KR20110074945A - Therapeutic agent for liver disease and hepatic function-ameliorating agent - Google Patents

Abstract

It is an object of the present invention to provide an agent for treating liver disease that has few side effects, oral administration, high versatility, and low cost.
The hepatic disease therapeutic agent of the present invention for solving such a problem comprises lipamycin B or a derivative of rifamycin B or a pharmacologically acceptable salt thereof as an active ingredient. When this liver disease treatment agent is administered to a patient with hepatic disease, liver function is improved and ALT values and AST values, which are indices of liver function, are lowered.

Description

Hepatic disease treatment and liver function improving agent {THERAPEUTIC AGENT FOR LIVER DISEASE AND HEPATIC FUNCTION-AMELIORATING AGENT}

The present invention relates to, for example, agents for treating liver disease and agents for improving liver function.

The liver has various functions such as detoxification, nutrient synthesis, decomposition, storage, and bile secretion, and is an important organ for maintaining homeostasis, but acute or chronic liver may be caused by various factors such as hepatitis virus, drugs, and alcohol. There may be a malfunction. This causes hepatic diseases such as viral hepatitis, pharmaceutical liver disorders and alcoholic liver disorders.

Viral hepatitis, a representative hepatic disease, is hepatitis caused by viral infection. Representative examples of viral hepatitis include hepatitis C and hepatitis B, and these hepatitis are known to lead to the development of cirrhosis and liver cancer when symptoms worsen.

The number of carriers of hepatitis C virus (HCV) in Japan is estimated at 1.5 million (see Non-Patent Document 1). Among carriers of hepatitis C virus, 70 to 80% of carriers move to chronic hepatitis C and become chronic hepatitis C patients. About 30% of chronic hepatitis C patients become hepatitis C patients within 10 to 30 years, and about 80% of those patients with hepatitis C develop liver cancer within 5 to 10 years. As described above, since the incidence of liver cancer in patients with chronic hepatitis C is very high, the treatment of chronic hepatitis C becomes very important.

Conventionally, interferon and ribavilin have been used as a component for the treatment of viral hepatitis. Specifically, interferon is administered to the patient alone or in combination with interferon and ribavirin. Since the hepatitis virus is removed in the body by this, viral hepatitis may be able to be treated (refer patent document 1).

Patent Document 1: Japanese Unexamined Patent Publication No. 6-234657

[Non-Patent Document 1] Treatment Guide for Chronic Hepatitis, Japanese Soy Society Society Edition, Bunkodo, p21-p23

However, since the treatment method shown in the said patent document 1 has severe side effects, such as fever, platelet reduction, leukocyte reduction, hair loss, headache, tinnitus, and depression, the physical burden on a patient was large. In addition, since interferon is a protein and cannot be administered orally, it cannot be relied on by injection and there is a problem in terms of convenience and safety. In addition, since the cost of treatment is high, there are cases where treatment is difficult financially.

In addition, depending on the genotype of the hepatitis virus and the administration time of the therapeutic component, there have been many cases where the therapeutic effect is not achieved. Specifically, even in the case of the combined administration of interferon and ribavirin, the rate at which hepatitis virus can be removed from the body was at most about 50%.

Due to these problems, when the treatment method described in Patent Document 1 becomes inappropriate, in order to suppress the progression to cirrhosis and liver cancer, liver asthma therapy may be performed. In this hepatic asymptomatic therapy, potent minopagen C and ursodeoxycholic acid are used as a liver function improving agent. Thereby, liver function can be improved, but this can be confirmed with the fact that liver function indicators, such as aspartic acid aminotransferase (AST) and alanine aminotransferase (ALT), are kept at low values.

However, potent minopagen C has been problematic in terms of convenience and safety because it is administered by injection. In addition, in some cases, the injection site hardens when administered for a long time, making it difficult to continue the administration.

Although ursodeoxycholic acid can be administered orally, it cannot be said to be effective for all patients, and in some cases, it cannot be effective for some chronic hepatitis C patients.

In addition, also in other liver diseases, there existed the same problem as the said problem seen with viral hepatitis.

Therefore, an object of the present invention is to provide a therapeutic agent for hepatic disease with less side effects, which can be administered orally, and which has high versatility and is inexpensive.

MEANS TO SOLVE THE PROBLEM The present inventors found that lipamycin antibiotics can improve liver function in hepatic diseases such as viral hepatitis and, as a result, inhibit the progression of hepatitis to cirrhosis and prevent the development of liver cancer. The present invention was found to have been found to be possible.

Incidentally, the lipamycin antibiotic is Streptomyces Rifamycin, an antibiotic produced by mediterranei ), and its derivatives, have been used for many years as a component of anti-tuberculosis drugs.

