JP7493936B2 - Fibrosis inhibitors - Google Patents

Description

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

Fibrosis is a phenomenon in which connective tissue accumulates in tissues. For example, if fibrosis progresses in the liver, it can lead to cirrhosis. It is also known that fibrosis can lead to various diseases in organs such as the kidneys, lungs, heart, and pancreas.

Fibrosis not only causes health problems, but can also affect the 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 that occurs when adipose tissue undergoes fibrosis and degeneration, resulting in uneven skin tone, and is a symptom that differs from obesity in terms of clinical features and pathophysiology.

Ingredients that suppress fibrosis have been reported for the purpose of preventing or improving various symptoms related to fibrosis. For example, Patent Document 1 describes a fibrosis inhibitor that contains as an active ingredient a polynucleotide encoding a protein belonging to the Sema6 family or a partial fragment thereof; a protein belonging to the Sema6 family or a partial fragment thereof; or an agonist for a receptor that uses the protein or a partial fragment thereof as a ligand. Non-Patent Document 2 describes that isoliquiritigenin, a component of the herbal medicine 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 2018-21026 A

Kampo and herbal medicines are based on traditional Eastern medicine and are medicines that aim to improve physical constitution and regulate the entire body. They are psychologically acceptable because they use natural herbal medicines, and have a wide range of applications due to their few side effects. The inventors therefore focused on licorice, a herbal medicine that contains isoliquiritigenin, which has been reported as an ingredient that inhibits fibrosis. However, they faced the problem that the fibrosis-inhibiting effect of licorice extracts was insufficient.

The present invention aims to provide a herbal medicine that is effective as a fibrosis inhibitor.

As a result of extensive research, the present inventors unexpectedly discovered that extracts of bofutsushosan and boiyogito, which contain licorice as a constituent herbal medicine, have superior fibrosis-inhibiting effects that surpass those of licorice extract. Furthermore, the present inventors unexpectedly discovered that extracts of daisaikoto also have superior fibrosis-inhibiting effects. The present invention was completed based on these findings and through further research.

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

The present invention provides a herbal medicine that is effective as a fibrosis inhibitor.

1 shows the results of comparing the area of fibrotic parts in adipose tissue when bofu-tsusho-san extract, boi-ogi-to extract, daisai-ko-to extract, or licorice extract was administered to menopausal lipofibrosis model mice with the control.

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

The active ingredient Bofutsushosan is preferably a Kampo prescription described in "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 mixed herbal medicines consisting of Angelica Root, Peony Root, Cnidium Root, Sanshishi, Forsythia Fruit, Mint, Ginger, Cabbage, Scutellaria Baicalensis, Ephedra, Rhizome, Boswellia Scutellaria, Byakujutsu, Platycodon Root, Scutellaria Root, Licorice, Scutellaria Root, and Cassia Root. Some letters do not contain Byakujutsu among the above-mentioned herbal medicines (for example, "Experience Kampo Prescription Quantities Collection," supervised by Otsuka Keisetsu and Yakazu Domyo, published by Ido no Nihonsha), and some do not contain Scutellaria Root (for example, "Continued Kampo Arekore," edited by Osaka Yomiuri Shimbun, published by Naniwasha). Additionally, some Bofu-tsushosan prescriptions contain Glehnia Root instead of Bofu-fu, and some contain Sou-atracto Root instead of Byaku-atracto Root.

As for Boihogito, the Kampo prescription described in the "New Guide to General Kampo Prescriptions" (edited by Goda Yukihiro and Hakamzuka Takashi, edited by the Japanese Kampo Herbal Medicine Preparation Association, published by Jiho Co., Ltd.) is preferable, and examples of the mixed herbs include Bowi, Astragalus Root, Atractylodes Root, Shokyo, Taisou, and Kanzo. In addition, Boihogito includes the mixed herbs (Kampo prescriptions) described in currently widely used Kampo-related letters, as stipulated in the "Basic Handling Guidelines for Kampo Preparations" established by the Kampo Herbal Medicine Investigation Committee.

As for Daisaikoto, the Kampo prescription described in the "New Guide to General Kampo Prescriptions" (supervised by Goda Yukihiro and Hakamzuka Takashi, edited by the Japan Kampo Herbal Medicine Preparation Association, published by Jiho Co., Ltd.) is preferable, and includes a mixture of herbs consisting of Saiko, Pinellia Root, Scutellaria Root, Pheasant's Root, Peony Root, Shokyo, Taisou, and Daio. In addition, Daisaikoto includes the mixture of herbs (Kampo prescriptions) described in currently widely used Kampo-related letters, as stipulated in the "Basic Handling Policy for Kampo Preparations" established by the Kampo Herbal Medicine Investigation Committee.

The bofutsushosan extract, boihogito extract, and daishaikoto extract of 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.

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 the spray drying method and a method in which a suitable adsorbent (e.g., silicic anhydride, starch, etc.) is added to a soft extract with an increased concentration of the extract liquid to produce an adsorbed powder.

