KR100626414B1 - A pharmaceutical composition for hepatitis - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for treating hepatitis, and more particularly, a pharmaceutical composition useful as a therapeutic agent for chronic hepatitis B and C obtained by containing a certain amount of biphenyl dimethyl dicarboxylate (BDD) and amantadine hydrochloride (AH). It is about.

Hepatitis, Biphenyl Dimethyl Dicarboxylate, Amantadine Hydrochloride

Description

A pharmaceutical composition for hepatitis             

Figure 1 shows the inhibitory ability of HBsAg gene expression according to the time change (1 day, 3 days and 5 days) of the agent according to the present invention and conventionally used hepatitis treatment.

Figure 2 shows the inhibitory ability of HBcAg gene expression of the agent for treating hepatitis and the examples according to the present invention.

Figure 3 shows the expression activity of 6-16 gene according to the time change (1 day, 3 days and 5 days) of the agent according to the present invention and conventionally used for hepatitis treatment.

Figure 4 shows the LDH assay of the agent for treating hepatitis and the examples according to the present invention used conventionally.

Figure 5 shows the NO assay according to the time changes (1 day, 3 days and 5 days) of the agent according to the present invention and conventionally used for hepatitis treatment.

The present invention relates to a pharmaceutical composition for treating hepatitis, and more particularly, a pharmaceutical composition useful as a therapeutic agent for chronic hepatitis B and C obtained by containing a certain amount of biphenyl dimethyl dicarboxylate (BDD) and amantadine hydrochloride (AH). It is about.

Chronic hepatitis B (HBV) and viral hepatitis C (HCV) are widespread in the world, and the incidence of chronic hepatitis B is particularly high in Asia, especially in other parts of the world. Chronic hepatitis B (HBV) and hepatitis C (HCV) infections can progress to cirrhosis after 5-20 years of infection in some patients and are highly associated with the pathogenesis of primary hepatocellular carcinoma. Although many drugs today are being used to treat chronic HBV and HCV infections, they are not satisfactory as hepatitis agents. To date, interferon-2α is the only commonly used agent for the treatment of chronic HBV and HCV infection as a monotherapy or combination therapy with ribavirin. However, the effectiveness of interferon-2α therapy is less than 30% in patients with chronic HBV and rather high side effects.

Therefore, recently, high-efficiency long-acting Peg-interferon-2α has been developed and used for the treatment of chronic HCV, but the cost is still very high for the patient. Nucleoside homologues such as lamivudine have been developed in addition to interferon, but the continuous treatment effect is limited due to high rebound after discontinuation of lamivudine. Furthermore, lamivudine causes drug resistance by causing mutations in wild-type hepatitis B virus. In addition, several types of hepatoprotectants, such as glycidine and silymarin, have also been used to treat HBV, but these drugs have no inhibitory effect on viral replication. Therefore, new strategies are needed for the treatment of chronic HBV and HCV.

Combination therapy has thus emerged as a new trend in the treatment of chronic HBV and HCV.

On the other hand, biphenyl dimethyl dicarboxylate (BDD) represented by the following general formula (1) is well known as a chronic hepatitis therapeutic agent (US Patent No. 4,868,207).

The biphenyl dimethyl dicarboxylate (BDD), originally developed by scientists at the Institute of Drug Research, is a synthetic homologue of Schizandrin C isolated from the natural herb, Schisandra chinensis. Since 1979, BDD has been used as a treatment for HBV, and since 1983, it has been widely used in the treatment of chronic HBV and drug-induced edema. Meanwhile, since the 1990s, it has been applied to the treatment of chronic HBV and HCV patients in Egypt, Indonesia, Vietnam and Korea. The clinical effect of BDD can be expressed as significantly lowering serum GPT without side effects. It has recently been reported that high doses of BDD can inhibit HBV replication, as indicated by the conversion of positive HBeAg and HBV-DNA to negative in patients.

The pharmacological action of BDD is: (1) hepatocellular protection against damage caused by hepatotoxic and biological toxins such as BCG plus lipopolysaccharide (LPS) through stabilization of the cell membrane, and (2) human hepatocellular carcinoma consistent with the human HBV genome. 2.2.15 inhibition of HBV replication in the cell line, (3) increased liver detoxification through the induction of liver microsomal cytochome P-450, which plays an important role in liver detoxification mechanisms, and (4) aflatoxin Antagonists of mutagenesis of chemical carcinogens such as B1.

In addition, amantadine hydrochloride (AH) represented by the following formula (2) is known as an antiviral agent.

Amantadine hydrochloride is a synthetic antiviral agent originally used for the treatment and prevention of influenza virus, which was later used in Parkinson's disease and has recently been applied to chronic HCV. In other words, amantadine hydrochloride has been attempted to be used for the treatment of chronic hepatitis C in combination with interferon, but only one-third of patients with persistent reactions have not been put to practical use for this purpose. It was.