By the way, the angiogenesis inhibitory effect of the lipamycin antibiotic was discovered recently, and based on this discovery, it was disclosed that the lipamycin antibiotic was able to suppress the progression of liver cancer. See 2004-75665). However, the purpose of administration of the rifamycin antibiotic did not prevent the development of cancer cells in the liver tissue caused by the liver disease by treatment of the liver disease. Therefore, the patients targeted for the administration of rifamycin antibiotics have already been limited to patients with a high possibility of having cancer cells in liver tissue.

In addition, lipamycin antibiotics have been conventionally administered as an antimicrobial agent to patients with tuberculosis and Hansen's disease, and have not been used for patients who do not develop these diseases.

In addition, hepatotoxicity was concerned when rifamycin antibiotics were used for the treatment of tuberculosis. In particular, in combination with other anti-tuberculosis drugs, sometimes serious side effects have been reported. Therefore, conventionally, rifamycin-based antibiotics have not been used as a hepatic disease treatment or liver function improving agent. Only in a model of animal hepatitis caused by carbon tetrachloride (CCl ₄ ), which is a type of poison, it has been reported that the administration of rifampicin reduces the damage of liver cells and lowers the value of liver function indicators. (Huang. R., Okuno, H., Takasu, M., Shiozaki, Y., and Inoue, K. Protective effect of rifampicin against acute liver injury induced by carbon tetrachloride in mice.Jpn J Pharmacol, 69: 325-334 Takeda, K., Watanabe, J. Inoue, K., and Kanamura, S. Rifampicin suppresses hepatic CYP2E1 expression and minimizes DNA injury caused by carbon tetrachloride in perivenular hepatocytes of mice.Alcohol Exp Res, 24: 87S- 92S, 2000). However, chemical hepatitis caused by carbon tetrachloride is induced by cell damage in the toxicity of chemicals, and the pathogenesis mechanism is completely different from hepatitis C, which is believed to be involved in the immune response. The present invention is remarkable in that rifampicin is effective in treating hepatitis C in humans, which is considered to be deeply involved in a kind of immune response, hepatitis caused by ConA in mice, or galactosamine in rats. .

The present invention specifically provides the following.

(1) A medicament for treating liver disease, comprising as an active ingredient rifamycin B or a derivative of rifamycin B or a pharmacologically acceptable salt thereof.

Here, the "derivative of rifamycin B" means a compound synthesized directly from rifamycin B or via a plurality of intermediates, and specific examples thereof include rifamycin SV, rifampicin, rifabutin, and riffentin.

In addition, the "pharmacologically acceptable salt" means the salt which does not lose the therapeutic effect of a liver disease, and, specifically, acid addition salts, such as a hydrochloride, and base addition salts, such as a sodium salt, are mentioned.

"Hepatic disease" is a generic term for chronic or acute diseases caused by endogenous or exogenous causes in hepatic tissues. Specifically, as endogenous or exogenous causes, obesity, viral infections, ingestion of alcohol, abnormalities of the immune system , Bile duct retention in the liver.

An "active ingredient" means the component which shows the therapeutic effect of a liver disease. In addition, the hepatic disease therapeutic agent may contain components other than an active ingredient, so long as the therapeutic effect of a liver disease is lost.

(2) The therapeutic agent for hepatic disease according to the above (1), wherein the rifamycin B or the derivative of rifamycin B is a lipamycin antibiotic or pharmacologically acceptable salt thereof represented by the following general formula (I):

 [Formula I]

[Wherein, R ¹ is hydrogen or C _{1 -} represents a _{3-alkyl-carbonyl,} R ² is hydrogen, C _{1 - 3} alkyl carbonyl, hydroxycarbonyl methylene group or represents an amino-carbonyl-methylene which may have a substituent , R ³ is hydrogen, formyl, C _{1 - 10} shows an alkoxyimino Reno imino group is not already a group, a 2,4-piperazinyl nitro blood which may have a substituent or group.

Here, the "C _{1 - 3} alkyl carbonyl group" refers, indicates that the carbon number of 1 to 3 linear or branched alkyl group of shape bonded to the carbonyl carbon of the carbonyl group.

"Hydroxycarbonyl methylene group" shows that the hydroxycarbonyl group which is a group which the hydroxyl group couple | bonded with the carbonyl carbon of a carbonyl group substituted one of the methyl group hydrogen atoms.

"Aminocarbonylmethylene group which may have a substituent" is a group represented by the following general formula (III). Wherein R ⁶ and R ⁷ each represent hydrogen, a linear or branched alkyl group having 1 to 3 carbon atoms:

[Formula III]

.

.

