JPH11171763A - Agent for treating liver disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an excellent composition capable of treating liver diseases such as hepatitis and hepatic failures and capable of improving, relaxing or recovering the syndromes, abnormalities or complications of fervescence, feeling of fatigue, anorexia, emesis, stomachache, ascites, etc., (excluding hepatic encephalopathy) and slightly producing side effects. SOLUTION: A composition contains valine as an active ingredient, and does quite or substantially not contain an amino acid except the valine as an active ingredient. The composition is used as a medicine or food for treating or preventing the liver diseases.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a composition for treating a liver disease or improving liver function, which comprises valine as an active ingredient and substantially does not contain an amino acid other than valine as an active ingredient. Specifically, a pharmaceutical or food composition containing valine as an active ingredient, which has a therapeutic or ameliorating effect on liver diseases such as acute hepatitis, liver failure, chronic hepatitis, and cirrhosis, and substantially containing no amino acid other than valine as an active ingredient About things.

[0002]

2. Description of the Related Art Conventionally, various amino acid preparations have been used for liver diseases such as liver failure and cirrhosis. For example,
Amino acid preparations such as aminolevan (registered trademark), molyhepamine (registered trademark), aminolevan (registered trademark) EN, hepan (registered trademark) ED, and rebact (registered trademark) granules may cause hepatic disorders associated with liver diseases such as cirrhosis and liver failure. It is used to improve encephalopathy and hypoalbuminemia. However, these amino acid preparations do not directly treat and improve these liver diseases, but rather improve nutritional disorders caused by liver diseases, that is, improve nitrogen metabolism and lower blood ammonia level by correcting imbalance of plasma amino acids. Used in expectation. Moreover, these preparations are a mixture of amino acids, and it is hardly known that a single amino acid improves these liver diseases. On the other hand, Tokubo 57-29
No. 446 describes that L-valine is useful alone as an infusion for the treatment of hepatic encephalopathy, but hepatic encephalopathy is one of the complications that accompanies the deterioration of liver disease. Toxic substances such as ammonia increased in the blood damage the central nervous system and cause various neurological symptoms, which is different from the liver disease according to the present invention. The publication does not suggest that the liver disease itself is directly treated or ameliorated. In fact, in the treatment of hepatic encephalopathy, the current situation is that blood ammonia lowering agents such as lactulose are used,
No case in which a therapeutic agent for liver disease was used for the treatment of hepatic encephalopathy also indicates that the present invention cannot be easily derived from the publication.

[0003] On the other hand, the present inventors first found that valine caused liver damage.
It has been found that it has an action to regenerate hepatocytes after resection of the liver such as cirrhosis, and has reached a patent application (Japanese Patent Application Laid-open No. Hei 8-
No. 67628). Although the publication states that valine is effective in hepatocyte regeneration, valine has hepatitis,
It is neither disclosed nor suggested to be effective for liver diseases such as cirrhosis.

[0004]

However, chronic hepatitis,
Although some drugs are known as remedies for cirrhosis, none of them is satisfactory in terms of efficacy and safety. For example, glycyrrhizin preparations such as minophagen C are used for these liver diseases, but they are mainly used as injections because they are inactivated in the intestine, so that their oral administration cannot be expected to be very effective. Further, as side effects, an increase in blood pressure, hypokalemia, and a tendency to retain water due to sodium retention based on its aldosterone-like action have been reported, and this is a problem particularly in severe liver disorders with ascites or in long-term administration. ing.

Japanese Patent Publication No. 57-29446 discloses that L-valine as a single amino acid is useful for the treatment of hepatic encephalopathy. This is because succinylcoenzyme A, in which valine is a member of the citric acid cycle, is used. It is based on the decrease in ammonia concentration due to decomposition, and is applied only to hepatic encephalopathy where the ammonia concentration in the tissue is extremely high. As mentioned above, hepatic encephalopathy is not a disease of the liver itself, but one of the complications that accompany the deterioration of the liver disease.Therefore, the publication shows that the liver disease itself is directly treated or ameliorated. Not.

[0006]

DISCLOSURE OF THE INVENTION In view of such circumstances, the present inventors have developed a therapeutic agent for liver diseases which is highly effective and has no problem in safety, and is effective not only by injection but also by oral administration. We have been diligently examining, but this time, one kind of amino acid valine contains no amino acids other than valine,
Or, in a form substantially free of amino acids other than valine as an active ingredient, has an excellent ameliorating effect on liver diseases such as liver failure, acute hepatitis, chronic hepatitis, cirrhosis, etc. when administered orally or parenterally, and is safe. The present inventors have found that there is no problem in terms of aspect and completed the present invention.

