JPH0789865A - Improver for alcoholic liver disorder - Google Patents

Abstract

PURPOSE:To obtain a medicine effective for treating and preventing liver diseases caused by alcohol. CONSTITUTION:This improver for alcoholic liver disorder comprises at least one selected from KAKKON-OUREN-OUGON-TOU comprising root of Pueraria lobata, root of Scutellaria basicalensis, rhizome of Coptis japonia and root of Glyrrhiza glabra, root of Scutellaria basicalensis KEISHIKYOKEIKA- BUKURYU-BYAKUJUTU-TOU comprising root of Paeonia albiflora, rhizome of Atractylodes lancea, rhizome of Zingiber offichinale, Ziziphus jujuba, fungus of Pachyma cocos and root of Glyrrhiza glabra and SAIKATU-KAIKI-TOU comprising root of Pueraria lobata, root of Glyrrhiza glabra, root of Paeonia albiflora, Bupeurum falcatum, root of Scutellaria basicalensis, rhizome of Zingiber offichinale, etc., as an active ingredient.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medicine effective for treating liver diseases caused by alcohol.

[0002]

2. Description of the Related Art Liver diseases have been increasing in recent years, and liver diseases are also said to be a national disease in the 21st century. In particular, alcoholic liver injury has been treated as a representative of liver disease for a long time, but it has been increasing year by year with the recent increase in consumption of alcoholic beverages, and its severe form has been recognized.

[0003] In general, alcoholic liver injury is a disease caused by the intake of a large amount of alcohol. Among them, in alcoholic hepatitis, symptoms of acute liver injury such as jaundice and laboratory findings are shown, and liver histology shows that of hepatocytes. It is known as a liver disease with degeneration / necrosis and neutrophil infiltration. In recent years, it has been proved that not only liver cell destruction / necrosis but also liver cirrhosis are caused by the direct action of alcohol, and the relationship between direct liver toxicity of alcohol and its metabolites and the occurrence of liver cirrhosis is drawing attention.

In the usual alcoholic liver disorder, it is usual to go to a cure by resting and supplementing adequate nutrition including vitamins in addition to alcohol. However, in severe cases of alcoholic hepatitis, such treatment alone cannot often save lives. Therefore, various attempts have been conventionally made for such alcoholic hepatitis. Examples include administration of corticosteroids or glucagon-insulin therapy, but there are consensus on the effectiveness of each, and in general, there are many reports that they are not effective, and there is no definitive effective treatment method. The current situation.

Therefore, there has been a demand for the development of a medicine effective for treating liver diseases caused by alcohol.

[0006] On the other hand, since ancient times, it has been a classic
, Which is widely known in Japan, is used for the following symptoms, but it is effective for alcoholic liver disease. There is no report that it is.

(1) Root Oren-gogonto Acute enteritis, asthma, shoulder aches, toothache, epidemics, hypertension, stomatitis, glossitis, insomnia. (2) Katsushika Keika Keirei Hakushuto Nephritis, nephrosis, whiplash, after sweating, hangover, chronic headache, tinnitus. (3) Saikakatsu-kaiseki-to Cold, bronchitis, pneumonia, pleurisy, pneumonia, epilepsy, neuropathy, hyperacidity, gastric / duodenal ulcer.

[0008]

[Means for Solving the Problems] The inventors of the present invention have conducted extensive studies on various Kampo prescriptions in order to solve the above problems. It was found that Keirei-Baisho-to and Sai-Katsu-Kai-to have an effective effect on the treatment of alcoholic liver injury, and completed the present invention.

[0009] That is, the present invention relates to root-root oren-goto,
It is an alcoholic liver injury ameliorating agent containing as an active ingredient (hereinafter collectively referred to as an active ingredient of the present invention) at least one prescription selected from Keishi-Keikei-Kairei-Shirayu-to and Sai-Katsuka-to.

[0010] The active ingredients of the present invention, which are root-root oren-go-to, keishi-keikei-karei-baku-baku-to or shiba-katsu-ka-to, are slightly different, but the ranges of the herbal medicines are generally as follows. Is.

