fibrosis inhibitors

Abstract

To provide a Chinese medicine effective as a fibrogenesis inhibitor.SOLUTION: Bofutsushosan extract, Boiogito extract, and / or Daisaikoto extract are effective as a fibrogenesis inhibitor.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a fibrosis inhibitor. More specifically, the present invention relates to a new use of bofutsushosan, daishaikoto, and boiogito as a fibrosis inhibitor. [Background technology]

[0002] Fibrosis is the accumulation of connective tissue in tissues. For example, progression of fibrosis in the liver can lead to cirrhosis. It is also known that fibrosis in organs such as the kidneys, lungs, heart, and pancreas can lead to various diseases.

[0003] Fibrosis not only causes health problems but can also affect appearance. For example, fibrosis of adipose tissue leads to the formation of cellulite. As described in Non-Patent Document 1, cellulite differs from obesity in that it is a skin condition manifested as unevenness due to fibrosis and degeneration of adipose tissue, and is a symptom that differs from obesity in terms of both clinical features and pathophysiology.

[0004] Components that suppress fibrosis have been reported for the purpose of preventing or improving various symptoms associated with fibrosis. For example, Patent Document 1 discloses a protein belonging to the Sema6 family or a polynucleotide encoding a partial fragment thereof; a protein belonging to the Sema6 family; or A fibrosis inhibitor containing as an active ingredient a partial fragment thereof or an agonist for a receptor that uses the protein or a partial fragment thereof as a ligand is described. Non-Patent Document 2 describes that isoliquiritigenin, a component of the herbal medicine licorice, acts on adipocytes to inhibit fibrosis. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Clinical Dermatology, Vol. 69, No. 5, April 10, 2015, pp. 148-150 [Non-patent document 2] Scientific Reports, 6:23097, DOI: 10.1038 / srep23097 [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Publication No. 2018-21026 Summary of the Invention [Problem to be solved by the invention]

[0007] Kampo medicines and herbal medicines are based on traditional Eastern medicine and are primarily intended to improve physical constitution and overall health. Because they use natural herbal medicines, they are psychologically acceptable and have few side effects, making them widely applicable. Therefore, the present inventors focused on licorice, a herbal medicine containing isoliquiritigenin, which has been reported as a component that inhibits fibrosis. However, they encountered the problem that the fibrosis-inhibiting effect of licorice extracts was insufficient.

[0008] Therefore, an object of the present invention is to provide a Chinese herbal medicine that is effective as a fibrosis inhibitor. [Means for solving the problem]

[0009] As a result of extensive research, the present inventors have unexpectedly found that extracts of Bofutsushosan and Boiogito, which contain licorice as a constituent herbal medicine, have superior fibrosis inhibitory effects that surpass those of licorice extract. Furthermore, the present inventors have unexpectedly found that extracts of Daisaikoto also have superior fibrosis inhibitory effects. The present invention was completed based on these findings and through further research.

[0010] That is, the present invention provides the following aspects. Item 1. A tissue fibrosis inhibitor containing bofutsushosan extract, boiogito extract, and / or daishaikoto extract. Item 2. The fibrosis inhibitor according to Item 1, wherein the tissue is adipose tissue. Item 3. The fibrosis inhibitor according to Item 1 or 2, wherein the tissue is adipose tissue of a menopausal woman. [Effects of the Invention]

[0011] According to the present invention, a Chinese herbal medicine effective as a fibrosis inhibitor is provided. [Brief explanation of the drawings]

[0012] [Figure 1] 1 shows the results of comparing the area of ​​fibrotic parts in adipose tissue when bofutsushosan extract, boiogito extract, daishakoto extract, or licorice extract was administered to menopausal lipofibrosis model mice with that of the control. DETAILED DESCRIPTION OF THE INVENTION

[0013] The fibrosis inhibitor of the present invention is characterized by containing bofutsushosan extract, boiogito extract and / or daishaikoto extract.

