JPH0551320A - Medicine for improvement of liver function - Google Patents

Abstract

PURPOSE:To provide a highly safe medicine for improving liver functions containing scymnol sulfate, especially shark liver mainly composed of scymnol sulfate as the active component, showing an effect for preventing hepatopathy and useful as a new medicine and a new food. CONSTITUTION:A medicine for improving liver functions containing scymnol sulfate of the formula (M is cation such as H, Na or Ca) as the active component. The compound of the formula can be obtained, e.g. by extraction and isolation from shark liver and/or cholecyst. Since of the formula or the above- mentioned aqueous extract from shark liver or cholecyst is excellent in solubility in water or ethanol, the resultant medicine for improving liver functions can be used in a form of not only an oral medicine or food but a parenteral medicine such as an injection.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention has a liver function-improving and liver-damaging-preventing effect, which comprises, as an active ingredient, an aqueous extract of shark liver and / or gall bladder, which is mainly composed of cymnol sulfate. It relates to new medicines and foods.

[0002]

2. Description of the Related Art The liver controls various chemical reactions to the extent that they are likened to a chemical factory in the human body, and its serious damage causes a life threat. Most of the causes of liver damage are caused by viruses, but those caused by excessive intake of alcohol are regarded as the most familiar ones.
It is estimated that there are about 1.2 million chronic hepatitis patients in Japan, including those with alcohol. It has been found that most of the hepatitis that has been conventionally called non-A non-B type is caused by the hepatitis C virus. On the other hand, it is estimated that 180,000 patients with acute hepatitis occur each year, of which about 10
About 100% of patients have chronic hepatitis. The number of carriers of hepatitis virus is about 6 million, and the number of carriers of hepatitis B virus is estimated to be 3.1 million. Chronic hepatitis often transforms into liver cancer through cirrhosis, and it is desired to establish a reliable preventive and therapeutic method.

As a therapeutic method for acute cases of liver diseases, resting and supplementation of sugar solution and vitamins are sufficient, but it is obviously effective among preparations marketed as liver protection agents. There is nothing. Among chronic hepatitis, a well-balanced diet of three major nutrients and vitamins is sufficient for those with mild liver function and poor subjective symptoms, but for active chronic hepatitis in which transamylase activity is intense, As in the case of acute hepatitis, in addition to basic treatment such as rest and diet therapy, administration of liver agents, immunosuppressants, and antiviral agents should be carefully considered.

Many drugs have been marketed as general hepatic preparations, but most of them are Kampo preparations, glutathione and SH compounds. Although the double-blind method shows a significant improvement in liver function test values as compared with the control, in the actual clinical setting, its effect is currently questioned. Further, the daily dose of many drugs is several hundred milligrams or more, and its effect specificity is considered to be low. Therefore, development of a liver function improving agent having a novel mechanism of action is strongly desired.

[0005]

Therefore, the present invention is intended to provide a novel agent for improving liver function and preventing liver damage.

[0006]

[Means for Solving the Problems] In order to achieve the above-mentioned object, the present inventors have used ethanol or carbon tetrachloride to cause liver damage in mice, thereby changing biochemical markers in serum. As a result of searching for a liver function-improving agent using the improvement of the value as an index, it was found that the synolsulfate has a very small amount of an excellent liver function-improving action and is highly safe, and completed the present invention.

[0007] That is, the present invention provides a liver function improving agent containing cymnol sulfate as an active ingredient.

[0008] The active ingredient of the liver function-improving agent of the present invention, shiminol sulfate, is a component of shark bile and has the following formula.

[0009]

[Chemical 1]

This Simnolusulfate is special table 2-
It is a compound described in Japanese Patent No. 503554 and already known, which is produced by extracting and isolating from the liver and / or gallbladder of a shark according to the method described in the same publication. In the present invention, the synol sulfate may be pure or a crude product containing the synol sulfate, and may be used in the form of various pharmacologically acceptable salts. Crude products containing Symnol sulphate include, in particular, aqueous extract of liver and / or gall bladder (MDF) of shark, which is prepared, for example, as in the preparations described below.