[0007] The effects of valine on liver disease can be confirmed in liver disease animal models and liver disease patients as shown in the Examples below. Acute hepatitis and liver failure were evaluated using a drug-induced acute liver injury model such as galactosamine and carbon tetrachloride and a 90% hepatectomy liver failure model. Valine was effective in these models using chronic liver injury models. In addition, when administered orally or the like to patients with chronic hepatitis, valine has hepatic function (GOT,
GPT, platelets, etc.). These results indicate that valine is useful as an agent for liver disease in animals including humans.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The valine used in the present invention can be used irrespective of a commercial product, a synthetic product, and other production methods. Further, any of D-form, L-form and DL-form can be used,
In particular, the L-form can be preferably used.

In the present invention, valine can be expected to have a therapeutic or ameliorating effect on various liver diseases such as acute hepatitis, chronic hepatitis, liver failure and cirrhosis, but exhibits particularly excellent therapeutic effects on acute hepatitis, liver failure and the like. Examples of hepatitis that can be expected to have a therapeutic effect include acute and chronic hepatitis caused by hepatitis viruses such as A, B, C, D, and E. Liver failure includes acute liver failure and chronic liver failure. Further, the valine of the present invention improves various symptoms and abnormalities caused by these diseases such as hepatitis and hepatic insufficiency or complications not affected by ammonia concentration, such as fever, malaise, anorexia, vomiting, abdominal pain, ascites and pleural effusion. , Relaxation,
It also has an effect on recovery. Complications listed here do not include hepatic encephalopathy, which is affected by ammonia levels.

When the composition for treating or improving liver disease of the present invention is administered to a living body, it is administered orally or parenterally such as rectally, subcutaneously, intrathecally, intramuscularly, intravenously, intraarterially, transdermally, etc. Although it can be administered orally, it is preferably administered orally or intravenously.

When the valine according to the present invention is administered to a living body, it is preferable that the valine is formulated into an appropriate dosage form and used, for example, tablets, powders, granules, fine granules, pills, capsules, troches, It can be used in formulations such as chewables, solutions, emulsions, suspensions, suppositories, syrups, lotions, ointments, cataplasms and the like. Formulation into these dosage forms can be carried out using appropriate pharmaceutically acceptable carriers, excipients, additives and the like.

A preferred dosage form for intravenously administering the composition for treating or improving liver disease of the present invention is a liquid. For preparing the liquid, for example, purified water, physiological saline, ethanol / propylene glycol / glycerin -It can be carried out using an alcohol such as polyethylene glycol or a solvent such as triacetin. Such formulations may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, and stabilizing agents. It can also be administered as a suspension.

Tablets, pills, powders, granules, fine granules,
For preparing solid preparations such as troches and chewables, for example, carriers such as sodium bicarbonate, calcium carbonate, starch, sucrose, mannitol and carboxymethylcellulose, and additives such as calcium stearate, magnesium stearate and glycerin are added. Can be carried out by a conventional method. Also cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate,
Spraying a solution of an enteric substance such as polyvinyl alcohol phthalate, styrene-maleic anhydride copolymer, methacrylic acid-methyl methacrylate copolymer in an organic solvent or water, spraying an enteric coating and formulating it as an enteric preparation You can also. Pharmaceutically acceptable carriers include other adjuvants, fragrances, stabilizers or preservatives usually used as needed. Further, the composition for treating or improving liver disease of the present invention can be used in combination with an infusion preparation such as a high-calorie infusion preparation, or can be used by adding valine to another infusion preparation.

[0014] The composition for treating or improving liver disease of the present invention can also be applied as a food for improving liver function. in this case,
Use valine directly by adding it to existing foods and beverages, or use valine as gum, candy, jelly, gummy, cookies, biscuits, chocolates and other confectionery,
Soft drinks such as juice, dairy products such as cheese, butter, yogurt, processed agricultural products such as ice cream, ham, processed fish products such as chikuwa, hampon, noodles such as buckwheat, udon,
It can be applied by directly adding to flour processed products such as bread and cakes, canned or seasoned foods such as salt, pepper, sugar and artificial sweeteners, or by mixing and processing valine at the processing stage of these foods . It can also be applied as a drug for specified health use for improving liver function. When adding and mixing valine to food, valine can be used in a solid form such as powder, granules, fine granules, or a liquid form. Further, when valine is processed into food, it can be performed based on a normal food processing method.

The composition for treating or improving liver disease according to the present invention contains valine as an active ingredient and, unlike the conventionally known mixed preparation of other amino acids, contains no amino acid other than valine at all. It does not contain as an active ingredient of a therapeutic agent for liver disease, that is, it does not substantially contain an amino acid other than valine as an active ingredient, and is an excellent solution to the previously feared efficacy and safety issues A composition.

