JP2024028682A - Fibrogenesis inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: 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

COPYRIGHT: (C)2024,JPO&INPIT

Description

TECHNICAL FIELD The present invention relates to a fibrosis inhibitor. More specifically, the present invention relates to a new use of Bofutsushosan, Daisaikoto, and Hokiokito as fibrosis inhibitors.

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

Fibrosis not only causes health problems, but can also affect appearance. For example, when adipose tissue becomes fibrotic, cellulite is formed. As described in Non-Patent Document 1, unlike obesity, cellulite is a skin condition in which adipose tissue undergoes fibrosis and degeneration, resulting in uneven skin. It is also a different symptom from obesity from a physical perspective.

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 that 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 whose ligand is the protein or a partial fragment thereof; A fibrosis inhibitor contained as a component is described. Non-Patent Document 2 describes that isoliquiritigenin, a component of the crude drug licorice, acts on adipocytes and suppresses fibrosis.

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

JP 2018-21026 Publication

Chinese herbal medicine and herbal medicine preparations are medicines that focus on improving the constitution and regulating the entire body, based on ideas based on ancient Oriental medicine, and because they use natural herbal medicines, they are easily accepted psychologically and have fewer side effects. It has a wide range of applications. Therefore, the present inventors focused on licorice, a crude drug containing isoliquiritigenin, which has been reported as a component that suppresses fibrosis. However, we encountered the problem that the fibrosis inhibiting effect of the licorice extract was insufficient.

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

As a result of intensive studies, the present inventor unexpectedly discovered that the extracts of Bofutsushosan and Bokiokito, which contain licorice as a constituent herbal medicine, have an excellent fibrosis-inhibiting effect that exceeds that of licorice extract. Furthermore, the present inventor unexpectedly discovered that the extract of Daisaikoto also has an excellent fibrosis-inhibiting effect. The present invention was completed through 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, Bokikokito 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 3. 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 herbal medicine effective as a fibrosis inhibitor is provided.

Comparison of the area of fibrotic parts in adipose tissue when Bofutsushosan extract, Hokikoto extract, Daisaikoto extract, or licorice extract was administered to menopausal fat fibrosis model mice compared to controls. The results are shown below.

The fibrosis inhibitor of the present invention is characterized in that it contains Bofutsushosan extract, Bokiokito extract, and/or Daisaikoto extract.

The active ingredient Bofutsushosan is published in the ``New General Chinese Herbal Prescription Guide'' (supervised by Yukihiro Goda and Takashi Hakamazuka).
Preferably, the Chinese herbal formulas listed in the Japanese Herbal Medicine Preparation Association (edited by the Japan Traditional Chinese Medicine Preparation Association, published by Jiho Co., Ltd.) are preferred, including Chinese herbal medicine, peony, nebula, sorghum, forsythia, mentha, ginger, staghorn, forsythia, ephedra, rhubarb, sagebrush, sandalwood, and bellflower. A mixed herbal medicine consisting of , scutellariae, licorice, gypsum, and kasseki is included. Depending on the letter, some of the above-mentioned herbal medicines do not contain sandalwood (e.g., "Experienced Traditional Chinese Medicine Prescription Quantity Collection," edited by Keisetsu Otsuka and Michiaki Yakazu, published by Ido Nippon Sha), and others do not contain scutellariae (e.g., There is a book titled ``Zoku Kanpo Various Things'' (edited by Osaka Yomiuri Shimbun, published by Naniwasha). Additionally, some formulations of Bofutsushosan include hamabofu instead of bofu, and others include soujutsu instead of byakujutsu.

As Boki-okito, it is preferable to use the Chinese herbal prescriptions listed in the "New General Chinese Herbal Prescription Guide" (supervised by Yukihiro Goda and Takashi Hakamazuka, edited by the Japan Traditional Chinese Herbal Medicine Preparation Association, published by Jiho Co., Ltd.). , jutsu, ginger, licorice, and licorice are mixed herbal medicines. In addition, Bokiokito contains the mixtures listed in the letters related to herbal medicines that are currently frequently used, as stipulated in the "Basic Handling Policy for Chinese Herbal Preparations" established by the Kampo Herbal Medicine Investigation Committee. Includes crude drugs (Chinese herbal prescriptions).

