JP7846962B2 - Liver function improving agent - Google Patents

Description

This invention relates to a liver function improving agent. More specifically, this invention relates to a traditional Chinese medicine having a liver function improving effect.

The liver is often called a "silent organ" because symptoms don't appear until the disease has progressed significantly. Even if there's a problem with the liver, people often don't notice it until the disease is quite advanced.

According to the "National Survey Results" (Non-Patent Literature 1) published by the Japan Society for Human Dock in 2016, "abnormal liver function" was observed in 33.2% of people who underwent human dock (health checkups), making it the second most common condition after "high cholesterol" (33.4%). The percentage of people with "abnormal liver function" has increased by 10.5 percentage points compared to 20 years ago, affecting 40.2% of men and 22.8% of women. Therefore, the importance of liver function care is increasing.

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

In recent years, novel treatments for liver diseases have been developed based on maintaining and activating PPARα function. For example, Patent Document 5 presents transcriptome analysis of mouse and human livers using a novel PPARα modulator (SPPARMα) K-877, and Patent Document 6 demonstrates the inhibitory effect of PPARα modulator-pemafibrate on hepatitis and liver dysfunction.

National summary 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 Abstracts of the 26th Hepatocyte Research Meeting, 2019.

Because the liver is often called a "silent organ," it is desirable to address liver function decline as early as possible. However, the application of drugs to improve liver function is difficult and not easily accessible.

On the other hand, in today's era of self-medication, herbal medicine is attracting attention as an easily accessible tool for managing one's health. If herbal medicine could be applied to improve liver function, daily liver care would become significantly easier. However, currently, no herbal medicines with pharmacological effects based on factors related to liver function have been scientifically proven.

Therefore, the present invention aims to provide a novel herbal medicine that can improve liver function.

Through diligent research, the inventors discovered that Bofu-tsusho-san extract has a PPARα expression-increasing effect that can improve liver function. This invention was completed based on this finding and further investigation.

In other words, the present invention provides inventions in the following embodiments.
Item 1. A liver function improving agent containing Bofu-tsusho-san extract.
Item 2. A liver function improving agent as described in Item 1, used for metabolizing fat in the liver.
Item 3. A liver function improving agent as described in item 1 or 2, used for subjects with normal ALT levels.
Item 4. An α-type peroxisome proliferator-activated receptor expression enhancer containing Bofu-tsusho-san extract.

According to this invention, a new herbal medicine capable of improving liver function is provided.

The liver function improving agent of the present invention is characterized by containing Bofu-tsusho-san extract. The liver function improving agent of the present invention will be described in detail below.

Active Ingredient The liver function improving agent of the present invention contains Bofu-tsusho-san extract as an active ingredient. According to the "Handbook of General-Use Kampo Prescriptions" (supervised by the Pharmaceutical Affairs Bureau of the Ministry of Health and Welfare, edited by the Kampo Expert Committee of the Japan Pharmaceutical Association, published by Yakugyo Jihosha), the crude drugs that make up Bofu-tsusho-san are Angelica acutiloba, Paeonia lactiflora, Ligusticum chuanxiong, Gardenia jasminoides, Forsythia suspensa, Mentha arvensis, Zingiber officinale, Schizonepeta tenuifolia, Saposhnikovia divaricata, Ephedra sinica, Rheum palmatum, Sodium sulfate, Atractylodes macrocephala, Platycodon grandiflorus, Scutellaria baicalensis, Licorice, Gypsum, and Talc. Some sources do not include Atractylodes macrocephala among the above crude drugs (for example, "Collection of Dosages of Experienced Kampo Prescriptions," supervised by Keisetsu Otsuka and Michiaki Yakazu, published by Ido no Nipponsha), or do not include Scutellaria baicalensis (for example, "Continued Kampo Miscellany," edited by Osaka Yomiuri Shimbunsha, published by Naniwa-sha). Furthermore, depending on the formulation of Bofu-tsusho-san, some contain Hamabofu instead of Byakujutsu, or Soju instead of Byakujutsu. The Bofu-tsusho-san extract that can be used in the present invention may be obtained from any of these Bofu-tsusho-san formulations, but from the viewpoint of obtaining an even higher liver function improving agent, it is preferable that the Bofu-tsusho-san formulation contains Byakujutsu and Ogon.