[Kakkon Hengren Hougoto] Cuckon 5.0-8.0 Ouren 3.0 Augon 3.0 Kanzo 2.0

[Keiedashi Gakkei Karei Hakushokuyu] Peony 3.0-4.0 Taiso 3.0-4.0 Showkyo 1.0-4.0 Bukuro 3.0-4.0 ~ 4.0 Fern 2.0

[Shibatsu and Kashikoto] Kacon 3.0-4.0 Maoh 2.0-3.0 Kanzo 1.0-1.5 Keishi 2.0-3.0 Peony 2.0-3.0 Gourd 0.5-1.5 Psycho 4.0 Hange 3.0-4.0 Awegon 2.0-3.0 Gypsum 5.0-6.0

As the active ingredient of the present invention, at least one prescription selected from the above-mentioned combination of root-root oren-go-to, keishi-keikei-ka-kei-rei-saku-to and shiba-katsu-kaito-wa, or an extract thereof, is used. As an active ingredient, and this may be combined with a known pharmaceutical carrier to prepare a pharmaceutical preparation.

Examples of the extract include various aqueous solvent extracts, and it is preferable to use the water extract. As a specific example of the preparation of the extract, 10 to 10 of the above-mentioned combination of root-root oren-go-to, keishige-keikei-karei-baku-baku-to or shikakatsu-kaiseki-to is used.
Examples include a method of extracting with 20 times the amount of hot water and filtering the obtained extract. This extract is dried if necessary,
It can be used as a dry powder.

Specific examples of the active ingredient of the present invention will be shown and described in detail.

Concrete Example 1 6.0 g of Cuckon, 3.0 g of Coptis, 3.0 of Coptis
g and licorice 2.0 g
140 g of purified water was added to g), and the mixture was heated and extracted at 100 ° C. for 1 hour. The obtained extract was filtered and then spray-dried to obtain 2.5 g of dry extract powder.

Specific Example 2 Peony 4.0 g, Thyroid 4.0 g, Gypsum 1.5 g, Bukyou 4.0 g, Sandalwood 4.0 g
And licorice 2.0 g (Keishi Kakei Karei Shirasuyu: 19.
5 g) was added with 195 g of purified water, and the mixture was heated and extracted at 100 ° C. for 1 hour. The obtained extract was filtered and then spray-dried to obtain 5.0 g of dry extract powder.

Concrete Example 3 4.0 g of Cuckon, 2.5 g of Ephedra, 1.0 of licorice
g, Keishi 2.0g, Peony 2.0g, Ginger 0.5g, Psycho 4.0g, Hange 3.0g, Ougon 2.0g and gypsum 6.0g
Add 270 g of purified water to 7.0 g), and add 1 at 100 ° C.
It was extracted by heating for an hour. The obtained extract was filtered and then spray-dried to obtain 4.0 g of dry extract powder.

Concrete Example 4 600 g of Cuckon, 300 g of Coptis, 300 Coptis
g and licorice 200g (root root orengou hot water: 1.4
14 liters of purified water was added to (kg) and heated to 100 ° C., and then extracted for 1 hour. The obtained extract was centrifuged and the residue was separated to obtain a solution.

This solution was subjected to aseptic clarification filtration with a 0.3 μm membrane filter (manufactured by Toyo Roshi Kaisha, Ltd.). The obtained filtrate was ultrafiltered using a diafilter G-10T (manufactured by Bio Engineering Co., Ltd .: molecular weight cut off 10,000). For this ultrafiltration, a membrane with a diameter of 152 mm was set on the lower surface of a container with an internal volume of 2.0 l and the pressure was 3 kg / cm ^2.
Then, purified water was added as the liquid in the container was concentrated. As a result, an ultrafiltrate was obtained.

Practical Example 5 Peonies 400 g, seaweed 400 g, ginseng 150 g, syrup 400 g, white pearl syrup 400 g
And licorice 200g (Keishi Kakei Karei Shirasuyu: 1.9
5 kg) with 19.5 l of purified water and heated to 100
Extraction was carried out for 1 hour after reaching ° C. The obtained extract was centrifuged and the residue was separated to obtain a solution.

This solution was subjected to aseptic clarification with a 0.3 μm membrane filter (manufactured by Toyo Roshi Kaisha, Ltd.). The obtained filtrate was ultrafiltered using a diafilter G-10T (manufactured by Bio Engineering Co., Ltd .: molecular weight cut off 10,000). For this ultrafiltration, a membrane with a diameter of 152 mm was set on the lower surface of a container with an internal volume of 2.0 l and the pressure was 3 kg / cm ^2.
Then, purified water was added as the liquid in the container was concentrated. As a result, an ultrafiltrate was obtained.

