JP2021104952A - Fibrogenesis inhibitor - Google Patents

Abstract

To provide a Chinese medicine effective as a fibrogenesis inhibitor.SOLUTION: Provided is a tissue fibrogenesis inhibitor that contains Bofutsushosan extract, Boiogito extract, and/or Daisaikoto extract.SELECTED DRAWING: Figure 1

Description

The present invention relates to an inhibitor of fibrosis. More specifically, the present invention relates to new uses of bofutsushosan, daisaikoto and boiogito as fibrosis inhibitors.

Fibrosis is a phenomenon in which connective tissue accumulates in tissues. For example, advanced fibrosis in the liver leads to cirrhosis. It is also known that fibrosis leads to various diseases in organs such as kidney, lung, heart and pancreas.

Fibrosis not only causes health hazards, but can also affect appearance. For example, when adipose tissue becomes fibrotic, it forms cellulite. As described in Non-Patent Document 1, unlike obesity, cellulite is a skin condition in which fibrosis occurs in adipose tissue and degeneration occurs, resulting in unevenness on the skin. It is a symptom different from obesity from the point of view.

Ingredients that suppress fibrosis have been reported for the purpose of prevention or improvement of various symptoms related to fibrosis. For example, Patent Document 1 discloses an agonist for a polynucleotide encoding a protein belonging to the Sema6 family or a fragment thereof; a protein belonging to the Sema6 family or a partial fragment thereof; or an agonist for a receptor having the protein or a fragment thereof as a ligand. The fibrosis inhibitor contained as an ingredient is described. Non-Patent Document 2 describes that isoliquiritigenin, a component of the crude drug licorice, acts on adipocytes to suppress fibrosis.

Clinical Dermatology, Vol. 69, No. 5, April 10, 2015, pp. 148-150 Scientific Reports, 6: 23097, DOI: 10.1038 / srep23097

JP-A-2018-21026

Traditional Chinese medicine and herbal medicines are drugs that focus on improving the constitution and conditioning the whole body based on the idea based on ancient oriental medicine. Since they use natural herbal medicines, they are psychologically acceptable and have few side effects. It has a wide range of applications. Therefore, the present inventor focused on licorice, which is a crude drug containing isoliquiritigenin, which has been reported as a component that suppresses fibrosis. However, we faced the problem that the fibrosis inhibitory effect of the licorice extract was insufficient.

Therefore, an object of the present invention is to provide a Chinese medicine effective as an inhibitor of fibrosis.

As a result of diligent studies, the present inventor unexpectedly found that the extracts of Bofutsushosan and Boiogito, which contain licorice as a constituent crude drug, have an excellent antifibrosis effect over licorice extract. Furthermore, the present inventor unexpectedly found that the extract of daisaikoto also has an excellent antifibrosis effect. The present invention has been completed by further studies based on these findings.

That is, the present invention provides the inventions of the following aspects.
Item 1. A tissue fibrosis inhibitor containing Bofutsushosan extract, Boiogito extract and / or daisaikoto extract.
Item 2. Item 2. The fibrosis inhibitor according to Item 1, wherein the tissue is adipose tissue.
Item 3. Item 2. The fibrosis inhibitor according to Item 1 or 2, wherein the tissue is adipose tissue of a menopausal woman.

According to the present invention, a Chinese medicine effective as an inhibitor of fibrosis is provided.

The area of the fibrotic part in the adipose tissue when Bofutsushosan extract, Bofutsushosan extract, Oshiba Koto extract, or licorice extract was administered to the menopausal fat fibrosis model mouse was compared with the control. The result is shown.

The fibrosis inhibitor of the present invention is characterized by containing bofutsushosan extract, boiogito extract and / or daisaikoto extract.