Regarding the toxicity of symnor sulfate, IC of MDF (symnosulfate content 64%), which is an aqueous extract of liver and gallbladder of shark obtained in the production examples described later, was used.
As a result of an acute toxicity test using R male mice (SPF) (3 weeks old was purchased from CLEA Japan, Inc. and used for the test at 4 to 5 weeks old), the LD ₅₀ value was 570 mg / intraperitoneal administration. k
g, 200 mg / kg by oral administration, and cynomol sulfate has low toxicity.

The liver function-improving agent of the present invention is highly soluble in water and ethanol in an aqueous extract of liver and / or gall bladder of symnosulfate or shark thereof, and therefore, it can be used not only in a pharmaceutical or food form for oral administration, It may be in the form of a parenterally administered drug such as intramuscular injection, subcutaneous injection and intravenous injection.

The form of oral administration is not particularly limited and may be solid or liquid. That is, supplements that are commonly used in the field of medicines and foods such as excipients, carriers, and the like, such as lactose, sucrose, liquid sugar, honey, magnesium stearate, oxypropylcellulose, various vitamins, and cimnol sulfate. Liquids, powders, capsules, tablets, powders, granules, drinks, along with acids, malic acid, flavors, inorganic salts, etc.
It can be formulated into injections, infusions and the like. In addition, it is also possible to make soft drinks, beverages such as juice, coffee, tea and the like, and confectionery such as candy, chewing gum, candy, chocolate, gummy and the like, by using any base commonly used in the food field. Further, it may be an easily soluble agent added to alcoholic beverages and mineral water at the time of use.

The hepatic function-improving agent of the present invention includes functional ingredients known in the art, such as plant lipids, seafood lipids, dietary fibers and various vitamins, to the extent that the effects of the present invention are not impaired. For example, linoleic acid, linolenic acid, dihomo-γ-linolenic acid, eicosapentaenoic acid,
It can contain apple fiber, glycomannan, vitamin A and the like.

In the case of a drink, if desired, other physiologically active ingredients, minerals, vitamins, hormones, nutritional ingredients, flavors and the like can be mixed to give the beverage a personal taste. As a modified example of the drink, it is also possible to take the form of mineral water. Furthermore,
When used as a seamless capsule, the seamless capsule is a preferred form because it can prevent oxidation by oxygen in the air as much as possible and can be taken in an appropriate amount. Seamless capsules are difficult to manufacture because Simnole sulfate is insoluble in edible oil, but after dissolving Simnole sulfate in a small amount of ethanol, it is dissolved in medium-chain fatty acid triglyceride (MCT) which is edible oil and fat. It can be manufactured by using. The dose of the liver function-improving agent of the present invention varies depending on the age, weight, condition, etc. of the administration subject, but as a synolsulfate, it is 0.01 to 100 mg / day, preferably 0.1 to 50 mg / day when orally administered, and particularly Preferably 1-10 mg
/ Day.

Further, the liver function-improving agent of the present invention is effective not only for acute liver injury due to carbon tetrachloride as described below but also for daily administration of ethanol. It is clear that it also has an improving and preventive effect on abnormal lipid metabolism.

[0017]

EXAMPLES Next, examples of producing MDF and examples of the present invention will be described.

Production Example Production of MDF: Rhizoprionod
Gallium bladder (65 g) taken out from 5 animals (40 kg) (on acutus, 8 kg) was homogenized and freeze-dried to obtain 10.3 g of a freeze-dried product. N-hexane 1
Degreasing was performed 3 times with 00 ml to remove lipid as much as possible. Then, the mixture was extracted three times with 100 ml of ethanol and the solvent was removed by a rotary evaporator to obtain 3.7 g of a yellow candy-like substance. Dissolve this in 80 ml of distilled water and use Amberlite XA
It was applied to a D-2 column (3 x 29 cm). Distilled water 400ml
After washing with ethanol, it was then eluted with 400 ml of ethanol.
The ethanol elution fraction was concentrated by a rotary evaporator. Then, it was applied to a Sephadex LH-20 column (3 × 32 cm) and eluted with a mixed solution of chloroform / ethanol (1: 1) (200 ml), and then with ethanol (50 ml). The solvent was removed from the ethanol-eluted fraction with a rotary evaporator to obtain 1.1 g of a candy substance. This product was treated with reverse-phase high performance liquid chromatography (eluent: acetonitrile-sodium phosphate buffer (1: 1)) and fractionated, and the sodium salt of symnol sulfate (symnol sulfate content 64% was prepared by a conventional method. Was obtained as a pale yellow powder.