Concrete Example 6 400 g of Cuckon, 250 g of Ephedra, 100 liquorice
g, 200 g of peony, 200 g of peony, 50 g of ginger, 400 g of psyche, 300 g of hanger, 200 g of sardine and 600 g of gypsum (Shibatsu and Hadaito: 2.7
27 l of purified water was added to (kg) and heated to 100 ° C., and then extracted for 1 hour. The obtained extract was centrifuged and the residue was separated to obtain a solution.

This solution was subjected to aseptic clarification filtration with a 0.3 μm membrane filter (manufactured by Toyo Roshi Kaisha, Ltd.). The obtained filtrate was ultrafiltered using a diafilter G-10T (manufactured by Bio Engineering Co., Ltd .: molecular weight cut off 10,000). For this ultrafiltration, a membrane with a diameter of 152 mm was set on the lower surface of a container with an internal volume of 2.0 l and the pressure was 3 kg / cm ^2.
Then, purified water was added as the liquid in the container was concentrated. As a result, an ultrafiltrate was obtained.

Next, the experimental examples will be shown to explain that the active ingredient of the present invention has an effective effect for treating alcoholic liver injury.

Experimental Example 1 (Effect on Alcohol / Pyrazole Hepatitis) About 200 g of Wistar male rats were used as one group, and
The animals were kept on a liquid diet containing alcohol (36% of total calories were alcohol) according to the following classification.

Al alone group (negative control): Alcohol-containing liquid feed to which nothing other than alcohol is added. Al + Py group (positive control): Alcohol-containing liquid feed supplemented with 2 mM pyrazole. Group A: cut obtained in 2mM pyrazole and example 1
Alcohol-containing liquid feed supplemented with root oren gogonto (0.5 g / l). Group B: Keishi obtained in 2mM pyrazole and example 2
An alcohol-containing liquid feed supplemented with Keikei Karei Shirasu-to (1 g / l). Group C: The Shiba obtained in 2mM pyrazole and example 3
Alcohol-containing liquid feed supplemented with Sokaito (0.8 g / l).

In the above 5 groups, the group A is a pilot (pil
group pair feeding (Gr)
Oup Pair-feeding) was performed for 12 weeks. Details of the composition of the liquid feed containing alcohol / pyrazole have been reported previously (Alcoholism: Exp. Cli.
n. Res. , 10: 403, 1986. ).

As a blood biochemical test, blood was collected from the retro-orbital sinus before and every two weeks after breeding, and serum GPT activity, triglyceride, and protein amount were measured over time, and serum transferrin ( The appearance of micro-transfections was also analyzed. After 12 weeks of breeding, the animals were sacrificed by decapitation, and biochemical and histological examinations of serum and liver were performed.

Serum GPT activity was measured by the enzymatic method (Am. J. C.
lin. Pathol. , 28:56, 1957. ) Is used for neutral fat, and the method for the neutral fat is the method of Fletcher et al. (Clin. Chi.
m. Acta, 22: 393, 1968. ) Was used for the measurement. The appearance of small mutations in serum transferrin was confirmed by isoelectric focusing, followed by Western blotting using anti-transferrin antibody (We.
stern blotting method (Nissho 89:14)
07, 1992. ). Serum and liver total protein levels were determined by the Lowry method (J. Biol. Che.
m. , 193: 265, 1951. ), Total liver fat content was extracted with chloroform / methanol, evaporated to dryness by heating, and the weight was measured. The amount of hydroxyproline in the liver can be determined by the method of Kiviriko et al. (Anal. Bi.
ochem. , 19: 249, 1967. ).

For histological examination of the liver, formalin-fixed, paraffin-embedded, HE-stained, Atzan-Mallory (A
Zan-Mallory) staining and silver plating were performed. In addition, with respect to the section after embedding in paraffin, peroxidase (per) using an anti-rat transferrin antibody was used.
Staining with the oxidase) labeling method was also carried out, and the accumulation of transferrin in the liver was also examined (Stain Tec).
hnol. 55: 307, 1980. ).

The results are expressed as the mean value ± standard deviation value, and the test for comparison between the groups is conducted by the Student's Tea Test (Stu).
dent's t test) or χ ² test.

The results obtained in the above experiment will be described in detail below.

Serum GPT The time course of serum GPT is shown in FIG. Al + P
In the y group, a slight increase tendency was observed at 8 weeks, and a clear increase was observed from 10 weeks, but in the groups A, B and C to which the active ingredient of the present invention was added and the Al alone group, G was observed throughout the course.
No clear increase in PT was observed, which was 1 in the Al + Py group.
The values at week 0 and 12 were significantly higher than those of the other 4 groups.

