JP2022094421A - Liver function improver - Google Patents

Abstract

To provide a new Chinese herbal agent that can improve liver functions.SOLUTION: A bofu-tsusho-san extract shows an action of increasing the expression of PPARα, which can improve liver functions, so that the extract is useful as an active ingredient of a liver function improver.SELECTED DRAWING: None

Description

The present invention relates to a liver function improving agent. More specifically, the present invention relates to a Chinese herbal medicine having an effect of improving liver function.

The liver is also said to be a silent organ that does not show symptoms unless the disease progresses, and even if there is an abnormality in the liver, it is not noticed, and when it is noticed, the disease is often quite advanced.

According to the "National Aggregation Results" (Non-Patent Document 1) published by the Japan Society of Human Dock in 2016, "liver dysfunction" was observed in 33.2% of the people who consulted the human dock, and "high cholesterol" (33.4). %) Was followed by many. The number of people with "liver dysfunction" has increased by 10.5 points compared to 20 years ago, and is found in 40.2% of men and 22.8% of women. For this reason, it can be said that the importance of liver function care is increasing.

Peroxisome proliferator receptor (PPAR), which is highly expressed in the liver, is involved in fatty acid metabolism, cell cycle regulation (Non-Patent Document 2), and anti-inflammatory (Non-Patent Documents 3 and 4) in the liver. .. As described in these prior literatures, PPARα is known as a factor associated with liver function.

In recent years, new therapeutic methods for liver diseases have been developed based on the maintenance and activation of PPARα function. For example, Patent Document 5 shows a transcriptome analysis of a novel PPARα modulator (SPPARMα) K-877 in mice and human liver, and Patent Document 6 shows hepatitis / liver dysfunction due to PPARα modulator-pemafibrate. The suppressive effect has been shown.

National tabulation results, Japan Society for Human Dock, 2016 Carcinogenesis 19: 1989-1994, 1998 Curr Opin Lipidol 10: 151-159, 1999 J BiolChem 275: 36703-36707,2000 The Lipid Vol.27 No.4, 23-32, 2016 Abstract of the 26th Hepatocyte Study Group, 2019

Since the liver is called a silent organ, it is desirable to take care of the deterioration of liver function at the earliest possible stage. However, the application of therapeutic agents for improving liver function has high hurdles and cannot be easily selected.

On the other hand, in the age of self-medication, Chinese herbs are attracting attention as an easily usable physical condition management tool. If Kampo can be applied to improve liver function, it will be much easier to take care of liver function on a daily basis. However, there are currently no known Chinese herbs that have been demonstrated to have pharmacological effects based on factors related to liver function.

Therefore, an object of the present invention is to newly provide a Chinese herbal medicine capable of improving liver function.

As a result of diligent studies by the present inventors, it was found that Bofutsushosan extract has an action of increasing PPARα expression that can improve liver function. The present invention has been completed by further studies based on such findings.

That is, the present invention provides the inventions of the following aspects.
Item 1. A liver function improving agent containing Bofutsushosan extract.
Item 2. Item 2. The liver function improving agent according to Item 1, which is used for metabolizing liver fat.
Item 3. Item 2. The liver function improving agent according to Item 1 or 2, which is used for a subject having a normal ALT value.
Item 4. An α-type peroxisome proliferator-activated receptor expression promoter containing Bofutsushosan extract.

According to the present invention, a Chinese herbal medicine capable of improving liver function is newly provided.

The liver function improving agent of the present invention is characterized by containing bofutsushosan extract. Hereinafter, the liver function improving agent of the present invention will be described in detail.

Active ingredient The liver function improving agent of the present invention contains bofutsushosan extract as an active ingredient. According to the "Guide to Prescription of Chinese Medicine for General Use" (supervised by the Pharmaceutical Affairs Bureau of the Ministry of Health, edited by the Japan-Yakuren Chinese Medicine Expert Committee, published by Yakuhin Jihosha), the crude drugs that make up Bofutsushosan are Touki, Shakuyaku, and Senkyu. Sanshishi, Forsythia, Hakka, Shokyo, Schizonepeta, Siler, Maou, Daiou, Bosho, Byakujutsu, Kikyo, Ogon, Licorice, Sekko, and Kaseki. Some letters do not include the herbal medicines (for example, "Experienced Chinese Medicine Prescription Amount Collection", Keisetsu Otsuka / Domei Yakazu, published by the Japanese company of Ido), and those that do not contain Atractylodes (for example, "" There is a series of Chinese herbal medicines, edited by Osaka Yomiuri Shimbun, published by Naniwasha). In addition, some prescriptions of Bofutsushosan contain Hamaboufu instead of Bowfu, and some contain Sojutsu instead of Byakujutsu. The bofutsushosan extract that can be used in the present invention may be obtained from any of these bofutsushosan, but from the viewpoint of obtaining a higher liver function improving agent, bofutsushosan is used. It is preferable that the formulation contains Byakujutsu and Scutellaria baicalensis.