According to the "Handbook of General Use Kampo Prescriptions" (supervised by the Pharmaceutical Affairs Bureau of the Ministry of Health and Welfare, edited by the Kampo Expert Committee of the Japan Pharmaceutical Association, published by Yakugyo Jihosha), the "17th Revised Japanese Pharmacopoeia," etc., the amounts of each crude drug that make up Bofu Tsusho San are 1.2 parts by weight of Angelica acutiloba, 1.2 parts by weight of Paeonia lactiflora, 1.2 parts by weight of Ligusticum chuanxiong, 1.2 parts by weight of Gardenia jasminoides, 1.2 parts by weight of Forsythia suspensa, 1.2 parts by weight of Mentha arvensis, 0.3 to 1.2 parts by weight of Zingiber officinale, 1.2 parts by weight of Schizonepeta tenuifolia, 1.2 parts by weight of Saposhnikovia divaricata or Saposhnikovia divaricata, 1.2 parts by weight of Ephedra sinica, 1.5 parts by weight of Rheum palmatum, 0.6 to 1.5 parts by weight of Sodium sulfate (anhydrous sodium sulfate equivalent), 2 parts by weight of Atractylodes macrocephala, 2 parts by weight of Platycodon grandiflorus, 2 parts by weight of Scutellaria baicalensis, 2 parts by weight of Glycyrrhiza uralensis, 2 to 3 parts by weight of Gypsum, and 3 to 5 parts by weight of Talc. Furthermore, some letters use 1.5 parts by weight for all of the aforementioned quantities (for example, "Meikai Kampo Hosho," co-authored by Kazuo Nishioka and Shintaro Takahashi, published by Naniwa-sha). Additionally, among the quantities of each crude drug shown in the above letters, the amount of ginger may be 0.6 to 1.5 parts by weight.

The Bofu-tsusho-san extract usable in this invention can be obtained by extracting a mixture of the above-mentioned crude drugs using a known method. For example, one method involves adding approximately 10 to 20 times the amount of water to the crude drug mixture and stirring at approximately 80 to 100°C for 1 to 3 hours for extraction.

The form and shape of the extract obtained from the above-mentioned crude drugs or crude drug preparations are not particularly limited and may be in liquid or viscous form (liquid extract form or soft extract form) containing a solvent, or in a dried form (extract powder form). These forms of extract can be obtained by subjecting the extract obtained by the above extraction method to concentration or drying treatment as needed. Specific drying methods include spray drying, vacuum concentration drying, and freeze-drying. Furthermore, when subjecting to drying treatment (especially spray drying), excipients such as dextrin may be added to the extract as needed.

Other Components The liver function improving agent of the present invention may consist only of the above-mentioned herbal extract, which is the active ingredient, or it may contain additives and bases depending on the formulation. Such additives and bases are not particularly limited as long as they are pharmaceutically acceptable, but examples include excipients, binders, disintegrants, lubricants, isotonic 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, flavoring agents, fragrances, powders, thickeners, pigments, chelating agents, etc. These additives may be used individually or in combination of two or more. The content of these additives and bases is appropriately determined depending on the type of additive and base used, the formulation of the liver function improving agent, etc.

Furthermore, in addition to the above-mentioned herbal extract, which is the active ingredient, the liver function improving agent of the present invention may contain other nutritional and pharmacological components as needed. Such nutritional and pharmacological components are not particularly limited as long as they are pharmaceutically acceptable, but examples include antacids, stomachic agents, digestive agents, intestinal regulators, antispasmodics, mucosal repair agents, anti-inflammatory agents, astringents, antiemetics, antitussives, expectorants, anti-inflammatory enzymes, sedatives, antihistamines, caffeines, cardiotonic and diuretic agents, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, herbal extracts, vitamins, menthols, etc. These nutritional and pharmacological components may be used individually or in combination of two or more. The content of these components will be appropriately determined depending on the type of component used.

Formulation The formulation of the liver function improving agent of the present invention is not particularly limited as long as it can be administered orally, but examples include solid formulations such as powders, fine granules, granules (including dry syrup), tablets, pills, and capsules (soft capsules, hard capsules); semi-solid formulations such as jellies; and liquid formulations such as liquids, suspensions, and syrups. To prepare the liver function improving agent of the present invention in these formulations, the above-mentioned crude drug extract, which is the active ingredient, and additives, bases, and pharmacological components added as needed can be used to formulate the agent according to conventional formulation methods.