The bofutsushosan extract, bofutsushosan extract, and daishaikhoto extract used in the present invention may be an extract prepared by the above-mentioned method, or may be a commercially available product. For example, as extract powder of bofutsushosan, "Bofutsushosan Dried Extract A", "Bofutsushosan Dried Extract AM", "Bofutsushosan Dried Extract E", "Bofutsushosan Dried Extract EM" (all manufactured by Nippon Powder Co., Ltd.), and "Bofutsushosan Dried Extract-C", "Bofutsushosan Dried Extract-F" (all manufactured by Alps Pharmaceutical Co., Ltd.) are known as commercial products and can be obtained commercially. As extract powder of bofutsushosan, Bofutsushosan Dried Extract A and Bofutsushosan Dried Extract AZ (all manufactured by Nippon Powder Co., Ltd.), Bofutsushosan Extract Powder and Bofutsushosan Dried Extract-F (all manufactured by Alps Pharmaceutical Co., Ltd.) are known as commercial products and can be obtained commercially. 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 can be obtained commercially.

In the fibrosis inhibitor of the present invention, the contents of bofutsushosan extract, boiogito 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 converted into the amount of dried extract. When a dried extract (extract powder) is used, the amount converted into the amount of the dried extract itself, and when an extract liquid or soft extract is used, the amount converted into the amount remaining after removing the solvent. In addition, when the dried extract powder contains additives such as adsorbents added during production, the amount is the amount excluding the additives.

Other components The fibrosis inhibitor of the present invention may contain other pharmacological components as necessary, in addition to the above-mentioned herbal medicine. The types of such pharmacological components are not particularly limited, but include, for example, antacids, stomachic agents, digestive agents, 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, menthols, etc. These pharmacological components may be used alone or in combination of two or more. The content of these pharmacological components may be appropriately set from known ones according to the type of pharmacological components to be used, etc.

The fibrosis inhibitor of the present invention may contain pharma- ceutically acceptable bases and additives, etc., as necessary, in order to prepare 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 inhibitors, preservatives, flavorings, fragrances, powders, thickeners, dyes, chelating agents, etc. 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 set from known ones depending on the type of added component used and the dosage form, etc.

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, from the viewpoint of ease of administration, etc., preferred are tablets, granules, and films. 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 formulation technology.

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

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

Furthermore, since the fibrosis inhibitor of the present invention has excellent fibrosis inhibitory ability, the target tissue of 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 cellulite due to fat fibrosis.

Dosage and Usage: The fibrosis inhibitor of the present invention is administered orally. The dosage of the fibrosis inhibitor of the present invention is appropriately set according to the symptoms and age related to fibrosis. For example, the daily intake amount is 400 to 10,000 mg in terms of dry extract amount (total amount), 1000 to 10,000 mg, preferably 2000 to 8000 mg, more preferably 3000 to 7000 mg, and even more preferably 4500 to 6000 mg in terms of dry extract amount of Bofutsushosan extract, 1300 to 6000 mg, preferably 2000 to 4800 mg, more preferably 3000 to 4000 mg in terms of dry extract amount of Boiyogi-to extract, and 1300 to 6000 mg, preferably 1700 to 5800 mg, more preferably 2000 to 3000 mg in terms of dry extract amount of Daisaiko-to extract.

There are no particular limitations on the timing of administration of the fibrosis inhibitor of the present invention, and it may be administered before or after meals, or between meals, but it is preferably administered before or between meals. 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.

The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

1. Preparation of Extract Powder The raw herbs shown in Table 1 were prepared as raw herbs. The amount of each extract powder (mg) in Table 1 is the amount per day, and the amount of each herb (g) is the amount per day in terms of the raw herb. In the preparation of the extract powder, the raw herbs were prepared in the same ratio as in Table 1, and a sufficient amount was prepared to allow spray drying of the extract. The herbs were 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, Boiyogito extract powder, Daisaikoto extract powder, and Glycyrrhiza extract powder. The drying using the spray dryer was performed by dropping the extract into an atomizer rotating at 10,000 rpm and supplying hot air at 150°C.

2. Experimental method Mice (C57BL/6J mice, 6 weeks old, female) were bilaterally ovariectomized (OVX) to reproduce menopause, and were fed a normal diet for one week of recovery after surgery. After that, they were fed a high-fat diet (HFD32, CLEA Japan, Inc.) ad libitum for 10 days to create menopausal lipofibrosis model mice.

Menopausal lipofibrosis model mice were divided into 5 groups (7 mice per group), including a non-administered group (control), a Bofutsushosan group, a Boiyogito group, a Daisaikoto group, and a Kanzo group. The non-administered group (control) was allowed to freely consume high-fat diet without extract powder for 7 weeks. The Bofutsushosan group, the Boiyogito group, the Daisaikoto group, and the Kanzo group 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, the adipose tissue was extracted and HE stained. The HE-stained tissue was photographed under a microscope, and the average area of the fibrous tissue stained with eosin dye in one screen (649,000 μm ² ) for each group was calculated as the fibrosis area. The analysis results of the fibrosis area are shown in FIG. 1.

As is clear from Figure 1, the fibrosis-inhibiting effect of licorice extract is insufficient at about 10%, while Bofutsushosan and Boiogito, which contain licorice as one of their component herbal medicines, and Daisaikoto, showed a remarkable fibrosis-inhibiting effect that was more than double that of licorice extract alone (5 g in herbal medicine equivalent).

Claims (2)

An agent that inhibits adipose tissue fibrosis, containing Daisaikoto extract. The fibrosis inhibitor according to claim 1 , wherein the adipose tissue is adipose tissue of a menopausal woman.