Example 1 Seven-week-old CDF1 male mice were fed with normal diet (CE-2 for 1 week).
After acclimation with solid feed, CLEA Japan), 7 animals per group,
Divided into 6 groups. Except for the control group, the animals were bred for 7 days in a chamber adjusted to contain 11.5 ppm ethanol in the air. MDF (hygroscopic fine powder, purity about 70%) was dissolved in water and orally administered by gavage every day for 6 days. The doses were set at 0.05, 0.1, 0.5, and 1.0 mg / kg. Food and water were available ad libitum. Body weight was measured every two days. After fasting for 16 hours under 12 ppm ethanol,
Blood was collected from the heart under Nembutal anesthesia (7th day). Put the blood in an Eppendorf tube, leave it for about 30 minutes, and then
Serum was obtained by centrifugation at 00 rpm for 10 minutes. The amount of total cholesterol (T-CHO) and triglyceride (TG) in serum was measured by a biochemical automatic analyzer (Hitachi 7050).
The results are shown in Table 1. By daily inhalation of ethanol,
The amounts of T-CHO and TG in serum were significantly increased as compared with the control group. T-CHO value is MDF0.05mg
At all doses ≥ / kg, its titer was significantly reduced to near the control value. The TG value also decreased depending on the dose of MDF, and its value was significantly decreased at 0.1 mg / kg or more. Further, no decrease in body weight due to MDF administration was observed.

[0020]

[Table 1]

Example 2 Male Wistar rats aged 4 weeks were fed with normal diet (CE) for 1 week.
-2 solid feed, CLEA Japan Co., Ltd.), and after acclimation and breeding, each group consisted of 6 animals and divided into 3 groups. As in Example 1, the control group was removed, and the animals were bred for 8 days in a chamber adjusted to contain 10 ppm of ethanol in the air. MD
F was dissolved in water and was orally forcibly administered at a rate of 1.0 mg / kg daily for 8 days. Food and water were available ad libitum. Body weight was measured every two days. After fasting for 16 hours under 10 ppm ethanol, serum analysis was performed as in Example 1. The analysis items are
Total bilirubin (T-BIL) and triglyceride (TG) in serum. The results are shown in Table 2. T-BIL and TG in serum by daily inhalation of ethanol
The amount was significantly higher than that in the control group. MDF
Administration of (1.0 mg / kg) could significantly reduce the increase in these values caused by inhalation of ethanol.

[0022]

[Table 2]

Example 3 After being fed a normal diet for 1 week as in Example 1, the mice were divided into 5 groups, each group consisting of 7 mice. MDF is 1
It was orally administered at a rate of mg / kg 24, 3 hours before or simultaneously with carbon tetrachloride administration. 1 ml / kg for carbon tetrachloride administration group
Was dissolved in olive oil and administered intraperitoneally. After administration of carbon tetrachloride and fasting for 18 hours, serum analysis was performed in the same manner as in Example 1. The measurement items are glutamate oxaloacetate aminotransferase (GOT), total bilirubin (T
-BIL), T-CHO, and TG. The results are shown in Table 3. GOT and T-BI with carbon tetrachloride
L value was significantly higher than that of control group, but MDF
It could be lowered by administration. Moreover, TG and T-CHO values were significantly decreased by carbon tetrachloride as compared with the control group, but it was possible to recover to near the control value by MDF administration. These effects were most strongly exhibited after 3 hours of pre-administration, but were well observed even after 24 hours of pre-administration except for GOT. This effect was also confirmed by histopathological examination. That is, by the administration of carbon tetrachloride, a large number of so-called balloon-like cells with vacuoles developed appear in the hepatic lobule intermediate zone, but the appearance of these cells is
It was completely suppressed in the MDF administration group.