The pharmacological action of amantadine hydrochloride is (1) as an antiviral agent that inhibits the replication of certain myxo-viruses, namely influenza, rubella and some tumor viruses, and (2) as a therapeutic for Parkinson's disease. Its anti-muscarinic effect causes the release of dopamine from the central ganglion.

On the other hand, in the 1990s, amantadine hydrochloride was used alone or in combination with other drugs, but several researchers tried to treat chronic HCV, but the results were not good. The efficacy and safety of amartadine hydrochloride in patients with chronic HCV who failed treatment with interferon showed normalization of ALT after 6 months in patients treated with amantadine hydrochloride, while 18% stopped amantadine hydrochloride in 6 months after PCR. It has been reported that there was a sustained response due to the loss of HCV RNA by.

In addition, ursodeoxycholic acid (UDCA) represented by the following formula (3) is known as an antagonist.

As described above, many studies, such as monotherapy and combination therapy, have been attempted for the treatment of chronic HBV and HCV, but are not satisfactory.

Therefore, the present invention has been repeated in order to overcome this in consideration of the fact that the conventionally used drugs for the treatment of chronic HBV and HCV are mostly unsatisfactory, the ratio represented by the formula (1) used as a conventional treatment for chronic hepatitis A combination of phenyl dimethyl dicarboxylate (BDD) and amantadine hydrochloride (AH) represented by the formula (2) used as an antiviral agent and / or ursodeoxycholic acid (UDCA) of the formula (3) used as a bottling agent A new pharmaceutical composition was prepared, confirming the chronic clinical improvement of chronic hepatitis B and C infection (HBV and HCV) and completing the present invention.

Accordingly, an object of the present invention is to provide a pharmaceutical composition useful for treating hepatitis.

The present invention provides a pharmaceutical composition for treating hepatitis containing 7.5 to 200 parts by weight of biphenyl dimethyl dicarboxylate (BDD) represented by Formula 1 and 50 to 200 parts by weight of amantadine hydrochloride (AH) represented by Formula 2. It is characterized by.

Referring to the present invention in more detail as follows.

The present invention is a combination of the pharmaceutical composition useful for the treatment of hepatitis, such as hepatitis B virus and hepatitis C virus, biphenyl dimethyl dicarboxylate (BDD) of Formula 1 and Amantadine hydrochloride (AH) of Formula 2 and / Or prepared by containing a certain amount of ursodeoxycholic acid (UDCA) of the formula (3).

Looking at the components of the pharmaceutical composition of the present invention as described above in more detail.

First, the pharmaceutical composition of the present invention contains 7.5 to 200 parts by weight of biphenyl dimethyl dicarboxylate (BDD) represented by the formula (1) used as a chronic hepatitis therapeutic agent, and if the content is less than 7.5 parts by weight There is a problem of insufficient efficacy, and if it exceeds 200 parts by weight, there is a problem in safety.

In addition, the pharmaceutical composition of the present invention contains 50 to 200 parts by weight of amaradiate hydrochloride represented by the formula (2) used as an antiviral agent, and if the content is less than 50 parts by weight, there is a problem of insufficient efficacy, 200 parts by weight If exceeded, there is a safety problem.

In addition, the pharmaceutical composition of the present invention may further contain 50 to 100 parts by weight of ursodeoxycholic acid (UDCA) represented by Formula 3 used as an antagonist, if the content is less than 50 parts by weight There is an inadequate problem, and if it exceeds 100 parts by weight, there is a problem in safety.

In addition to the above components, the pharmaceutical composition according to the present invention may contain pharmaceutically acceptable excipients such as lactose, starch, magnesium stearate, and carboxymethyl cellulose which can be easily selected by those skilled in the art.

In particular, a preferred example of the pharmaceutical composition of the present invention is 50 parts by weight of biphenyl dimethyl dicarboxylate (BDD) represented by Formula 1, 50 parts by weight of amantadine hydrochloride (AH) represented by Formula 2 and pharmaceutical Pharmaceutical compositions containing acceptable excipients.

Another preferred example of the pharmaceutical composition of the present invention is 15 parts by weight of biphenyl dimethyl dicarboxylate (BDD) represented by Formula 1, 50 parts by weight of amantadine hydrochloride (AH) represented by Formula 2, Formula 3 It is a pharmaceutical composition containing 50 parts by weight of ursodeoxycholic acid (UDCA) and a pharmaceutically acceptable excipient.

Biphenyl dimethyl dicarboxylate (BDD), amantadine hydrochloride (AH), and ursodeoxycholic acid (UDCA) used as an active ingredient in the present invention as described above are widely commercialized drugs and their stability has been widely demonstrated. The stability of the pharmaceutical composition according to the present invention is also very high.