As Daisaiko-to, it is preferable to use the Chinese herbal prescriptions listed in the "New Guide to General Chinese Herbal Prescriptions" (supervised by Yukihiro Goda and Takashi Hakamazuka, edited by the Japan Traditional Chinese Herbal Medicine Preparation Association, published by Jiho Co., Ltd.), including Saiko, Hange, Ogon. Examples include mixed herbal medicines consisting of pheasant, peony, ginger, turmeric, and rhubarb. In addition, Daisaikoto contains mixed herbal medicines listed in letters related to herbal medicines that are currently in frequent use, as stipulated in the "Basic Handling Policy for Kampo Preparations" established by the Kampo Herbal Medicine Investigation Committee. Chinese herbal prescriptions) are included.

In the present invention, Bofutsushosan extract, Bokiokito extract, and Daisaikoto extract are obtained by extracting the above-mentioned mixed herbal medicines and concentrating the obtained extract liquid as necessary. Alternatively, it may be obtained as an extract powder by drying the extract liquid.

In the production of Bofutsushosan extract, Bokiokito extract, and Daisaikoto extract, the extraction solvent used in the extraction process is not particularly limited, but water or aqueous ethanol can be mentioned as an example. The drying process is not particularly limited, and may be performed using a known method such as spray drying, or by adding an appropriate adsorbent (for example, silicic anhydride, starch, etc.) to a soft extract with increased concentration of the extract liquid. Examples include a method of making an adsorbed powder.

As the Bofutsushosan extract, Bokiokito extract, and Daisaikoto extract used in the present invention, extracts prepared by the above-mentioned method may be used, or commercially available ones may be used. . For example, the extract powder of Bofutsushosan is ``Bofutsushosan dried extract A'', ``Bofutsushosan dried extract AM'', ``Bofutsushosan dried extract E'', and ``Bofutsushosan dried extract EM''. ” (all manufactured by Nippon Powder Co., Ltd.), “Bofutsusho Sanryo Dry Extract-C” and “Bofutsusho Sanryo Dry Extract-F” (both manufactured by Alps Yakuhin Kogyo Co., Ltd.), etc. known and commercially available. Examples of the extract powder of Hoki-okito include Hoki-okito dry extract A and Boki-okito dry extract AZ (both manufactured by Nippon Powder Co., Ltd.), Boki-okito extract powder and Boki-ko. Daito Dry Extract-F (all manufactured by Alps Yakuhin Kogyo Co., Ltd.) and the like are known as commercial products and can also be obtained commercially. Daisaikoto dry extract powder includes Daisaikoto dry extract AM, Daisaikoto dry extract SN, Daisaikoto dry extract powder (all manufactured by Nippon Powder Co., Ltd.), Daisaikoto dry extract F, and Daisaikoto dry extract powder. Koto Dry Extract-F (all manufactured by Alps Yakuhin Kogyo) and the like are known as commercial products and can also be obtained commercially.

In the fibrosis inhibitor of the present invention, the content of Bofutsushosan extract, Bokiokito extract, and Daisaikoto extract is not particularly limited as long as it achieves the effects of the present invention, but in terms of dry extract amount, for example, Examples include 1 to 100% by weight. The term "converted amount of dry extract" refers to the amount itself when using a dry extract (extract powder), and when using an extract liquid or soft extract, it refers to the amount converted to the remaining amount after removing the solvent. Moreover, when the dry extract powder contains additives such as adsorbents added during production, the amount is the amount excluding the additives.

Other Ingredients The fibrosis inhibitor of the present invention may contain other pharmacological ingredients in addition to the above-mentioned Chinese herbal medicine, if necessary. The types of such pharmacological ingredients 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, and anti-inflammatory agents. Enzymes, sedative-hypnotics, antihistamines, caffeine, cardiotonic diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, herbal medicines, herbal extract powders, vitamins, menthol, etc. These pharmacological ingredients may be used alone or in combination of two or more. Moreover, the content of these pharmacological components may be appropriately set from known ones depending on the type of pharmacological components to be used.

The fibrosis inhibitor of the present invention may contain a pharmaceutically acceptable base, additives, etc., as necessary, in order to prepare it into a desired dosage form. Such bases and additives include, for example, excipients, binders, disintegrants, lubricants, tonicity agents, plasticizers, dispersants, emulsifiers, solubilizers, wetting agents, and stabilizers. agents, suspending agents, adhesives, coating agents, brightening 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, ultraviolet 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. Moreover, the contents of these base materials and additives may be appropriately set from known ones depending on the type of additive components used, the dosage form, etc.