"C _{1 - 10} alkoxyimino group" that is, having 1 to 10 linear or branched alkyl group of shapes, indicates that the combination of the oxygen atoms with oxime groups.

"Piperazinyl imino group which may have a substituent" is group represented by the following general formula (IV). R ⁸ to R ¹⁵ each represent hydrogen, a linear or branched alkyl group having 1 to 3 carbon atoms, and R ¹⁶ represents hydrogen, a linear or branched alkyl group having 1 to 6 carbon atoms, and 3 to 8 carbon atoms. Cyclic aliphatic hydrocarbon groups, benzyl groups:

[Formula IV]

.

.

"2, 4- dynatroanilininomino group" shows that the hydrogen atom couple | bonded with the nitrogen atom of an imino group is substituted by the group remove | excluding one hydrogen atom from the amino group of 2, 4- dynatroaniline.

(3) The therapeutic agent for hepatic disease according to the above (1), wherein the rifamycin B or the derivative of rifamycin B is a lipamycin antibiotic or a pharmacologically acceptable salt thereof represented by the following general formula II:

[Formula II]

[Wherein, R ⁴ is hydrogen or C _{1 - 6} alkyl group denotes a _- represents a _{3-alkyl-carbonyl,} R ⁵ is hydrogen, C _1].

Here, the "C _{1 - 6} alkyl group" is, represents a C 1 -C 6 linear or branched alkyl group of shape.

(4) The agent for treating hepatic disease according to the above (2), wherein the rifamycin-based antibiotic is selected from the group consisting of rifampicin, rifamycin-SV, 3-formamipamycin, rifaptine and rifamycin B.

(5) The liver disease treatment agent according to the above (3), wherein the rifamycin antibiotic is rifabutin.

(6) the above (1) to (5) used for the treatment of hepatic diseases selected from the group consisting of fatty hepatitis, viral hepatitis, cirrhosis, primary biliary cirrhosis, alcoholic liver disease, autoimmune hepatitis, primary sclerotic cholangitis The hepatic disease therapeutic agent of any one of Claims).

According to the hepatic disease therapeutic agent according to the above (6), since hepatic function is improved, hepatic disease can be treated. Therefore, it is possible to prevent the development of cancer cells in the liver tissue that occurs as a result of the progression of liver disease, and to prevent the development of liver cancer.

Here, "viral hepatitis" means hepatitis caused by a hepatitis virus, and examples thereof include hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E.

(7) Liver function improving agent which contains rifamycin B or the derivative of rifamycin B or its pharmacologically acceptable salt as an active ingredient.

Here, "pharmacologically acceptable salt" means the salt which does not lose the effect of improving liver function, and can specifically mention acid addition salts, such as hydrochloride, and base addition salts, such as sodium salt.

An "active ingredient" means the component which shows the improvement effect of liver function. Moreover, the liver function improving agent may contain components other than an active ingredient, unless the effect of improving liver function is lost.

According to the hepatic disease therapeutic agent of the present invention, the following effects can be obtained.

Since lipamycin antibiotics are used as active ingredients, hepatic diseases can be treated. Thereby, liver cancer which can develop as a result of progression of liver disease can also be prevented.

Since lipamycin-based antibiotics can treat hepatic disease at a lower dosage than the conventional dosage as an antimicrobial agent, the possibility of side effects can be reduced.

According to the liver function improving agent of the present invention, the following effects can be obtained.

Since lipamycin antibiotics are used as active ingredients, liver function can be improved. Thereby, for example, hepatic disease can be treated, and hepatic cancer which can develop as a result of the progression of hepatic disease can also be prevented.

Since lipamycin-based antibiotics can improve liver function at a small dose compared with the conventional dosage as an antimicrobial agent, the possibility of side effects can be reduced.

Moreover, according to the hepatic disease therapeutic agent or liver function improving agent of this invention, the following effects can be acquired.

Rifamycin-based antibiotics are easily absorbed from the digestive tract and are less susceptible to digestive enzymes and can be administered orally.

As lipamycin antibiotics can treat viral hepatitis even in patients who cannot achieve the effect of treatment with, for example, interferon or ursodeoxycholic acid, they are highly versatile.

In addition, since the lipamycin antibiotics are inexpensive, a hepatic disease treatment agent or a liver function improving agent can be provided at a low cost, thereby reducing the economic burden on the patient.

BRIEF DESCRIPTION OF THE DRAWINGS The figure which shows the time-dependent change of the liver function of a patient after drug administration of the Example of this invention.

EMBODIMENT OF THE INVENTION Hereinafter, embodiment of this invention is described.