The amount of each crude drug that makes up Bofutsushosan is "Guide for General Chinese Medicine Prescription" (supervised by the Pharmaceutical Affairs Bureau of the Ministry of Health and Welfare, edited by the Japan-Yakuren Chinese Medicine Expert Committee, published by Yakuhin Jihosha), "17th Amendment Japan". According to "Pharmaceuticals", 1.2 parts by weight of Touki, 1.2 parts by weight of Shakuyaku, 1.2 parts by weight of Senkyu, 1.2 parts by weight of Sanshishi, 1.2 parts by weight of Renkyo, 1.2 parts by weight of Hakka, 0.3 to 1.2 parts by weight of Shokyo, 1.2 parts by weight of Keigai, 1.2 parts by weight of Siler or 1.2 parts by weight of Hamaboufu, 1.2 parts by weight of Maou, 1.5 parts by weight of Daiou, Bowsho (sulfuric acid) Sodium anhydride equivalent amount) 0.6 to 1.5 parts by weight, 2 parts by weight of Byakujutsu, 2 parts by weight of Kikyo, 2 parts by weight of Ogon, 2 parts by weight of Kanzo, 2 to 3 parts by weight of Sekko, and 3 to 5 parts by weight of Kaseki Is. In addition, depending on the letter, 1.2 parts by weight of the above amount may be 1.5 parts by weight (for example, "Meikyou Kampo Prescription", co-authored by Kazuo Nishioka and Shintaro Takahashi, published by Naniwasha). Further, among the amounts of each crude drug shown in the above letter, the amount of ginger may be 0.6 to 1.5 parts by weight.

The bofutsushosan extract that can be used in the present invention can be obtained by extracting a crude drug formulation containing the above crude drugs by a known method. For example, a method of adding about 10 to 20 times the amount of water to the crude drug formulation and stirring at about 80 to 100 ° C. for about 1 to 3 hours for extraction can be mentioned.

The form and shape of the extract extracted from the above crude drug or crude drug formulation are not particularly limited, and may be either a liquid or viscous form containing a solvent (extract form or soft extract form) or a dry form (extract powder form). May be. The extracts in these forms can be obtained by subjecting the extract obtained by the above extraction method to a concentration treatment or a drying treatment, if necessary. Specific methods of the drying treatment include spray drying, vacuum concentration drying, freeze drying and the like. Further, when subjected to a drying treatment (particularly, a drying treatment by spray drying), an excipient such as dextrin may be added to the extract, if necessary.

Other Ingredients The liver function improving agent of the present invention may consist only of the above-mentioned crude drug extract as an active ingredient, or may contain additives and bases according to the pharmaceutical form. Such additives and bases are not particularly limited as long as they are pharmaceutically acceptable, but for example, excipients, binders, disintegrants, lubricants, tonicity agents, plasticizers, etc. Dispersants, emulsifiers, solubilizers, wetting agents, stabilizers, suspending agents, pressure-sensitive agents, 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, emulsifiers, fragrances, powders, Examples include thickeners, pigments, chelating agents and the like. These additives may be used alone or in combination of two or more. The contents of these additives and bases are appropriately set according to the types of additives and bases to be used, the form of the hepatic function improving agent, and the like.

Further, the liver function improving agent of the present invention may contain other nutritional components and pharmacological components, if necessary, in addition to the above-mentioned crude drug extract which is an active ingredient. Such nutritional components and pharmacological components are not particularly limited as long as they are pharmaceutically acceptable, but for example, antihypertensive agents, stomachic agents, digestive agents, intestinal regulators, antispasmodics, mucosal repair agents, antiinflammatory agents, and astringents. Agents, antiemetics, antitussives, expectorants, anti-inflammatory enzyme agents, sedative hypnotics, antihistamines, caffeines, cardiotonic diuretics, antibacterial agents, vasoconstrictors, vasoconstrictors, local anesthetics, crude drug extracts, vitamins, menthol Kind and the like. These nutritional components and pharmacological components may be used alone or in combination of two or more. Further, the content of these components is appropriately set according to the type of the component to be used and the like.

Pharmaceutical form The pharmaceutical form of the hepatic function improving agent of the present invention is not particularly limited as long as it can be orally administered, but for example, powders, fine granules, granules (including dry syrup), tablets, and capsules. , Solid formulations such as capsules (soft capsules, hard capsules); Semi-solid formulations such as jelly; Liquid formulations such as liquids, suspensions and syrups. In order to prepare the hepatic function improving agent of the present invention in these pharmaceutical forms, the above-mentioned crude drug extract as an active ingredient and additives, bases and pharmacological components added as necessary are used as usual. It may be formulated according to the formulation method.

