic acid esters, etc.) and the like may be blended.

When the organ fibrosis-suppressing composition of the present invention is a food or drink, the food or drink is at least acceptable as a food or drink such as a turmeric extract, an additive permitted in terms of food hygiene, and a normal food raw material. It can be in a form containing one kind of other component. When the organ fibrosis-suppressing composition of the present invention is a food additive, the food additive is at least one allowed as a food additive such as a turmeric extract and an additive permitted in food hygiene. It can be in a form containing other components.

The food and drink and food additives include turmeric extract and at least one additive permitted in terms of food hygiene, for example, capsules, tablets (coated tablets such as sugar-coated tablets or multi-layer tablets, mouth disintegrants, etc.). It may be formulated in the form of a solid composition such as (including), powder or granules, or it may be formulated in the form of a liquid composition. Examples of the additive include excipients (eg, lactose, dextrin, corn starch, crystalline cellulose, etc.), lubricants (eg, magnesium stearate, sucrose fatty acid ester, glycerin fatty acid ester, etc.), and disintegrants (eg, glycerin fatty acid ester, etc.). Carboxymethyl cellulose calcium, anhydrous calcium hydrogen phosphate, calcium carbonate, etc.), binders (eg, starch paste solution, hydroxypropyl cellulose solution, Arabic rubber solution, etc.), dissolution aids (eg, Arabic rubber, polysolvate 80, etc.), sweetness Foods (eg sugar, fructose, glucose syrup, honey, aspartame, etc.), colorants (eg β-carotene, edible tar pigments, riboflavin, etc.), preservatives (eg, sorbic acid, methyl paraoxybenzoate, sodium sulfite) Etc.), thickeners (eg, sodium alginate, sodium carboxymethyl cellulose, sodium polyacrylate, etc.), antioxidants (eg, dibutylhydroxytoluene, butylhydroxyanisole, ascorbic acid, tocopherol, etc.), fragrances (eg, hackers, etc.) Strawberry flavors, etc.), acidity agents (eg, citric acid, lactose, DL-apple acid, etc.), seasonings (eg, DL-alanine, 5'-sodium inosinate, sodium L-glutamate, etc.), emulsifiers (eg, glycerin) Examples thereof include fatty acid esters, sucrose fatty acid esters, etc.), pH adjusters (for example, citric acid, trisodium citrate, etc.), vitamins, minerals, amino acids, pigments, and the like. The solid composition can be produced according to a conventional method. In addition, the liquid composition can be produced in the same manner as the liquid preparation as a pharmaceutical product suitable for oral administration.

Examples of the food and drink include confectionery (for example, gum, candy, caramel, chocolate, cookie, snack confectionery, jelly, gummy, tablet confectionery, etc.), noodles (for example, buckwheat, udon, ramen, etc.), and dairy products (for example, ramen). , Milk, ice cream, yogurt, etc.), seasonings (eg, miso, soy sauce, etc.), soups, beverages (eg, juice, coffee, tea, tea, carbonated beverages, sports beverages, etc.) Examples include nutritional supplements (eg, nutritional drinks, etc.). The food also includes foods containing food additives.

When the organ fibrosis-suppressing composition of the present invention is a health food, the health food is permitted as a health food such as a corn extract, an additive permitted in terms of food hygiene, and a normal health food raw material. It can be in a form containing at least one other component. The health food means a food composition for the purpose of health, health maintenance / promotion, etc., and includes a licensed specific functional food and a so-called health food not approved for the specific functional food. The health food is, for example, a liquid or semi-solid or solid product, and examples thereof include sweets such as cookies, senbei, jelly, yokan, yogurt, and manju, soft drinks, nutritional drinks, and soups. Alternatively, it may be dissolved in hot water or water and drunk as it is. These liquid or semi-solid or solid products can be produced according to a conventional method.

When the organ fibrosis suppressing composition of the present invention is a supplement, the supplement is at least one that is permitted as a supplement such as a turmeric extract, a food hygiene-acceptable additive, and a normal supplement raw material. It can be in a form containing other components. Supplements not only mean dietary supplements and nutritionally functional foods for supplementing nutrients, but also health supplements and health functional foods that have functions that are useful for maintaining, recovering, and promoting health. Also means. The shapes of such supplements include, for example, tablets, rounds, capsules (including hard capsules, soft capsules, and microcapsules), powders, granules, fine granules, troches, and liquids (syrups, emulsions, suspensions). (Including turbidity) and the like. These can be manufactured according to a conventional method.