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 that can be improved by promoting the expression of PPARα (alpha-type peroxisome proliferator-activated receptor). For example, specific embodiments of liver function improvement include fatty acid metabolism and inflammation suppression in the liver.

The liver function improving agent of the present invention can preferably be used for the purpose of metabolizing hepatic fat. Since metabolizing hepatic fat suppresses the accumulation of fat in the liver, more specifically, the liver function improving agent of the present invention can be used for purposes such as improving fatty liver, suppressing the progression from fatty liver to steatohepatitis or cirrhosis, or suppressing the progression from symptoms that do not reach fatty liver to fatty liver. Here, examples of 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 PPARα expression even in subjects with normal ALT levels (specifically, ALT levels of 30 U/L or less). Therefore, the liver function improving agent of the present invention is also preferably used in subjects with normal ALT levels. Specific examples of when the liver function improving agent of the present invention is used in subjects with normal ALT levels include its use for purposes such as suppressing the progression from symptoms that do not yet lead to fatty liver to fatty liver, and more specifically, its application to individuals who have lifestyle habits that make them prone to developing fatty liver in the future. Examples of lifestyle habits that make individuals prone to developing fatty liver in the future include overeating, alcohol consumption, and maintaining a state of malnutrition (e.g., rapid dieting).

The liver function improving agent of the present invention is applicable to individuals who meet the above examples, including not only obese individuals but also non-obese individuals.

Dosage and Administration The liver function improving agent of the present invention is administered orally. The dosage of the liver function improving agent of the present invention is appropriately set according to the type of active ingredient, the age, sex, and constitution of the recipient, but for example, the total amount of the active ingredient of the liver function improving agent, Bofu-tsusho-san extract, per person per day may be about 1 to 10 g, preferably about 3 to 8 g, more preferably about 4 to 6 g, and taken 1 to 3 times a day, preferably 2 or 3 times. There are no particular restrictions on the timing of administration, and it may be taken before meals, after meals, or between meals, but before meals (30 minutes before a meal) or between meals (2 hours after a meal) is preferred.

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 Bofu-tsusho-san extract The raw crude drugs were used in the following proportions: Angelica root 1.2 (parts by weight, same hereinafter), Peony root 1.2, Ligusticum root 1.2, Gardenia fruit 1.2, Forsythia fruit 1.2, Mentha arvensis 1.2, Zingiber officinale 1.2, Schizonepeta root 1.2, Saposhnikovia root 1.2, Ephedra herb 1.2, Rhubarb 1.5, Anhydrous sodium sulfate 1.5, Atractylodes rhizome 2.0, Platycodon root 2.0, Scutellaria root 2.0, Licorice root 2.0, Gypsum 2.0, and Talc 3.0. After chopping these, they were extracted with 12 times the weight of water at approximately 100°C for 30 minutes, and the extract was obtained by centrifugation. The extract was concentrated under reduced pressure and dried using a spray dryer. The drying process using a spray dryer involved 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, 5 weeks old, male) were fed a high-fat diet (HFD32, CREA Japan Co., Ltd.) ad libitum for 4 weeks and were divided into two groups: a control group and an experimental group (6 mice in each group). These mice showed an increase in white adipose tissue in their internal organs such as the liver, but by shortening the period of feeding on the high-fat diet, their ALT levels were kept normal (no significant difference was observed compared to the group fed with normal feed instead of the high-fat diet). Therefore, although there was an increase in fat in the liver, their ALT levels were still normal and they could be considered a model that had not yet reached fatty liver disease.

In the test group, a diet containing 2% by weight of Bofu-tsusho-san extract was fed for one week. In the control group, a high-fat diet without Bofu-tsusho-san extract was fed for one week.

After one week of feeding, liver tissue was extracted, RNA extraction was performed, and PPARα expression levels were analyzed. The relative expression levels in the test group were calculated by setting the PPARα expression level in the control group to 1. The results are shown in Table 1.

As shown in Table 1, compared to the control group, the expression level of PPARα was significantly increased in the test group administered Bofu-tsusho-san.

Claims (3)

A liver function improving agent containing Bofu-tsusho-san extract, intended for use in patients with increased liver fat and normal ALT levels. A liver function improving agent according to claim 1, used for metabolizing fat in the liver. An α-type peroxisome proliferator-activated receptor expression promoter containing Bofu-tsusho-san extract, intended for use in patients with increased hepatic fat and normal ALT levels.