The present invention relates to a hepatic disease treatment agent and a liver function improving agent comprising as an active ingredient a pharmacologically acceptable derivative of a rifamycin antibiotic and / or a lipamycin antibiotic.

<Composition>

The hepatic disease therapeutic agent and liver function improving agent of the present invention contain a lipamycin antibiotic or the like as an active ingredient.

[Active ingredient]

(Rifamycin antibiotic)

The lipamycin antibiotic is not particularly limited as long as it is a compound that can be used as a hepatic disease therapeutic agent or a liver function improving agent. That is, the rifamycin-based antibiotic is a compound represented by Formula I or Formula II. Here, with respect to Formula I, R ¹ is hydrogen, C _{1 - 3} alkyl represents a carbonyl group, R ² is hydrogen, C _{1 - 3} alkyl carbonyl, hydroxycarbonyl methylene group, an amino which may be substituted carbonyl represents a methylene carbonyl, R ³ is hydrogen, formyl, C _{1 - 10} alkoxyimino group, piperazinyl which may have a substituent; an imino group. In the formula II, R ⁴ is hydrogen, C _{1 -} represents a _{3-alkyl-carbonyl,} R ⁵ is hydrogen, C _{1 - 6} alkyl group represents a.

"Aminocarbonylmethylene group which may have a substituent" in R ² is a group represented by the general formula (III). Wherein, R ⁶ and R ⁷ is hydrogen, C _{1 respectively} represent the _three groups.

"Piperazinyl imino group which may have a substituent" in R ³ is a group represented by the general formula (IV). Here, R ⁸ to R ¹⁵ are each hydrogen, C _{1 - 3} alkyl group, R ¹⁶ is hydrogen, C ₁₆ alkyl, C _{3 - 8} cycloalkyl group, a phenyl group as a benzyl group, a 2,4-night Indicates.

Here, the "C _{1 - 6} alkyl" refers to C 1 -C 6 linear or branched alkyl group of shape, specifically, methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-1 -Propyl group, 2-methyl-2-propyl group, 1-butyl group, 2-butyl group, 1-pentyl group, 2-pentyl group, 3-pentyl group, 2-methyl-1-butyl group, 3-methyl -1-butyl group, 2-methyl-2-butyl group, 3-methyl-2-butyl group, 2,2-dimethyl-1-propyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group , 2-methyl-1-pentyl group, 3-methyl-1-pentyl group, 4-methyl-1-pentyl group, 2-methyl-2-pentyl group, 3-methyl-2-pentyl group, 4-methyl- 2-pentyl group, 2-methyl-3-pentyl group, 3-methyl-3-pentyl group, 2,3-dimethyl-1-butyl group, 3,3-dimethyl-1-butyl group, 2,2 -Dimethyl-1-butyl group, 2-ethyl-1-butyl group, 3,3-dimethyl-2-butyl group, 2,3-dimethyl-2-butyl group, etc. are mentioned.

"C _{1 - 3} alkyl group" is a C _{1 - 6} indicates that the carbon number of the alkyl groups one to three.

"C _{1 - 10} alkoxyimino group" means, C ₁ represents an alkyl group having 1 to 10 linear or branched chain shape _{- 10} alkyl group, indicates that the combination of the oxygen atoms with oxime groups, specifically, methoxy already No group, ethoxyimino group, 1-propyloxyimino group, 2-propyloxyimino group, 2-methyl-1-propyloxyimino group, 2-methyl-2-propyloxyimino group, 1-butyloxyimino group, 2-butyloxyimino group, 1-pentyloxyimino group, 2-pentyloxyimino group, 3-pentyloxyimino group, 2-methyl-1-butyloxyimino group, 3-methyl-1-butyloxyimino group, 2-methyl-2-butyloxyimino group, 3-methyl-2-butyloxyimino group, 2,2-dimethyl-1-propyloxyimino group, 1-hexyloxyimino group, 2-hexyloxyimino group, 3-hexyloxyimino group, 1-octyloxyimino group, 2-octyloxyimino group, 3-octyloxyimino group, 1-nonyloxyimino group, 2-nonyloxyimino group, 3-no Oxy group, 1-decyloxy group, 2-decyloxy group, 3-decyloxy group, 2-methyl-1-pentyloxyimino group, 3-methyl-1-pentyloxyimino group, 4-methyl-1-pentyl Oxyimino group, 2-methyl-2-pentyloxyimino group, 3-methyl-2-pentyloxyimino group, 4-methyl-2-pentyloxyimino group, 2-methyl-3-pentyloxyimino group, 3- Methyl-3-pentyloxyimino group, 2,3-dimethyl-1-butyloxyimino group, 3,3-dimethyl-1-butyloxyimino group, 2,2-dimethyl-1-butyloxyimino group , 2-ethyl-1-butyloxyimino group, 3,3-dimethyl-2-butyloxyimino group, 2,3-dimethyl-2-butyloxyimino group, and the like.

