JP7780556B2 - 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, daishaikoto, and boiogito as fibrosis inhibitors.

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

Fibrosis not only poses health risks, but can also affect appearance. For example, cellulite is formed when adipose tissue becomes fibrotic. As described in Non-Patent Document 1, cellulite differs from obesity in that it is a skin condition caused by fibrosis and degeneration of adipose tissue, resulting in unevenness of the skin. It is a symptom that differs from obesity in both clinical presentation and pathophysiological perspective.

Ingredients that suppress fibrosis have been reported for the purpose of preventing or improving various symptoms associated with fibrosis. For example, Patent Document 1 describes a fibrosis inhibitor containing, 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

Japanese Patent Application Laid-Open No. 2018-21026

Kampo medicines and herbal medicines are based on traditional Eastern medicine and are primarily intended to improve physical constitution and balance the entire body. Because they use natural herbal medicines, they are psychologically acceptable and have few side effects, making them suitable for a wide range of applications. The inventors therefore focused on licorice, a herbal medicine containing isoliquiritigenin, which has been reported as a component that inhibits fibrosis. However, they faced the problem that the fibrosis-inhibiting effect of licorice extracts was insufficient.

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

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

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 an adipose tissue.
Item 3. The fibrosis inhibitor according to Item 1 or 2, wherein the tissue is adipose tissue of a menopausal woman.

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

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.

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

The active ingredient , Bofutsushosan, is described in "New Guide to General Kampo Prescriptions" (supervised by Yukihiro Goda and Takashi Hakamzuka,
Kampo prescriptions listed 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 include mixed herbs consisting of Angelica Root, Peony Root, Cnidium Rhizome, Gardenia Fruit, Forsythia Fruit, Mentha Root, Ginger Root, Celastrus Root, Safflower Root, Ephedra Root, Rhubarb, Bougainvillea Root, Byakujutsu Root, Platycodon Grandiflorum, Scutellaria Root, Glycyrrhiza Root, Geraniol Rhizome, and Cassia Root. Some letters do not include Byakujutsu Root among the listed herbs (e.g., "Experience Kampo Prescription Quantities Collection," edited by Otsuka Takanori and Yakazu Michiaki, published by Ido no Nihonsha), while others do not include Scutellaria Root (e.g., "Continued Kampo Allergy," edited by Osaka Yomiuri Shimbun, published by Naniwasha). Furthermore, some Bofutsushosan prescriptions include Glehnia Root instead of Bougainvillea Root, and Soujutsu Root instead of Byakujutsu Root.

As for boi-ohgi-to, the 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.) is preferred, and examples include a mixture of herbs consisting of bowi, astragalus, atractylodes, ginger, taiso, and licorice. Furthermore, as stipulated in the "Basic Handling Guidelines for Kampo Preparations" established by the Kampo Herbal Medicine Research Council, boi-ohgi-to also includes the mixture of herbs (Kampo prescriptions) listed in currently commonly used Kampo-related letters.

As for Daisaikoto, the Kampo prescription listed in the "New Guide to General Kampo Prescriptions" (edited by Goda Yukihiro and Hakamazuka Takashi, edited by the Japan Kampo Herbal Medicine Preparation Association, published by Jiho Co., Ltd.) is preferred, and includes a mixture of herbs consisting of Bupleurum Root, Pinellia Root, Scutellaria Root, Phellinus Root, Peony Root, Ginger Root, Chinese Herb, and Rhubarb. Furthermore, as stipulated in the "Basic Handling Guidelines for Kampo Preparations" established by the Kampo Herbal Medicine Research Council, Daisaikoto also includes the mixture of herbs (Kampo prescriptions) listed in currently commonly used Kampo-related letters.

The bofutsushosan extract, boiyogito extract, and daishaikoto extract of the present invention may be obtained as a liquid extract by extracting the above-mentioned mixed herbal medicines and concentrating the resulting extract as needed, or as an extract powder by drying the extract.

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 with an increased extract concentration to produce an adsorbed powder.

The bofutsushosan extract, bofutsushosan extract, and daishaikoto extract used in the present invention may be extracts prepared by the methods described above, or commercially available products may be used. 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" (both manufactured by Alps Pharmaceutical Co., Ltd.). Commercially available products include bofutsushosan extract powder, 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.). Known commercial extract powders of Daisaikoto include 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 (both manufactured by Alps Pharmaceutical Co., Ltd.), and are also available commercially.