As the active ingredient Bofutsushosan, the Chinese medicine prescription described in "Guide for New General Chinese Medicine Prescription" (supervised by Yukihiro Goda and Takashi Hazuka, edited by the Japan Herbal Medicine Association, published by Jiho Co., Ltd.) is preferable. Examples thereof include mixed crude drugs consisting of shakuyaku, senkyu, sanshishi, forsythia, mint, shokyo, schizonepeta, siler, maou, daiou, bosho, biakujutsu, kikyo, ogon, licorice, sekkou, and kaseki. Depending on the letter, some of the above-mentioned herbal medicines do not contain Byakujutsu (for example, "Experienced Kampo Prescription Amount Collection", Keisetsu Otsuka / Domei Yakazu, published by Japan Co., Ltd.), and those that do not contain Scutellaria baicalensis (for example, "" There is a series of Chinese medicines, edited by Osaka Yomiuri Shimbun, published by Naniwasha). In addition, depending on the prescription of Bofutsushosan, some contain Hamaboufu instead of Bowfu, and some contain Sojutsu instead of Byakujutsu.

Boiogito is preferably the Chinese medicine prescription described in the "Guide for New General Chinese Medicine Prescription" (supervised by Yukihiro Goda and Takashi Hakamatsuka, edited by the Japan Herbal Medicine Association, published by Jiho Co., Ltd.). , Jutsu, ginger, licorice, and licorice. In addition, boiogito is a mixture described in the letters related to traditional Chinese medicine that are currently in use, as stipulated in the "Basic Handling Policy for Chinese Herbal Medicines" established by the Chinese Herbal Medicine Research Association. Herbal medicine (Chinese medicine prescription) is included.

For daisaikoto, the Chinese medicine prescription described in "Guide for New General Chinese Medicine Prescription" (supervised by Yukihiro Goda and Takashi Hakamatsuka, edited by the Japan Herbal Medicine Association, published by Jiho Co., Ltd.) is preferable, and psycho, hange, and scutellaria baicalensis are preferable. , Kijitsu, Peonies, Ginger, Taiso, and Daiou. In addition, daisaikoto is a mixed crude drug described in the letters related to traditional Chinese medicine that are currently in use, as stipulated in the "Basic Handling Policy for Chinese Herbal Medicines" established by the Chinese Herbal Medicine Research Committee. Chinese herbal prescription) is included.

The Bofutsushosan extract, Bofutsushosan extract, and Oshiba Koto extract in the present invention can be used as extracts by extracting and treating the above mixed crude drugs and concentrating the obtained extracts as necessary. It may be obtained, or it may be obtained as an extract powder by drying the extract solution.

In the production of Bofutsushosan extract, Boiogito extract, and Oshiba Koto extract, the extraction solvent used in the extraction treatment is not particularly limited, but water or hydrous ethanol can be mentioned as an example. The drying treatment is also not particularly limited, and a known method, for example, a spray-drying method, or an appropriate adsorbent (for example, silicic acid anhydride, starch, etc.) is added to the soft extract having an increased concentration of the extract solution. Examples thereof include a method of using the powder as an adsorption powder.

As the bofutsushosan extract, boiogito extract, and daisaikoto extract used in the present invention, the extract prepared by the above-mentioned method may be used, or a commercially available one may be used. .. For example, as the extract powder of Bofutsushosan, "Bofutsushosan dry extract A", "Bofutsushosan dry extract AM", "Bofutsushosan dry extract E", "Bofutsushosan dry extract EM" "(Both made by Nippon Powder Co., Ltd.)," Bofutsushosan Dry Extract-C "," Bofutsushosan Dry Extract-F "(both made by Alps Yakuhin Kogyo Co., Ltd.), etc. It is known and can also be obtained commercially. Boiogito extract powders include boiogito dried extract A and boiogito dried extract AZ (both manufactured by Nippon Powder Co., Ltd.), and boiogito extract powder and boiogito. Boiogito dried extract-F (both manufactured by Alps Yakuhin Kogyo Co., Ltd.) is known as a commercial product and can be obtained commercially. The extract powders of daisaikoto include daisaikoto dried extract AM, daisaikoto dried extract SN, daisaikoto dried extract powder (all manufactured by Nippon Powder Co., Ltd.), daisaikoto dried extract F, and daisaikoto. Dried hu-to extract-F (both manufactured by Alps Yakuhin Kogyo Co., Ltd.) is known as a commercial product and can be obtained commercially.