"C _{3 - 8} cycloalkyl group" s is, represents 3 to 8 cyclic aliphatic hydrocarbon group having a carbon number of, for example, a cyclopropyl group, a cycloalkyl views group, a cyclopentyl group, a cyclohexyl group, cyclo heptyl, cyclooctyl group Can be.

"C _{1 - 3} alkyl carbonyl group" means C _{1 - 3} alkyl group indicates that the carbonyl group bonded to the carbon of a carbonyl group, e.g., methyl carbonyl, ethyl carbonyl group, propyl carbonyl group, 1-, 2-propyl-carbonyl The group can be mentioned.

A referent My New Territories antibiotic represented by Formula I is, R ¹ as hydrogen, methyl carbonyl groups are preferred, and methyl-carbonyl groups are more preferred, and R ² as preferably a hydrogen, hydroxy carbonyl methylene and R ³ As a hydrogen, a formyl group, an octaoxy imino group, the 4-methyl piperazinyl imino group, the 4-cyclopentyl piperazinyl imino group, the 4-benzyl piperazinyl imino group, 2, 6-dimethyl-4- A benzyl piperazinyl imino group and a 2, 4- dinitroanilininomino group are preferable, and a hydrogen, a formyl group, 4-methyl piperazinyl imino group, and 4-cyclopentyl piperazinyl imino group are more preferable.

As the rifamycin antibiotic represented by the general formula (II), R ⁴ is preferably hydrogen and methylcarbonyl group, more preferably methyl carbonyl group, and R ⁵ is preferably 2-methylpropyl group.

In addition, as a rifamycin-based antibiotic represented by the general formula I, rifampicin (R ¹ = methylcarbonyl group, R ² = hydrogen, R ³ = 4-methylpiperazinylimino group), rifamycin-SV (R ¹ = Methylcarbonyl group, R ² = hydrogen, R ³ = hydrogen), 3-formamiphamycin (R ¹ = methylcarbonyl group, R ² = hydrogen, R ³ = formyl group), ripaptine (R ¹ = methylcarbono More preferred are a silyl group, R ² = hydrogen, R ³ = 4-cyclopentylpiperazinylimino group), and rifamycin B (R ¹ = methylcarbonyl group, R ² = hydroxycarbonylmethylene group, R ³ = hydrogen) As the rifamycin antibiotic represented by the general formula (II), rifabutin (R ⁴ = methylcarbonyl group, R ⁵ = 2-methylpropyl group) is more preferable.

(Pharmacologically acceptable derivatives of lipamycin antibiotics)

Pharmacologically acceptable derivatives of rifamycin-based antibiotics are preferred in that they can increase the solubility in a solvent (for example, water), thereby improving the absorption efficiency into the body. Although it does not specifically limit as a pharmacologically acceptable derivative | guide_body, The salt generally used in preparation of a medicine, or the hydrate of these salts may be sufficient. Here, examples of the pharmacologically acceptable salts include acid addition salts and base addition salts.

Although it does not specifically limit as acid addition salt, For example, hydrochloride, acetate, sulfate, nitrate, oxalate, maleic acid, tartarate, citrate, carbonate, succinate, benzoic acid, acetate, hydrogen fluoride salt, iodide water Anti-inflammatory, phosphate, fumarate, gluconate, p-toluenesulfonate, methanesulfonate, ethanesulfonate.

Examples of the base addition salt include, but are not particularly limited to, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, organic amine salts such as ethanol amine salts, triethylamine salts and methylamine salts, and ammonium salts. Etc. can be mentioned.

[additive]

The hepatic disease therapeutic agent or liver function improving agent of the present invention may be administered alone, but is preferably administered in the form of a pharmaceutical composition further comprising a pharmacologically and pharmaceutically acceptable additive. Pharmacologically and pharmaceutically acceptable additives include, for example, excipients, disintegrants, disintegrating aids, emulsifiers, suspending agents, dispersing agents, binders, lubricants, coating agents, pigments, diluents, substrates, solubilizers, dissolution aids, isotonic agents , pH regulators, stabilizers, propellants, pressure-sensitive adhesives.

Examples of excipients include glucose, lactose, D-mannitol, starch, crystalline cellulose, and the like. Disintegrating agents and disintegrating aids include carboxymethylcellulose, starch, carboxymethylcellulose, and the like. As emulsifiers, suspending agents and dispersing agents, And polyoxyl stearate, sucrose fatty acid ester, sodium lauryl sulfate, and the like. Examples of the binder include hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, and the like. And magnesium stearate, aluminum silicate, talc and the like. Examples of the coating agent include hydroxypropylmethylcellulose, white sugar, polyethylene glycol, titanium oxide, and the like. Examples of the base material include petroleum jelly, liquid paraffin, and polyethylene glycol. Lycol, gelatin, kaolin, glycerin, purified product, hydrogenated oil and the like.