When the composition for treating or improving liver disease of the present invention is used as a medicament, it is used for patients with liver disease such as acute hepatitis, liver failure, chronic hepatitis, and cirrhosis.
Although it depends on the patient's sex, body type, constitution, age, symptoms, dosage form, etc., generally, valine can be appropriately selected as an active ingredient within a range of 0.1 to 300 g, preferably 1 to 100 g per day. The number of times of administration varies depending on the condition of the patient, the dosage form, and the like, but it is appropriate to use once or several times a day.

[0017]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

[0018]

Example 1 Effect on Acute Liver Injury 1) Experimental Method Crj: Donryu male rats of about 8 to 9 weeks of age, about 250 g, were used. During the experiment, rats were allowed to freely ingest feed MF (manufactured by Oriental Yeast) and water. D-Gala
ctosamine.HCl (D-galactosamine hydrochloride; manufactured by Sigma) is dissolved in physiological saline and 1N-NaO
After adjusting to pH 7.0 with H, D-Galactosami
ne (hereinafter, referred to as “galactosamine”) 100 mg
/ Ml solution. Carbon tetrachloride (manufactured by Wako Pure Chemical Industries) is 50% (v
/ V) used as solution. After a 12-hour fast, liver damage was induced in rats by intraperitoneal administration of galactosamine at a volume of 10 ml / kg or subcutaneous administration of a carbon tetrachloride solution at a volume of 4 ml / kg. Immediately thereafter, a catheter was inserted into the right jugular vein under ether anesthesia, and was left in the central vein. The central venous catheter was withdrawn through the subcutaneous space between the scapulas and, after Harness was attached, protected.
After the live coil, Swivel (Bio-Ca
nnula, Biomedica). The rats were transferred to metabolic cages, and the experiment was performed under anesthesia and unrestrained. The experimental solution was pumped at a rate of 100 ml / k.
g / day was set for continuous administration. The administration period of the experimental solution was 1 to 4 days, and the experimental solution group was prepared by adding L-valine to a lactate Ringer solution (Lactec (registered trademark), manufactured by Otsuka Pharmaceutical Co., Ltd.) group (control group) and a valine group (lactate Ringer solution to Lactate Ringer solution) , L-valine concentration was 16.88 g / l, L-Val group). In addition, the untreated group (Non-
treat, NT group) were also set. After the administration of the test solution, the blood was collected from the abdominal aorta under ether anesthesia, and the autopsy was performed, and the liver was collected.

2) Results a) Galactosamine-induced acute liver injury rat model The results are shown in Table 1. Administration of galactosamine caused liver damage in rats, but administration of L-valine improved it. In addition, the Fischer ratio (BCAA)
(Val, Leu, Ile) / AAA (Phe, Ty
r, Trp)) also improved.

[0020]

[Table 1]

B) Rat model of acute liver injury induced by carbon tetrachloride The results are shown in Table 2. Administration of carbon tetrachloride caused liver damage in rats, but administration of L-valine improved it. In addition, the Fischer ratio (BCAA (V
al, Leu, Ile) / AAA (Phe, Tyr, T
rp)) also improved.

[0022]

[Table 2]

[0023]

Example 2 Effect on liver failure 1) Experimental method Crj: Donryu male rats of about 8 to 9 weeks of age and around 250 g were used. During the experiment, rats were allowed to freely ingest feed MF (manufactured by Oriental Yeast) and water. After a 12-hour fast, a catheter was inserted into the right jugular vein under ether anesthesia and placed in the central vein. Subsequently, the method of Gaub et al. (J. Gaub et al., Hepatology, 4, 902).
-904, 1984). The central venous catheter was withdrawn through the subcutaneous space between the scapulas, and after Harness was attached, the protective c
After Oil, Swivel (Bio-Cannul)
a, Biomedica). The rats were transferred to metabolic cages, and the experiment was performed under anesthesia and unrestrained. The experimental solution was continuously administered at a pumping rate of 100 ml / kg / day. Immediately after the hepatectomy, 3 ml of a 20% glucose solution was subcutaneously administered.
% Glucose solution, and then tap water. The experimental solution was administered for 4 days or 6 days.
The experimental liquid group includes a lactate Ringer's solution (Lactec (registered trademark), manufactured by Otsuka Pharmaceutical Co., Ltd.) group (control group) and a valine group (L-valine was added to the lactate Ringer's solution, and the L-valine concentration was 16.88 g / l). L-Val group). In addition, a non-treatment group (Non-treat group, NT
Group) was also set. After the administration of the test solution, the blood was collected from the abdominal aorta under ether anesthesia, and the autopsy was performed, and the liver was collected.

2) Results a) Effect on survival rate in 90% hepatectomy hepatic failure rat model The results are shown in Table 3. Hepatic resection was induced in rats by 90% hepatectomy, and about half of the rats died in 6 days of observation. On the other hand, the survival rate was significantly improved by administration of L-valine for 6 days.