Serum Transferrin Micromutations Serum transferrin micromutations are primarily Al + P
Appeared in group y. When analyzing the appearance situation over time,
As shown in Table 1, in the Al + Py group, micro mutations appeared in more than half of the rats from 8 weeks, and were observed in all rats except one at 12 weeks. On the other hand, it did not appear at all in the Al alone group, and in the group administered with the active ingredient of the present invention, A
1 group every 10 weeks and 2 groups at 12 weeks
Example: Group B (Keiedashi Keikei Karei Shirasuyu) is 12 weeks, 1 case, C
Only one case of transferrin micromutation was observed in 1 group in the group (Saikatsuka-Hadoto) at 12 weeks, and the difference in the appearance frequency was statistically significant.

Table 1 Alcohol / pyrazole hepatitis: Frequency of occurrence of transferrin micromutation in each group (7 animals in each group)

Histological Findings of Liver (Hepatocyte Necrosis, Fat Deposition, Hepatocyte Balloon-like Changes, and Liver Fibrosis) The histological findings of the liver of the Al + Py group were mainly fat deposits in the center of the lobules and the liver. The balloon-like changes in the cells are remarkable,
Hepatocyte necrosis was also observed (Fig. 2). The silver staining revealed thickening of the central vein and fibrosis around it. Further, in some rat livers, formation of a thin fiber bridge between the central vein and the central vein or between the central vein and the portal vein region was observed (FIG. 3). However, in the active ingredient administration groups of the present invention (groups A, B, and C), hepatocyte necrosis and fibrosis were not observed at all, and mild fat deposition and hepatocyte balloon-like changes were observed in some rat livers. And the liver tissue findings were Al.
It was clearly smaller than that in the + Py group (FIGS. 4 and 5). Regarding the degree of hepatocyte necrosis, fat deposition, hepatocyte balloon-like changes, and liver fibrosis, each finding was not observed (-), mildly observed (+), moderate or higher ( When analyzed as ++), as shown in Table 2, hepatocyte necrosis and liver fibrosis were observed only in the Al + Py group. Balloon-like changes in hepatocytes were also observed in all the Al + Py groups, but in the other groups, they were only observed in each one group of the active ingredient administration groups (A, B, C groups) of the present invention. No
The appearance frequency was significantly lower than that of the Al + Py group.

Table 2 Comparison of liver tissue findings in alcohol / pyrazole hepatitis experimental groups (7 animals in each group)

Liver Transferrin Staining Findings Liver transferrin staining findings were found in hepatocytes showing a balloon-like change in the center of the lobules in rats of the Al + Py group, and especially in hepatocytes at the boundary with unchanged hepatocytes. It was strongly stained (Fig. 6). In the active ingredient administration group of the present invention,
Transferrin was mildly stained in one case of group A (Kakkon Orengoto), but transferrin was not stained in all other rats (FIG. 7). The staining of transferrin was determined to be highly stained (+
(+), Lightly stained ones (+), unstained ones (-).
Although highly stained in all cases except one in the y group, one mild case was a case in which the appearance of micromutation in serum was not clear. In the group to which the active ingredient of the present invention was administered, one case of mild staining was observed in group A (Kikone Oren Gogonto), but in this example, a slight mutation of serum transferrin appeared. . However, there was no case of transferrin staining in other rats.

Table 3 Degree of transferrin staining of liver of alcohol-pyrazole hepatitis (7 animals in each group)

Liver Hydroxyproline Amount Regarding liver hydroxyproline amount, Al + Py
In the group, the value was significantly higher (2.25 ± 0.46 μmole) than that in the Al group (1.0 ± 0.2 μmole), but in the three groups to which the active ingredient of the present invention was administered, the negative control Al was used. It showed a slightly higher value than that of the group,
There was no significant difference, and it was a significantly lower value when compared to the Al + Py group (Table 4).

Table 4 Liver hydroxyproline levels in alcohol / pyrazole hepatitis (7 animals in each group)

As is clear from the above results, it was confirmed that the active ingredient of the present invention has an effective effect on the treatment of alcoholic liver injury, especially alcoholic hepatitis.

The active ingredients of the present invention, rooted root oren, hot root, keishi, keikei, karei, bakushuto, and saikatsukaito have a long history as a herbal medicine and their safety has been confirmed. You can use it with confidence because it is a good one. For example, it is extremely safe as it is clear from the fact that no death is observed in the oral administration of 15 g / kg, which is the limit administration, to mice and rats.