In the fibrosis inhibitor of the present invention, the contents of bofutsushosan extract, boiogito extract, and daisaikoto extract are not particularly limited as long as the effects of the present invention are exhibited, but in terms of the amount of dry extract, for example. 1 to 100% by weight is mentioned. The dry extract amount conversion is the amount of the dry extract (extract powder) itself, and when the extract liquid or the soft extract is used, it is the amount converted to the remaining amount after removing the solvent. When the dried extract powder contains an additive such as an adsorbent added at the time of production, the amount is the amount excluding the additive.

Other Ingredients The fibrosis inhibitor of the present invention may contain other pharmacological ingredients, if necessary, in addition to the above-mentioned Chinese medicine. The type of such pharmacological component is not particularly limited, but for example, an antacid, a stomachic agent, a digestive agent, an intestinal regulator, an antispasmodic agent, a mucosal repair agent, an anti-inflammatory agent, an astringent, an antiemetic agent, an antitussive agent, a sputum, and an anti-inflammatory agent. Examples include enzyme agents, sedative hypnotics, antihistamines, caffeines, cardiotonic diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, crude drugs, crude drug extract powders, vitamins, menthols and the like. These pharmacological components may be used alone or in combination of two or more. Further, the content of these pharmacological components may be appropriately set from known ones according to the type of the pharmacological component to be used and the like.

The fibrosis inhibitor of the present invention may contain a pharmaceutically acceptable base, additive, or the like, if necessary, in order to prepare a desired dosage form. Such bases and additives include, for example, excipients, binders, disintegrants, lubricants, isotonic agents, plasticizers, dispersants, emulsifiers, solubilizers, wetting agents, stabilizers. Agents, suspending agents, pressure-sensitive adhesives, coating agents, brighteners, water, fats and oils, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble polymers, surfactants, metal soaps. , Lower alcohols, polyhydric alcohols, pH adjusters, buffers, antioxidants, UV inhibitors, preservatives, flavoring agents, fragrances, powders, thickeners, pigments, chelating agents and the like. These bases and additives may be used alone or in combination of two or more. Further, the contents of these bases and additives may be appropriately set from known ones according to the type and dosage form of the additive component to be used.

Dosage Form The dosage form of the fibrosis inhibitor of the present invention is not particularly limited and may be any of tablets, granules, powders, pills, capsules, films, liquids (drinks) and the like. Among these dosage forms, tablets, granules, and film preparations are preferable from the viewpoint of ease of administration and the like. These dosage forms can be prepared using pharmaceutically acceptable base materials and additives, and the types and amounts of the base materials and additives are also known in the field of pharmaceutical technology.

Uses The fibrosis inhibitor of the present invention is used for the purpose of suppressing fibrosis in tissues. The tissue to which the fibrosis inhibitor of the present invention is applied is not particularly limited, and examples thereof include adipose tissue, liver tissue, kidney tissue, lung tissue, heart tissue, and pancreatic tissue. The fibrosis inhibitor of the present invention is also used for the purpose of preventing or ameliorating various symptoms caused by fibrosis by utilizing the inhibitory action on fibrosis in these tissues. Such symptoms include cellulite, liver fibrosis / cirrhosis, interstitial pneumonia / pulmonary fibrosis, myocardial fibrosis, pancreatic fibrosis and the like.

Among the above uses, from the viewpoint of obtaining an even more excellent antifibrosis effect, it is used for the purpose of suppressing fibrosis of adipose tissue, specifically, prevention of cellulite caused by fibrosis of adipose tissue It is preferably used for the purpose of improvement (that is, used as a preventive or ameliorating agent for cellulite).

Furthermore, since the fibrosis inhibitor of the present invention is excellent in the ability to suppress fibrosis, the tissue targeted by the fibrosis inhibitor of the present invention is middle-aged (for example, 45 to 55 years old) in which fibrosis is likely to occur. ) Is preferably the adipose tissue of a person, and more preferably the adipose tissue of a climacteric woman who is prone to cellulite due to fibrosis of fat.