[0024]

[Table 3]

Example 4 Six-week-old male ICR mice were provided in groups of 10 and a normal diet group, a high cholesterol diet group and an MDF administration group were provided. Sample CE-2 (manufactured by CLEA Japan, Inc.) was added to the normal diet group, a sample having the composition shown in Table 4 to the high cholesterol diet group, and 0.1% of the sample given to the high cholesterol diet group to the MDF administration group. MDF (Symnol sulfate content about 64%)
Were mixed and fed for 13 days. Meanwhile, feed and water were available ad libitum. After fasting for 17 hours on day 14, serum was obtained by heart blood sampling. An automatic analyzer was used for serum analysis. The results are shown in Table 5. Display is mean ± standard deviation,
Student's t-test was used for the significance test.

[0026]

[Table 4]

[0027]

[Table 5]

As is clear from the results in Table 5, the serum GOT and GPT values were significantly decreased in the MDF-administered group mixed with MDF, indicating that liver damage due to high cholesterol diet loading was improved. It was Thus, the substance of the present invention can improve liver damage associated with high cholesterol load.

Formulation Example 1 (drink) Citric acid 120 mg Vitamin C 100 mg MDF 3 mg Perfume 10 ml Taurine 200 mg Valine 10 mg Leucine 10 mg Isoleucine 10 mg Liquid sugar 5 g Water balance The above ingredients are mixed to make 100 ml.

Formulation Example 2 (chewing gum) Gum base 20.00 g Flavor 1.00 g Citric acid 1.00 g MDF 0.003 g Sugar remaining amount 100.00 g

Formulation Example 3 (candy) starch syrup 49.00 g Fragrance 1.00 g MDF 0.003 g Sugar remaining amount 100.00 g

Formulation Example 4 (candy) MDF 0.003g Perfume 0.01g Sorbitol seed 0.05g Powdered sorbitol 50% dextrin blending Total amount 100.00g

Formulation Example 5 (soft drink) Concentrated lemon juice 5.0 g Sodium citrate 0.2 g L-ascorbic acid 0.02 g Flavor 0.01 g Citric acid 0.2 g MDF 0.003 g Carbonated water Total amount 100.00 g

Formulation Example 6 (Juice) Concentrated orange juice 5.0 g Sugar 7.0 g Citric acid 0.2 g L-ascorbic acid 0.02 g Flavor 0.1 g MDF 0.003 g Water remaining total amount 100.00 g

Formulation Example 7 (lactic acid bacterium beverage) Milk solid content 21% Fermented milk 14.76g Fructose-glucose liquid sugar 10.31g Pectin 0.5g Citric acid 0.08g Flavor 0.15g MDF 0.003g Water remaining amount 100.00g

Formulation Example 8 (Chocolate) Cocoa mass 18.00 g Cocoa butter 18.00 g Milk powder 15.00 g Lecithin 0.5 g MDF 0.003 g Sugar total amount 100.00 g

Formulation Example 9 (capsule) Lactose 48 mg Magnesium stearate 2 mg MDF 1 mg Dextrin Residual amount 200 mg or more The amount per capsule. MDF at the above rate
, Lactose and dextrin are mixed, tabletted and then crushed,
Mix magnesium stearate and mix 2 each
No. capsules were filled.

[0038]

INDUSTRIAL APPLICABILITY The liver function-improving agent of the present invention has an effect on acute liver injury due to carbon tetrachloride, liver damage due to ethanol intake and lipid metabolism abnormality, and therefore is effective for improving liver function and preventing liver damage. Is.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Koichi Hirai 1-1-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka Suntory Ltd. Research Laboratories

Claims (2)

[Claims] 1. A liver function-improving agent, which contains Symnol sulfate as an active ingredient. 2. The liver function-improving agent according to claim 1, which contains an aqueous extract of shark liver and / or gall bladder containing cymnol sulfate as a main component as an active ingredient.