Therefore, the active ingredients of the present invention, which are root-root oren-goto, keishi-keikei-karei-bakurei-to, and saikatsu-kaiseki-to, are useful as agents for improving alcoholic liver damage.

Next, the dose and formulation of the active ingredient of the present invention will be described.

The dosage form of the active ingredient of the present invention is not particularly limited and may be appropriately selected and used as needed. Oral preparations such as tablets, capsules, granules, fine granules and powders, injection preparations, Parenteral agents such as suppositories may be mentioned.

In order to exert the intended effect, it depends on the age, body weight and degree of disease of the patient, but usually 2 to 15 g of the active ingredient of the present invention is divided into several times a day in adults. Seems to be appropriate.

The active ingredient of the present invention includes tablets, capsules,
Oral preparations such as granules are produced by a conventional method using starch, lactose, sucrose, mannitol, carboxymethyl cellulose, corn starch, inorganic salts and the like.

In this type of preparation, a binder, a disintegrating agent, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a flavoring agent, etc. may be appropriately used in addition to the above-mentioned excipients. You can
Specific examples of each are as shown below.

[Binder] Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch,
Methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, ethyl cellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose.

[Surfactant] sodium lauryl sulfate,
Soy lecithin, sucrose fatty acid ester, polysorbate 80.

[Lubricant] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.

[Fluidity promoter] Light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The active ingredient of the present invention can also be administered as a suspension, emulsion, syrup or elixir, and these various dosage forms contain a flavoring agent and a coloring agent. Good.

On the other hand, parenteral preparations are manufactured by a conventional method,
Generally, distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol and the like can be used as the diluent. Further, if necessary, a bactericide, a preservative, and a stabilizer may be added. Further, from the viewpoint of stability, this parenteral preparation may be filled in a vial or the like and then frozen, the water content may be removed by a usual freeze-drying technique, and a liquid preparation may be re-prepared from the freeze-dried product immediately before use. Further, an isotonicity agent, a stabilizer, a preservative, a soothing agent and the like may be added as needed.

Next, the present invention will be described in more detail by showing Examples of the preparation of the active ingredient of the present invention, but the present invention is not limited thereto.

Example 1 200 g of root-root oren-gotonto obtained in Example 1 was mixed with 89 g of lactose and 1 g of magnesium stearate,
This mixture is tableted with a single-shot tableting machine to have a diameter of 20 m.
A slug tablet having a particle size of m and a weight of about 2.3 g was prepared, which was crushed by an oscillator, sized, and identified to obtain a good granule having 20 to 50 mesh particles. This granule is taken in a dose of 0.5 to 4.5 g (corresponding to 0.34 to 3.10 g as the dry extract weight of root root oren-goto) three times a day according to the symptoms. .

Example 2 200 g of Keishi-shi Keikarei-Shirayu-to obtained in Example 2 was mixed with 20 g of microcrystalline cellulose and 5 g of magnesium stearate, and the mixture was tableted with a single-shot tableting machine. A tablet having a diameter of 7 mm and a weight of 225 mg was produced. In each of these tablets, 2 dried extracts of Keishi-Keikei Karei-Shirayu-to.
Contains 00 mg. The daily dose of this tablet is 2 depending on the symptoms.
Take ~ 16 tablets 3 times a day.

[Brief description of drawings]

FIG. 1 is a graph showing that the active ingredient of the present invention suppresses elevation of serum GPT level in alcohol-pyrazole hepatitis rats.

[Explanation of symbols]

 ● Group A △ Group C ■ Group B ○ Group Al ★ p <0.01 (7 animals in each group)

FIG. 2 is a photograph showing the liver tissue of alcohol / pyrazole hepatitis rats.

FIG. 3 is a photograph of silver liver staining of alcohol / pyrazole hepatitis rat liver tissue.

FIG. 4 is an HE-stained photograph of liver tissue of rats with alcohol-pyrazole hepatitis improved by the use of root-root orogen-goto.

FIG. 5 is a photograph of silver liver staining of alcohol-pyrazole hepatitis rat liver tissue improved by root-root orogen-goto.

FIG. 6 is a photograph in which liver tissues of alcohol-pyrazole hepatitis rats are stained with transferrin.

FIG. 7 is a photograph of transferrin-stained liver tissue of alcohol-pyrazole hepatitis rats improved with root-root orogen-goto.

Claims (1)

[Claims] 1. An alcoholic hepatitis-improving agent containing, as an active ingredient, at least one prescription selected from Kakkon-enren-go-to, Keishi-geki-ka-rei-shirasu-to, and Shikakatsu-kaito.