Dosage and Usage The fibrosis inhibitor of the present invention is administered by oral administration. The dose of the fibrosis inhibitor of the present invention is appropriately set according to the symptoms related to fibrosis, age and the like. For example, the daily intake is 400 to 10000 mg in terms of the amount of dry extract (total amount), and the amount of dry extract of Bofutsushosan extract is 1000 to 10000 mg, preferably 2000 to 8000 mg, more preferably. 3000 to 7000 mg, more preferably 4500 to 6000 mg, and the dry extract amount equivalent amount of Boiogito extract is 1300 to 6000 mg, preferably 2000 to 4800 mg, more preferably 3000 to 4000 mg, and Oshibahu. In terms of the amount of dried extract of hot water extract, 1300 to 6000 mg, preferably 1700 to 5800 mg, and more preferably 2000 to 3000 mg can be mentioned.

The timing of taking the fibrosis inhibitor of the present invention is not particularly limited and may be before meals, after meals, or between meals, but pre-meal or inter-meal is preferable. Further, in order to obtain the effect of the present invention more satisfactorily, it is preferable to take the drug continuously for 3 weeks or longer, preferably 5 weeks or longer, more preferably 7 weeks or longer.

Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited to these Examples.

1. 1. Preparation of extract powder The crude drugs shown in Table 1 were prepared as raw material crude drugs. The amount (mg) of each extract powder in Table 1 is the amount per day, and the amount (g) of each crude drug is the amount equivalent to the crude drug per day. A sufficient amount of the extract was prepared and used at the same ratio as in Table 1 so that the extract could be spray-dried. The crude drug was chopped and mixed, extracted with about 20 times the amount of water at about 100 ° C. for 30 minutes, and centrifuged to obtain an extract. The extract was concentrated under reduced pressure and dried using a spray dryer to obtain bofutsushosan extract powder, boiogito extract powder, daisaikoto extract powder, and licorice extract powder. The drying with a spray dryer was performed by dropping the extract onto an atomizer having a rotation speed of 10000 rpm and supplying hot air with air at 150 ° C.

2. Experimental method Mice (C57BL / 6J mice, 6 weeks old, female) were subjected to bilateral ovariectomy (OVX) to reproduce the menopause, and were bred on a normal diet for the recovery period of 1 week after the operation. Then, a high-fat diet (HFD32, Japan Claire Co., Ltd.) was fed freely for 10 days and bred to prepare a model mouse for menopausal fat fibrosis.

The menopausal fat fibrosis model mice were divided into a total of 5 groups (7 animals per group): a non-administration group (control), a bofutsushosan group, a boiogito group, an Oshiba-koto group, and a licorice group. In the non-administration group (control), a high-fat diet containing no extract powder was freely ingested for 7 weeks. In the Bofutsushosan group, Boiogito group, Oshiba Koto group, and Licorice group, the high-fat diet was fed with a feed containing 4% by weight of the extract powder produced in item 1 above for 7 weeks. did. There was no difference in food intake between the groups. After 7 weeks of breeding, adipose tissue was removed and HE-stained. The HE-stained tissue was photographed with a microscope image, and the average value of the area of the fibrous tissue stained with the eosin dye in ^{one screen (649,000 μm 2) was derived as the fibrotic area for each group.} The analysis result of the fibrotic area is shown in FIG.

As is clear from FIG. 1, while the licorice extract has an insufficient inhibitory effect on fibrosis of about 10%, Bofutsushosan and Boiogito, which contain licorice as one of the constituent crude drugs, and Oshiba Koto. In addition, a remarkable inhibitory effect on fibrosis was observed, which was more than double the effect of licorice extract alone (also 5 g in terms of crude drug).

Claims (3)

A tissue fibrosis inhibitor containing Bofutsushosan extract, Boiogito extract and / or daisaikoto extract. The fibrosis inhibitor according to claim 1, wherein the tissue is adipose tissue. The fibrosis inhibitor according to claim 1 or 2, wherein the tissue is adipose tissue of a menopausal woman.

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