[0025]

[Table 3]

B) Effect on 90% hepatectomy rat model with hepatic failure The results are shown in Table 4. 90% hepatectomy resulted in hepatic failure in rats, which was improved by administering L-valine. In addition, the Fischer ratio (BCAA)
(Val, Leu, Ile) / AAA (Phe, Ty
r, Trp)) also improved.

[0027]

[Table 4]

[0028]

Example 3 Effect on Chronic Liver Injury 1) Experimental Method Crj: Donryu male rats of 8 to 9 weeks of age were used. During the experiment, rats were allowed to freely ingest feed MF (manufactured by Oriental Yeast) and water. Carbon tetrachloride (manufactured by Wako Pure Chemical Industries) is 50% (v
/ V) used as a solution and subcutaneously administered to rats at a dose of 2 ml / kg twice a week for 14 weeks (28 times) to produce a chronic liver injury model. During the experiment for 14 weeks, the experimental feed was fed. For the control group, the rat feed MF was used. For the L-Val group, the rat feed MF was added to the rat feed MF at 3% by weight.
-Feed was fed with valine. In the untreated group (N
On-treat group, NT group) were also set. After completion of the experiment for 14 weeks, blood was collected from the abdominal aorta under ether anesthesia, followed by necropsy, and the liver was collected.

2) Results The results are shown in Table 5. Chronic liver damage was induced in rats by administration of carbon tetrachloride for 14 weeks, and some deaths were observed. On the other hand, administration of L-valine in a diet for 14 weeks improved liver injury.

[0030]

[Table 5]

[0031]

Example 4 Administration of L-valine to patients with chronic hepatitis C
Effect of Oral Administration A chronic hepatitis C patient (female) was orally administered 1 g of L-valine three times a day. This patient had a mean (mean) GOT and GPT for 4 months before taking L-valine.
± SD; average value of four inspections once a month) are 89.0 ± 21.9 IU / l and 91.5 ± 23.1, respectively.
IU / l, but GO for 4 months from the month following the start of taking
The average value of T and GPT (mean ± SD; average value of four inspections once a month) was 68.3 ± 20.4 IU, respectively.
/ L and 73.0 ± 24.3 IU / l, which were significantly (p <0.05, t-test), respectively. An improvement effect was also observed with respect to platelets, and the average value of platelets (mean ± SD; an average of four tests once or once every two months) for 6 months before taking L-valine was 15.7 ± 1.7
(× 10 ⁴ ), but the average value of platelets (mean ± SD; the average of four tests once a month) for 2 months from the month following the start of administration was 20.4 ± 0.9 (× 10 ⁴ ), and increased significantly (p <0.01, t-test). Thus, L-valine was shown to be effective also in chronic hepatitis patients.

[0032]

EFFECTS OF THE INVENTION The composition of the present invention has fewer side effects than conventional drug treatments, and treats liver diseases such as acute hepatitis, liver failure, chronic hepatitis, and cirrhosis, as well as fever and malaise caused by the liver diseases. An excellent composition for treating liver disease or improving liver function, which can improve, alleviate and recover symptoms or abnormalities or complications (excluding hepatic encephalopathy) such as anorexia, vomiting, abdominal pain and ascites.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/00 601 A61K 31/00 601K (72) Inventor Hiromichi Komatsu 14016 Minowa Minamihara, Minowa-cho, Kamiina-gun, Nagano Prefecture Chugai Pharmaceutical Co., Ltd. (72) Inventor Hiroshi Koga 2-9-1 Kyobashi, Chuo-ku, Tokyo Chugai Pharmaceutical Co., Ltd.

Claims (10)

[Claims] 1. A method for treating liver disease or improving liver function, characterized by containing valine as an active ingredient and containing no amino acid other than valine at all, or containing substantially no amino acid other than valine as an active ingredient. Composition. 2. A food composition for improving liver function, comprising valine as an active ingredient and containing no amino acid other than valine at all or substantially containing no amino acid other than valine as an active ingredient. . 3. The composition according to claim 2, which is a functional food. 4. The method according to claim 1, wherein the liver disease is hepatitis.
A therapeutic or ameliorating composition as described. 5. The therapeutic or ameliorating composition according to claim 1, wherein the liver disease is liver failure. 6. The therapeutic or ameliorating composition according to claim 1, wherein the liver disease is cirrhosis. 7. The therapeutic or ameliorating composition according to claim 1, wherein the valine is L-valine. 8. The therapeutic or ameliorating composition according to claim 1, which is an injection. 9. The therapeutic or ameliorating composition according to claim 1, which is an infusion preparation. 10. The therapeutic or ameliorating composition according to claim 1, which is an oral preparation.