The additive used in the preparation for injection or instillation is not particularly limited. Examples of the dissolving agent or dissolution aid include distilled water for injection, physiological saline, propylene glycol, and the like. Organic acids, inorganic bases, organic bases and the like.

<Manufacturing Method>

(Method for producing lipamycin antibiotic)

Rifamycin B as an example of the rifamycin antibiotic according to the present invention is a kind of antibiotic produced by Streptomyces mediterranean, and can be separated from the culture solution of Streptomyces mediterranean by a known method (Japan See Japanese Patent Application Publication No. 37-1697, line 8 on the right side of page 2 to line 32 on the right side of page 4).

Rifampicin, rifaptine, rifabutin, rifamycin SV and derivatives thereof can be synthesized by a known method from this rifamycin B. (Japanese Patent Publication No. 62-41671, page 2, left column 30 to right column 27) Lines 34 to 34 on the left side of page 2 of Japanese Patent Publication No. 62-41672; 31 lines to 34 on the right column of Japanese Patent Publication No. 62-41673; -149790, page 12, bottom right, 12th page, 7th, top right, 7th row, page 8, bottom left, 4th, 10th page, bottom left 14th row; Japanese Patent Laid-Open No. 2-304090 No. 9, 9th row No. 21, line 20; Japanese Unexamined Patent Publication No. 2-56487, page 13, upper left row 18, page 18, upper left 9 rows, page 19, upper right row of page 19, page 13, upper left 13 lines; Japanese Patent Application Laid-Open No. 3-169884, Page 17, bottom right row 18, page 22, bottom left line 3, page 23, bottom right page 10, page 33, bottom left line 20; Japanese Patent Laid-Open No. 4-159283, paragraphs 0038-0070, 0081-0107 Japanese Patent Application Laid-Open No. 4-230688, Paragraph Nos. 0065 to 0103, 0118 to 0147; Japanese Patent Application Laid-Open No. 4-247088, Paragraph No. 0076 to 0120, 0136 to 0139; See US Patent No. 4,002,752. ). In addition, as a rifamycin antibiotic, rifampicin as "rifampicin" (manufactured by Alexis Inc.), as rifaptin "lipaputin tablet (trade name)" (manufactured by Sanfi-Aventis), and rifabutin as rifabutin (USP Reference Standards) Co., Ltd.) and "Ripamycin SV Sodium Salt" (manufactured by MP Biomedicals Co., Ltd.) and the like are commercially available, and these products may be used.

<Disease targeted for administration>

Hepatic disease treatment or liver function improving agent of the present invention, fatty hepatitis (for example, non-alcoholic fatty hepatitis), viral hepatitis, cirrhosis, primary biliary cirrhosis, alcoholic liver disease, autoimmune hepatitis, primary sclerotic cholangitis, liver cancer Etc. can be used. Here, as viral hepatitis, hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E are mentioned.

The present invention also provides a method for treating liver disease and a method for improving liver function as follows.

A procedure for administering rapamycin B or a derivative of rifamycin B or a pharmacologically acceptable salt thereof to a subject infected with hepatic disease (for example, humans or animals other than humans) containing a therapeutic agent for liver disease A method of treating liver disease comprising.

A method for improving liver function, comprising the step of administering lipamycin B or a derivative of rifamycin B or a pharmacologically acceptable salt thereof to a subject (eg, human, non-human) .

[Administration method, dosage form]

Among the hepatic disease therapeutic agents or liver function improving agents of the present invention, rifampicin, rifaptine and rifabutin are already used in a large number of patients, such as tuberculosis patients, and thus their usage and side effects are well known. Therefore, the hepatic disease treatment agent or the liver function improving agent of the present invention can select the administration method and dosage form which can suppress side effects based on experience.

The hepatic disease therapeutic agent according to the present invention can be used in combination with various existing components used for the treatment of liver disease. Specifically, it can be used in combination with at least one component selected from the group of hepatic disease therapeutic drugs such as strong neominophagen C, ursodeoxycholic acid, profagelmanium, glutathione, malotlate, and glycyronic acid. Also selected from the group consisting of various interferons such as interferon alpha, interferon alpha-2a, interferon alpha-2b, and interferon beta. It can be used in combination with at least one component. Moreover, it can be used together with at least 1 sort (s) of component chosen from the group of antiviral drugs, such as lamivudine and ribavilin.