In the fibrosis inhibitor of the present invention, the content of bofutsushosan extract, boiyogito extract, and daishaikoto extract is not particularly limited as long as the effects of the present invention are achieved, but can be, for example, 1 to 100% by weight converted into the amount of dry extract. When a dried extract (extract powder) is used, this refers to the amount itself. When a liquid extract 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 amount excludes these additives.

Other Components: The fibrosis inhibitor of the present invention may contain other pharmacological components, if necessary, in addition to the aforementioned herbal medicine. The types of such pharmacological components 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 components may be used alone or in combination of two or more. The content of these pharmacological components may be appropriately determined from known ones depending on the type of pharmacological component used.

The fibrosis inhibitor of the present invention may contain pharmaceutically acceptable bases and additives, as necessary, 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 protection agents, preservatives, flavoring agents, fragrances, powders, thickeners, dyes, and chelating agents. These bases and additives may be used alone or in combination of two or more. The amount of these bases and additives may be appropriately selected from known bases and additives depending on the type of added component and dosage form used.

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. These dosage forms can be prepared using pharmaceutically acceptable bases and additives, and the types and amounts of the bases and additives are well known in the field of formulation technology.

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. The fibrosis inhibitor of the present invention is also used for the purpose of preventing or ameliorating various symptoms caused by fibrosis, taking advantage of its inhibitory effect on fibrosis in these tissues. Examples of such symptoms include cellulite, liver fibrosis/cirrhosis, interstitial pneumonia/pulmonary fibrosis, myocardial fibrosis, and pancreatic fibrosis.

Of the above uses, from the perspective of achieving even more effective fibrosis inhibition, it is preferable that it be used for the purpose of inhibiting adipose tissue fibrosis, specifically for the purpose of preventing or improving cellulite caused by adipose tissue fibrosis (i.e., used as an agent for preventing or improving cellulite).

Furthermore, because 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 developing cellulite due to fat fibrosis.

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, and the like. For example, the daily intake amount (total amount ) may be 400 to 10,000 mg in terms of dry extract. The dry extract amount of bofutsushosan extract may be 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 may be 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 may be 1,300 to 6,000 mg, preferably 1,700 to 5,800 mg, and more preferably 2,000 to 3,000 mg.

There are no particular restrictions on the timing of administration of the fibrosis inhibitor of the present invention, and it may be administered before, after, or between meals, but is preferably administered before or between meals. Furthermore, to better obtain the effects of the present invention, it is preferable to administer the agent continuously for at least 3 weeks, preferably at least 5 weeks, and more preferably at least 7 weeks.

The present invention will be explained in more detail below using examples, but the present invention is not limited to these examples.

1. Preparation of Extract Powders : The herbal raw materials shown in Table 1 were prepared. The amounts (mg) of each extract powder in Table 1 are the daily amounts, and the amounts (g) of each herbal raw material are the amounts per day in terms of the original herbal raw material. In preparing the extract powders, the raw herbal raw materials were prepared in the same proportions as in Table 1, in sufficient quantities to allow spray drying of the extract. The herbal raw materials were chopped and mixed, extracted with approximately 20 times the amount of water at approximately 100°C for 30 minutes, and 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. Drying using a 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) underwent bilateral ovariectomy (OVX) to mimic menopause, and were maintained on a normal diet for one week of recovery after surgery. Subsequently, they were maintained on a high-fat diet (HFD32, CLEA Japan, Inc.) ad libitum for 10 days to create a menopausal lipofibrosis model mouse.

Menopausal lipofibrosis model mice were divided into five groups (7 mice per group): a non-administered group (control), a bofutsushosan group, a boiyogito group, a daishakoto group, and a kanzo group. The non-administered 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 containing 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. HE-stained tissue was photographed under a microscope, and for each group, one screen (649,000 μm ²
The average area of fibrous tissue stained with eosin in each sample was calculated as the fibrotic area. The analysis results of the fibrotic area are shown in Figure 1.

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

Claims (2)

An agent for inhibiting adipose tissue fibrosis containing Boiogito extract. The fibrosis inhibitor according to claim 1 , wherein the adipose tissue is adipose tissue of a menopausal woman.