[0014] Active ingredient Bofutsushosan is described in "New Guide to General Chinese Medicine Prescriptions" (edited by Yukihiro Goda and Takashi Hakamzuka, The Kampo prescriptions described in "The Japanese Association of Kampo Herbal Medicine Preparations, edited by the Japan Kampo Herbal Medicine Preparation Association, published by Jiho Co., Ltd." are preferred, and examples thereof include mixed herbal medicines consisting of Angelica Root, Peony Root, Cnidium Rhizome, Gardenia Fruit, Forsythia Fruit, Mentha Root, Ginger Root, Celastrus Root, Safflower Root, Ephedra Root, Rhubarb, Bouquet, Byakujutsu Root, Platycodon Root, Scutellaria Root, Glycyrrhiza Root, Glycyrrhiza Root, and Cassia Root. Some Bofutsushosan prescriptions contain Glehnia Root instead of Bofufu, and some contain Soujutsu Root instead of Byakujutsu.

[0015] Boi-ohgi-to is preferably a Kampo prescription described in the "New Guide to General Kampo Prescriptions" (edited by Goda Yukihiro and Hakamzuka Takashi, edited by the Japan Kampo Herbal Medicine Preparation Association, published by Jiho Co., Ltd.), and includes a mixture of herbs consisting of Bowi, Astragalus Root, Atractylodes Rhizome, Ginger, Licorice, and Glycyrrhiza. Furthermore, Boi-ohgi-to encompasses the mixture of herbs (Kampo prescriptions) described in currently commonly used Kampo-related letters, as stipulated in the "Basic Handling Guidelines for Kampo Preparations" established by the Kampo Herbal Medicine Research Council.

[0016] Daisaikoto is preferably a Kampo prescription listed in the "New Guide to General Kampo Prescriptions" (edited by Goda Yukihiro and Hakamzuka Takashi, edited by the Japan Kampo Herbal Medicine Preparation Association, published by Jiho Co., Ltd.), and includes a mixture of herbs consisting of Bupleurum Root, Pinellia Root, Scutellaria Root, Pheasant's Root, Peony Root, Ginger Root, Chinese Herb, and Rhubarb. Furthermore, Daisaikoto includes the mixture of herbs (Kampo prescriptions) listed in currently popular Kampo-related letters, as stipulated in the "Basic Handling Guidelines for Kampo Preparations" established by the Kampo Herbal Medicine Research Council.

[0017] The Bofutsushosan extract, Boiyogi-to extract, and Daisaiko-to extract in the present invention may be obtained as an extract liquid by extracting the above-mentioned mixed herbal medicines and concentrating the obtained extract liquid as necessary, or may be obtained as an extract powder by drying the extract liquid.

[0018] In the production of Bofutsushosan extract, Boiogito extract, and Daisaikoto extract, the extraction solvent used in the extraction process is not particularly limited, but examples include water or aqueous ethanol. The drying process is also not particularly limited, and includes known methods such as spray drying and a method in which a suitable adsorbent (e.g., silicic anhydride, starch, etc.) is added to a soft extract obtained by increasing the concentration of the extract liquid to obtain an adsorbed powder.

[0019] The bofutsushosan extract, bofutsushosan extract, and daishaikhoto extract used in the present invention may be prepared by the above-mentioned method or may be commercially available. For example, commercially available products include "Bofutsushosan Dried Extract A," "Bofutsushosan Dried Extract AM," "Bofutsushosan Dried Extract E," and "Bofutsushosan Dried Extract EM" (all manufactured by Nippon Powder Co., Ltd.), as well as "Bofutsushosan Dried Extract-C" and "Bofutsushosan Dried Extract-F" (all manufactured by Alps Pharmaceutical Co., Ltd.). Commercially available products include bofutsushosan extract powders such as Bofutsushosan Dried Extract A and Bofutsushosan Dried Extract AZ (both manufactured by Nippon Powder Co., Ltd.), as well as Bofutsushosan Extract Powder and Bofutsushosan Dried Extract-F (both manufactured by Alps Pharmaceutical Co., Ltd.). As extract powders of Daisaikoto, Daisaikoto Dried Extract AM, Daisaikoto Dried Extract SN, and Daisaikoto Dried Extract Powder (all manufactured by Nippon Powder Co., Ltd.), as well as Daisaikoto Dried Extract F and Daisaikoto Dried Extract-F (all manufactured by Alps Pharmaceutical Co., Ltd.), are known as commercial products and are also available commercially.