Dosage form The 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 films are preferred from the viewpoint of ease of administration. 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.

Applications The fibrosis inhibitor of the present invention is used for the purpose of suppressing fibrosis in tissues. Tissues to which the fibrosis inhibitor of the present invention is applied are not particularly limited, and include adipose tissue, liver tissue, kidney tissue, lung tissue, heart tissue, pancreatic tissue, and the like. The fibrosis inhibitor of the present invention is also used for the purpose of preventing or ameliorating various symptoms caused by fibrosis by utilizing its effect of inhibiting 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, it is used for the purpose of suppressing fibrosis of adipose tissue, specifically for preventing cellulite caused by fibrosis of adipose tissue, from the viewpoint of obtaining an even better fibrosis suppressing effect. It is preferably used for the purpose of improvement (that is, used as a preventive or improving agent for cellulite).

Furthermore, since the fibrosis inhibitor of the present invention has excellent fibrosis inhibitory ability, the target tissues of the fibrosis inhibitor of the present invention are those in middle age (for example, between 45 and 55 years old) when fibrosis is more likely to occur. ) is preferable, and more preferably adipose tissue from menopausal women who are prone to cellulite due to fat fibrosis.

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 symptoms related to fibrosis, age, etc. For example, the daily intake amount is 400 to 10,000 mg in terms of dry extract amount (total amount), and 1,000 to 10,000 mg, preferably 2,000 to 8,000 mg, more preferably 2,000 to 8,000 mg in terms of dry extract amount of Bofutsushosan extract. Examples include 3000 to 7000 mg, more preferably 4500 to 6000 mg, and examples include 1300 to 6000 mg, preferably 2000 to 4800 mg, more preferably 3000 to 4000 mg, in terms of dry extract amount of Boba Okito extract. The amount of hot water extract in terms of dry extract amount is 1300 to 6000 mg, preferably 1700 to 5800 mg, and more preferably 2000 to 3000 mg.

The timing of taking the fibrosis inhibitor of the present invention is not particularly limited, and may be taken before meals, after meals, or between meals, but preferably before meals or between meals. Furthermore, in order to better obtain the effects of the present invention, it is preferable to take the drug continuously for 3 weeks or more, preferably for 5 weeks or more, and more preferably for 7 weeks or more.

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

1. The crude drugs shown in Table 1 were prepared as crude drugs for preparing the extract powder. 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 equivalent amount of the crude drug per day. A sufficient amount of the extract liquid to be spray-dried was prepared and used at the same ratio as in Table 1. 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, Bokiokito extract powder, Daisaikoto extract powder, and Licorice extract powder. Note that drying with a spray dryer was performed by dropping the extract into an atomizer with a rotational speed of 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 simulate menopause, and were fed normal food during the 1-week recovery period after the surgery. Thereafter, the mice were fed ad libitum with a high-fat diet (HFD32, Nippon CLEA Co., Ltd.) for 10 days to produce a menopausal fat fibrosis model mouse.

Menopausal fat fibrosis model mice were divided into a total of 5 groups (7 mice per group): non-administration group (control), Bofutsushosan group, Hobakokito group, Daisaikoto group, and Licorice group. The non-administered group (control) was allowed to freely consume a high-fat diet containing no extract powder for 7 weeks. In the Bofutsushosan group, Bokiokito group, Daisaikoto group, and Licorice group, feed containing the extract powder prepared in item 1 above at 4% by weight was fed to the high-fat diet for 7 weeks. did. Furthermore, no difference in food intake was observed between the groups. After 7 weeks of rearing, adipose tissue was removed and HE stained. The HE-stained tissue was photographed using a microscope, and one screen (649,000 μm ²
The average value of the area of fibrous tissue stained with eosin dye in ) was derived as the fibrosis area. The analysis results of the fibrosis area are shown in Figure 1.

As is clear from Figure 1, the fibrosis inhibiting effect of licorice extract is only about 10%, which is insufficient. In addition, a remarkable fibrosis-inhibiting effect was observed, which was more than double the effect of licorice extract alone (5g in crude drug equivalent).

Claims (3)

A tissue fibrosis inhibitor that contains Hokiokito 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.