When the organ fibrosis-suppressing composition of the present invention is a feed, the feed includes a turmeric extract and at least one other component permitted as a feed such as a general feed additive and a feed material. It can be in a form including and. When the organ fibrosis-suppressing composition of the present invention is a feed additive, the feed additive includes a turmeric extract and at least one other acceptable feed additive such as a general feed additive. It can be in a form containing the components of.

The present invention will be specifically described based on the following experimental results, but the present invention is not limited thereto.

<Purpose>
-As an animal model of liver fibrosis, there is a mouse fed with a methionine / choline-deficient high-fat diet supplemented with a small amount of methionine (Int J Exp Pathol. 2013; 94 (2): 93-103).
Using this model, we investigated whether turmeric extract could suppress liver fibrosis.

<Materials, etc.>
1) Preparation of turmeric extract The turmeric extract was prepared by extracting the rhizome portion of turmeric (Curcuma longa) with water and drying the obtained extract under reduced pressure to remove water.

The amount of Bisacurone in the turmeric extract is a high-performance liquid using a solution prepared by mixing the turmeric extract and ethyl acetate, distilling ethyl acetate under reduced pressure from the supernatant obtained by centrifugation, and then dissolving it in acetonitrile. It was determined by subjecting to chromatography (HPLC). HPLC was performed under the following conditions.
Column: Thermo ODS HYPERSIL (registered trademark) 250 mm x φ4.6 mm (manufactured by Thermo Scientific)
Mobile phase: 65% acetonitrile (20 min) ⇒ 80% acetonitrile (5 min) ⇒ 65% acetonitrile (10 min)
Flow velocity: 0.7 ml / min
Temperature: 40 ° C
Detection wavelength: 242 nm
As a result, it was confirmed that the amount of Bisacurone in the turmeric extract was about 0.15% by mass or more and the amount of curcumin was 0.5% by weight or less.

<Method>
A high-fat diet containing 0.05% methionine and no choline was used as a feed for inducing liver fibrosis in mice. After feeding this feed to C57BL / 6J mice (male, 6 weeks old) for 2 weeks, turmeric extract was added to 0% (control group, n = 6), 0.02% (80 μg / kg / day as bisacron). The liver was removed after feeding the above-mentioned feed for inducing liver fibrosis, which was formulated so as to have n = 6) and 0.08% (320 μg / kg / day as bisacron, n = 6) for another 8 weeks. Then, a pathological specimen was prepared, and sirius red staining was performed to stain the fibrotic site of liver tissue.

<Result 1: Sirius red staining>
The fibrotic part of the liver was stained, and the stained area (the part where fibrosis occurred) was quantified to evaluate the degree of fibrosis.

The results of silius red staining are shown in FIGS. 1 and 2. FIG. 1 is a photograph of liver tissue image of each group. In FIG. 1, the arrow points to the liver fibrotic region. FIG. 2 shows the silius red positive area ratio (each n = 6) of each group. Sirius red positive area ratio is the ratio (%) of the area of the stained area to the area of the observed area of the stained liver specimen.

The sirius red positive area ratios of the turmeric extract 0.02% group and the turmeric extract 0.08% group were both significantly lower than those of the control group, suggesting that the turmeric extract suppresses liver fibrosis. Was done.

Since the composition of the present invention has an action of suppressing the fibrosis of an organ, it is useful in the application of suppressing the fibrosis of an organ in humans or animals.

Claims (3)

A non-alcoholic liver fibrosis inhibitory composition containing a turmeric (Curcuma longa) extract having a curcumin content of 0.5% by weight or less and not separately containing curcumin . The liver fibrosis inhibitory composition according to claim 1, wherein the turmeric extract contains a water-soluble turmeric extract. The liver fibrosis inhibitory composition according to claim 1 or 2, wherein the turmeric extract contains bisacron.