[0020] In the fibrosis inhibitor of the present invention, the contents of bofutsushosan extract, boiyogito extract, and daishaikoto extract are not particularly limited as long as the effects of the present invention are achieved, but may be, for example, 1 to 100% by weight in terms of the amount of dried extract. When a dried extract (extract powder) is used, this refers to the amount itself, and when an extract liquid or soft extract is used, this refers to the amount remaining after removing the solvent. Furthermore, when the dried extract powder contains additives such as adsorbents added during production, this refers to the amount excluding these additives.

[0021] Other ingredients The fibrosis inhibitor of the present invention may contain other pharmacological ingredients in addition to the aforementioned herbal medicine, as necessary. The types of such pharmacological ingredients are not particularly limited, but examples include antacids, stomachics, digestives, intestinal regulators, antispasmodics, mucosal repair agents, anti-inflammatory agents, astringents, antiemetics, antitussives, expectorants, anti-inflammatory enzymes, sedatives, hypnotics, antihistamines, caffeine, cardiac diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, herbal medicines, herbal extract powders, vitamins, and menthols. These pharmacological ingredients may be used alone or in combination of two or more. The content of these pharmacological ingredients may be appropriately determined from known ones depending on the type of pharmacological ingredient used.

[0022] The fibrosis inhibitor of the present invention may contain pharmaceutically acceptable bases and additives, etc., as necessary to prepare it into the desired dosage form. Examples of such bases and additives include excipients, binders, disintegrants, lubricants, isotonicity agents, plasticizers, dispersants, emulsifiers, solubilizers, wetting agents, stabilizers, suspending agents, adhesives, coating agents, glossing agents, water, oils and fats, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble polymers, surfactants, metal soaps, lower alcohols, polyhydric alcohols, pH adjusters, buffers, antioxidants, UV protection agents, preservatives, flavoring agents, fragrances, powders, thickeners, pigments, and chelating agents. These bases and additives may be used alone or in combination of two or more. The content of these bases and additives may be appropriately determined from known bases and additives depending on the type of additive used, dosage form, etc.

[0023] 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), etc. Among these dosage forms, tablets, granules, and films are preferred from the viewpoint of ease of administration, etc. These dosage forms can be prepared using pharmaceutically acceptable bases and additives, and the types and amounts of the bases and additives are also known in the field of formulation technology.

[0024] Purpose The fibrosis inhibitor of the present invention is used for the purpose of inhibiting fibrosis in tissues. The tissues to which the fibrosis inhibitor of the present invention is applied are not particularly limited, and examples include adipose tissue, liver tissue, kidney tissue, lung tissue, cardiac tissue, and pancreatic tissue. By utilizing its inhibitory effect on fibrosis in these tissues, the fibrosis inhibitor of the present invention is also used for the purpose of preventing or ameliorating various symptoms caused by fibrosis. Examples of such symptoms include cellulite, liver fibrosis / cirrhosis, interstitial pneumonia / pulmonary fibrosis, myocardial fibrosis, and pancreatic fibrosis.

[0025] Among the above uses, from the viewpoint of obtaining an even more excellent fibrosis-inhibiting effect, it is preferable to use it for the purpose of inhibiting adipose tissue fibrosis, specifically for the purpose of preventing or improving cellulite caused by adipose tissue fibrosis (i.e., use as an agent for preventing or improving cellulite).

[0026] Furthermore, since the fibrosis inhibitor of the present invention has excellent fibrosis inhibitory ability, the tissue targeted by the fibrosis inhibitor of the present invention is preferably the adipose tissue of middle-aged people (e.g., 45 to 55 years old), who are prone to fibrosis, and more preferably the adipose tissue of menopausal women, who are prone to developing cellulite due to fat fibrosis.