The hepatic disease therapeutic agent or liver function improving agent of the present invention can be administered either by oral administration or parenteral administration (eg, intravenous injection, intramuscular injection, subcutaneous injection). The dosage form may be appropriately selected depending on the condition of the patient to be administered, but oral administration is preferred from the viewpoint of convenience and safety.

In the case of oral administration, the lipamycin antibiotic may be administered in the form of a solid or liquid preparation, specifically, tablets, granules, capsules, powders, torokis, solutions, suspensions, emulsions and the like.

For parenteral administration, rifamycin antibiotics can be administered in a dissolved form in a suitable solvent.

[Dose]

The dose of the hepatic disease therapeutic agent or liver function improving agent of the present invention can be appropriately set depending on the target disease, administration method and the like. When orally administered rifampicin, the dosage is about 10 to 900 mg / day, preferably about 50 to 450 mg / day. In addition, when orally administering rifabutin, the dosage is about 10 to 600 mg / day, preferably about 20 to 300 mg / day. In addition, when orally administered lipopentin, the dosage is about 50 to 1800 mg / week, preferably about 50 to 1200 mg / week.

[Dose period]

The hepatic disease therapeutic agent or the liver function improving agent of the present invention also depends on the symptoms of the patient to be administered, but it is preferable to continuously administer at least one month or more, more preferably one year or more continuously every day.

<Example 1> Improved therapeutic effect in the liver of chronic hepatitis C patients caused by rifampicin low dose

To six patients with chronic hepatitis C (an example of hepatic disease), 150 mg (1 capsule) orally of "lipadin (registered trademark)" (product of Daiichi Pharmaceutical Co., Ltd.) is daily administered as a rifampicin preparation, and the blood of each patient Collected regularly. The alanine aminotransferase (ALT) value and the aspartic acid aminotransferase (AST) value in the collected blood were measured.

Here, the patient selected as the subject in the present Example was in the following state.

First, it was estimated from biopsy and platelet count that 5 out of 6 patients were liver type C liver cirrhosis patients with F3 to F4 equivalent.

Second, all patients were chronic hepatitis C patients with hepatitis C virus of type Ib, which is said to be difficult to treat with interferon. Although four patients were treated with interferon, one of them did not show a therapeutic effect. In addition, the treatment was discontinued because 4 patients had a strong side effect.

Third, all of these patients were treated with ursodeoxycholic acid, but there was no treatment effect.

1 is a view showing the change over time of the mean value of the ALT value and AST value of six patients with chronic hepatitis C. Since the ALT value and AST value represent the concentrations of aminotransferases flowing out of the damaged liver cells, the higher these values suggest that more liver cells are damaged and liver function is lowered.

The ALT value was measured by the following method.

First, serum is separated from the collected blood, and the serum is periodically measured by the lactic acid dehydrogenase conjugated UV method ("Hitachi automatic analyzer 7350", Hitachi High-Technologies Corporation) in accordance with JSCC. Was calculated.

In addition, the AST value was measured by the following method.

First, serum is separated from the collected blood, and the serum is periodically measured by the lactic acid dehydrogenase conjugated UV method ("Hitachi automatic analyzer 7350", Hitachi High Technologies Corporation) in conformity with JSCC. Was calculated.

As shown in Fig. 1, the ALT value and the AST value were significantly lowered by about 1 month after the start of the administration compared to before the administration of the drug, and then maintained at a low value until 6 months thereafter. In addition, the ALT value and the AST value are normal values of 11 to 40 IU / L, and in viral chronic hepatitis patients, the highest value exceeding the upper limit of the normal value is often shown. In chronic hepatitis, it is generally judged that the symptoms of hepatitis have improved when the ALT value and the AST value decrease. Therefore, from this result, it turns out that liver function improves by administration of a chemical | medical agent, and the symptoms of viral hepatitis are improved.

In addition, it was found that the drug can sufficiently improve the symptoms of viral hepatitis even by oral administration. Rifampicin was able to effectively improve the symptoms of hepatitis even in chronic hepatitis C patients with hepatitis C virus.

As a side effect of the administration of rifampicin, hepatic, gastrointestinal, blood, rash, fever and the like are known. However, in six patients who received rifampicin in this example, these side effects were not found. In addition, although rifampicin was administered to these patients for many years after the evaluation period of the present Example, no side effects occurred, the state of low ALT and AST values were maintained for a long time, and no onset of liver cancer was observed.

From the above results, it was found that rifampicin has an effect as a liver function improving agent in chronic hepatitis C.