Uses The liver function improving agent of the present invention is used for the purpose of improving liver function. Liver function is not particularly limited as long as it is a function improved by promoting the expression of PPARα (α-type peroxisome proliferator-activated receptor). For example, specific aspects of improving liver function include fatty acid metabolism and inflammation suppression in the liver.

The liver function improving agent of the present invention can be preferably used for the purpose of metabolizing liver fat. Since the accumulation of fat in the liver is suppressed by metabolizing the fat in the liver, more specifically, the liver function improving agent of the present invention improves fatty liver and progresses from fatty liver to fatty hepatitis or liver cirrhosis. It can be used for the purpose of suppressing the progression of fatty liver from a symptom that does not lead to fatty liver. Here, examples of the above-mentioned fatty liver include alcoholic fatty liver and non-alcoholic fatty liver (non-alcoholic fatty liver [NAFL], non-alcoholic fatty liver disease [NAFLD]).

The liver function improving agent of the present invention can promote the expression of PPARα even in a subject having a normal ALT value (specifically, an ALT value of 30 U / L or less). Therefore, the liver function improving agent of the present invention is preferably used for a subject having a normal ALT value. Specific examples of the case where the liver function improving agent of the present invention is used for a subject with normal ALT include the case where it is used for the purpose of suppressing the progression from the above-mentioned symptoms that do not lead to fatty liver to fatty liver. More specifically, it may be applied to a person who has a lifestyle that is likely to cause fatty liver in the future. Examples of lifestyles of people who are prone to fatty liver in the future include overeating, alcohol intake, and maintenance of malnutrition (for example, rapid dieting).

The person to which the liver function improving agent of the present invention is applied includes not only obese people but also non-obese people if the above example applies.

Dosage and Usage The liver function improving agent of the present invention is used by oral administration. The dose of the liver function improving agent of the present invention is appropriately set according to the type of the active ingredient, the age, sex, constitution, etc. of the subject to be administered. The total amount of Bofutsushosan extract, which is the active ingredient of the agent, is, for example, about 1 to 10 g, preferably about 3 to 8 g, more preferably about 4 to 6 g, 1 to 3 times a day, preferably 2 Alternatively, it may be taken 3 times. The timing of administration is not particularly limited and may be before meals, after meals, or between meals, but it is preferably before meals (30 minutes before meals) or between meals (2 hours after meals).

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

(1) Preparation of Bofutsushosan extract As raw material crude drugs, Touki 1.2 (part by weight, same below), Shakuyaku 1.2, Senkyu 1.2, Sanshishi 1.2, Renkyo 1.2, Hacka 1.2 , Shokyo 1.2, Keigai 1.2, Bowfu 1.2, Maou 1.2, Daiou 1.5, Sodium Sulfate Anhydrous 1.5, Byakujutsu 2.0, Kikyo 2.0, Ogon 2.0, It was used at a ratio of Kanzo 2.0, Sekko 2.0 and Kaseki 3.0, and after chopping these, it was extracted with 12 times the weight 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. 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, 5 weeks old, male) were bred by free feeding of a high-fat diet (HFD32, Nippon Claire Co., Ltd.) for 4 weeks, and were bred in two groups (control group and test group). Each group was divided into 6 animals). While these mice have an increased amount of white fatty tissue in the internal organs such as the liver, the ALT value is normal by shortening the feeding period of the high-fat diet (feeding a normal feed instead of the high-fat diet). It can be said that the model has an increase in fat in the liver, but the ALT is still normal and has not reached fatty liver.

In the test group, a feed containing bofutsushosan extract in an amount of 2% by weight was fed for one week to the high-fat diet. In the control group, a high-fat diet containing no bofutsushosan extract was fed for one week.

After feeding for one week, the liver tissue was excised, RNA was extracted, and the expression level of PPARα was analyzed, and the expression level of PPARα in the control group was set to 1, and the relative value of the expression level of PPARα in the test group was derived. The results are shown in Table 1.

As shown in Table 1, the expression level of PPARα was significantly increased in the test group to which Bofutsushosan was administered as compared with the control group.

Claims (4)

A liver function improving agent containing Bofutsushosan extract. The liver function improving agent according to claim 1, which is used for metabolizing liver fat. The liver function improving agent according to claim 1 or 2, which is used for a subject having a normal ALT value. An α-type peroxisome proliferator-activated receptor expression promoter containing Bofutsushosan extract.