[0027] Dosage / Usage The fibrosis inhibitor of the present invention is administered orally. The dosage of the fibrosis inhibitor of the present invention is appropriately determined depending on the symptoms related to fibrosis, age, etc. For example, the daily intake amount is 400 to 10,000 mg in terms of dry extract (total amount), and the dry extract amount of bofutsushosan extract is 1,000 to 10,000 mg, preferably 2,000 to 8,000 mg, more preferably 3,000 to 7,000 mg, and even more preferably 4,500 to 6,000 mg. The dry extract amount of boiyogito extract is 1,300 to 6,000 mg, preferably 2,000 to 4,800 mg, and more preferably 3,000 to 4,000 mg. The dry extract amount of daishaikoto extract is 1,300 to 6,000 mg, preferably 1,700 to 5,800 mg, and more preferably 2,000 to 3,000 mg.

[0028] The timing of administration of the fibrosis inhibitor of the present invention is not particularly limited, and it may be administered before meals, after meals, or between meals, but is preferably administered before meals or between meals. In addition, in order to obtain the effects of the present invention more effectively, it is preferable to administer the agent continuously for 3 weeks or more, preferably 5 weeks or more, and more preferably 7 weeks or more. [Example]

[0029] The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

[0030] 1. Preparation of extract powder The herbal ingredients listed in Table 1 were prepared. The amounts (mg) of each extract powder in Table 1 represent the daily amount, and the amounts (g) of each herb represent the amount of raw herb per day. The extract powders were prepared using the same ratios as in Table 1, in sufficient quantities to allow spray drying of the extract. The herbal ingredients were chopped and mixed, extracted with approximately 20 times the amount of water at approximately 100°C for 30 minutes, and then centrifuged to obtain the extract. The extract was concentrated under reduced pressure and dried using a spray dryer to obtain Bofutsushosan extract powder, Boiyogito extract powder, Daisaikoto extract powder, and Glycyrrhiza extract powder. The spray dryer drying was performed by dropping the extract into an atomizer rotating at 10,000 rpm and supplying hot air at 150°C.

[0031] [Table 1]

[0032] 2. Experimental Method Mice (C57BL / 6J, 6-week-old, female) underwent bilateral ovariectomy (OVX) to mimic menopause, and were maintained on a normal diet for one week after surgery for recovery. After that, they were maintained on a high-fat diet (HFD32, CLEA Japan, Inc.) ad libitum for 10 days to create a menopausal lipofibrosis model mouse.

[0033] Menopausal lipofibrosis model mice were divided into 5 groups (7 mice per group): a non-administration group (control), a bofutsushosan group, a boiyogito group, a daishakoto group, and a kanzo group. The non-administration group (control) was allowed to freely consume a high-fat diet without extract powder for 7 weeks. The bofutsushosan group, the boiyogito group, the daishakoto group, and the kanzo groups were fed the high-fat diet with 4% by weight of the extract powder produced in item 1 above for 7 weeks. No difference in food intake was observed between the groups. After 7 weeks of breeding, adipose tissue was extracted and subjected to HE staining. The HE-stained tissue was photographed under a microscope, and for each group, one screen (649,000 μm) was used. 2 The average area of ​​eosin-stained fibrous tissue in each sample was calculated as the fibrotic area. The analysis results of the fibrotic area are shown in Figure 1.

[0034] As is clear from Figure 1, the fibrosis-inhibiting effect of licorice extract is insufficient at around 10%, while Bofutsushosan and Boiyogi-to, which contain licorice as one of their constituent herbal medicines, as well as Daisaiko-to, showed a remarkable fibrosis-inhibiting effect that was more than twice the effect of licorice extract alone (equivalent to 5g of herbal medicine).

Claims

1. An agent for inhibiting adipose tissue fibrosis containing Boiogito extract.

2. The fibrosis inhibitor according to claim 1, wherein the adipose tissue is adipose tissue of a menopausal woman.

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