In addition, the dose of rifampicin as a hepatic disease treatment agent and a liver function improving agent is significantly at least compared to the dose as a tuberculosis treatment agent (for example, about 450 mg, once daily), and has a hepatic disease treatment effect and liver function improvement effect. I could see that it worked.

< Example 2> Liver asthma effect by administration of rifampicin (1)

The hepatoprotective effect of rifampicin was evaluated by a viral hepatitis model of mice induced by Concanavalin A (ConA). That is, as a rifampicin preparation, "GK-001" (manufactured by Lupin Limited) was administered to eight mice in each group at dosages of 50 mg / kg.day, 100 mg / kg.day, and 200 mg / kg.day for 4 days. Successive oral administration. One hour after the fourth day of administration, 0.2 mg of ConA dissolved in phosphate saline (PBS) was administered from the tail vein. The same operation was performed also for the mouse of the group which received 200 mg / kg of GK-001 only once, and the mouse of the group which did not administer GK-001. 24 hours after ConA administration, mice were anesthetized and arterial blood was collected. The ALT value, AST value and lactic acid dehydrogenase (LDH) value in the blood were measured.

LDH value was isolate | separated from the collected blood, and it measured and computed by the paranitrophenyl phosphate substrate method ("automatic analyzer 7170", Hitachi Seisakusho company) based on JSCC using this serum.

The above results are shown in Table 1 below.

GK-001 Dosage
(Mg / kgday) administration
Days ConA
administration ALT
(IU / ℓ) AST
(IU / ℓ) LDH
(IU / ℓ) 0 - - 15 ± 0 32 ± 0 126 ± 11 0 - + 5963 ± 1225 8655 ± 1819 22390 ± 4447 50 4 + 3565 ± 991 4378 ± 1568 12938 ± 4683 100 4 + 1950 ± 654 2178 ± 862 ^* 7120 ± 2750 200 4 + 870 ± 203 ^** 605 ± 136 ^** 1963 ± 403 200 One + 1940 ± 1003 ^* 2710 ± 1585 ^** 8090 ± 4327 Mean ± standard deviation (parameter 8)
^* p <0.05, ^** p <0.01
(About GK-001 dose 0mg / kgday, ConA administration (+))

Table 1 shows that in the group to which rifampicin was administered, the ALT value, the AST value, and the LDH value significantly decreased as the dose was increased. From these results, it was suggested that rifampicin suppresses the decrease in liver function induced by ConA.

< Example 3> Liver asthma effect by administration of rifampicin (2)

The hepatoprotective effect of rifampicin was evaluated by a viral hepatitis model of rats induced by galactosamine (Gal). That is, as a rifampicin preparation, "GK-001" (manufactured by Lupin Limited) was used in 8 rats of each group at dosages of 50 mg / kg.day, 100 mg / kg.day, and 200 mg / kg.day. Oral administration was continued for days. One hour after the fourth day of administration, 350 mg / kg of Gal dissolved in physiological saline was administered intraperitoneally. The same operation was performed also for the rat of the group which received 200 mg / kg of GK-001 only once, and the rat of the group which did not administer GK-001. 24 hours after Gal administration, rats were anesthetized and arterial blood was collected. The ALT value, AST value, and LDH value in the blood were measured. The results are shown in Table 2 below.

GK-001 Dosage
(Mg / kgday) administration
Days Gal
administration ALT
(IU / ℓ) AST
(IU / ℓ) LDH
(IU / ℓ) 0 - - 21 ± 1 64 ± 1 125 ± 9 0 - + 2218 ± 434 3330 ± 761 13815 ± 4850 50 4 + 738 ± 180 ^* 1915 ± 518 5658 ± 2084 100 4 + 953 ± 114 1910 ± 216 4985 ± 897 200 4 + 315 ± 102 ^** 800 ± 356 ^** 1493 ± 896 ^** 200 One + 435 ± 133 ^* 633 ± 160 ^** 1135 ± 536 ^** Mean ± standard deviation (parameter 8)
^* p <0.05, ^** p <0.01
(About GK-001 dose 0mg / kgday, Gal administration (+))

Table 2 shows that in the group to which rifampicin was administered, the ALT value, the AST value, and the LDH value significantly decreased as the dose was increased. From these results, it was suggested that rifampicin suppresses the fall of liver function induced by Gal.

Claims (1)

A lipamycin antibiotic or a pharmacologically acceptable salt thereof is an active ingredient, and the rifamycin antibiotic is selected from the group consisting of rifampicin, rifamycin-SV, 3-formamifamycin, rifaptine and rifamycin B. The agent is selected to improve the symptoms of hepatitis by improving the damage of hepatic cells following obesity, viral infections and ingestion of alcohol, thereby preventing the progression of cirrhosis and liver cancer.

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