As described above, the pharmaceutical composition of the present invention comprises biphenyl dimethyl dicarboxylate (BDD), amantadine hydrochloride (AH) and / or ursodeoxycholic acid (UDCA) as an active ingredient, and an appropriate amount of a pharmaceutically acceptable excipient. By using in combination, it shows strong protection against hepatotoxicity due to the synergistic effect of the above components and can be very useful as a therapeutic agent for hepatitis.

Such pharmaceutical compositions according to the invention can be formulated in the form of capsules or tablets by conventional methods.

In addition, the effective dosage of the pharmaceutical composition according to the present invention can be varied depending on the age, physical condition, weight, etc. of the patient, it is generally administered within the range of 1 to 100 mg / kg (weight) / day. In addition, within a daily effective dosage range is divided into once a day or several times a day.

Hereinafter, the present invention will be described in more detail based on the following examples, but the present invention is not limited by the examples.

Example 1 Preparation of Hard Capsule

The following excipients were added to a mixture of 15 mg of biphenyl dimethyl dicarboxylate (BDD), 50 mg of ursodeoxycholic acid (UDCA), and 50 mg of amantadine hydrochloride, followed by homogeneous mixing to prepare a conventional hard capsule. It was prepared according to.

Composition of active ingredient and excipient per capsule (300 mg) Active ingredient and content Excipients and Content Biphenyldimethyldicarboxylate 15 mg Ursodeoxycholic acid 50 mg Amantadine hydrochloride 50 mg                                              Lactose 90 mg Starch 40 mg Magnesium stearate 52 mg Carboxymethylcellulose 3.0 mg

Example 2 Preparation of Hard Capsule

The following excipients were added to a mixture of 50 mg of biphenyl dimethyl dicarboxylate (BDD) and 50 mg of amantadine hydrochloride (AH), followed by homogeneous mixing to prepare a conventional hard capsule preparation.

Composition of active ingredient and excipient per capsule (300 mg) Active ingredient and content Excipients and Content Biphenyldimethyldicarboxylate 50 mg Amantadine hydrochloride 50 mg Lactose 100 mg Starch 45 mg Magnesium stearate 52 mg Carboxymethylcellulose 3.0 mg

Example 3. Preparation of Tablets

The following excipients were added to a mixture of 50 mg of biphenyl dimethyl dicarboxylate (BDD) and 50 mg of amantadine hydrochloride (AH), followed by homogeneous mixing to prepare a conventional tablet.

Composition of Active Ingredients and Excipients per Tablet (300 mg) Active ingredient and content Excipients and Content Biphenyldimethyldicarboxylate 50 mg Amantadine hydrochloride 50 mg Lactose 100 mg Starch 45 mg Magnesium stearate 52 mg Carboxymethylcellulose 3.0 mg

Example 4. Preparation of Tablets

To a mixture of 15 mg of biphenyl dimethyl dicarboxylate (BDD), 50 mg of ursodeoxycholic acid (UDCA) and 50 mg of amantadine hydrochloride (AH), the following excipients were added and mixed homogeneously before It was prepared according to the preparation method.

Composition of Active Ingredients and Excipients per Tablet (300 mg) Active ingredient and content Excipients and Content Biphenyldimethyldicarboxylate 15 mg Ursodeoxycholic acid 50 mg Amantadine hydrochloride 50 mg Lactose 90 mg Starch 40 mg Magnesium stearate 52 mg Carboxymethylcellulose 3.0 mg

Test Example 1

Mouse hepatitis virus known as an animal model of human epidemic hepatitis in order to characterize the antiviral and hepatoprotective effects of the formulations of Examples 1 to 4 against chronic hepatitis B and C infection (HBV and HCV) (MHV-2 week) was used to test.

The mice used in the experiment were 6-week-old SPF ICR mice (Samta Co., Ltd.) (weight 25 ± 2 g). The test group was to induce acute viral hepatitis by infecting mouse hepatitis virus-2 strain, it was divided into eight as follows and placed 13 dogs in each group.

(1) MHV-2 + distilled water administration group

(2) MHV-2 + Gepix ™ (trade name, Glaxowelcome, UK) (100 mg / kg) group

(3) MHV-2 + UDCA (40 mg / kg) administration group

(4) MHV-2 + BDD (40 mg / kg) administration group

(5) MHV-2 + AH (40 mg / kg) administration group

(6) MHV-2 + AD (AH + BDD complex) (80 mg / kg) administration group

(7) MHV-2 + ADU (AH + BDD + UDCA combination) (100 mg / kg) administration group

(8) distilled water alone administration group

MHV-2 weeks were intraperitoneally inoculated to all the test groups at a concentration of 1 × 10 ³ PFU / 0.2 ml per mouse, and each day was orally dosed with the above-mentioned drugs daily, and blood was collected from the vein on the third day of virus inoculation. Survival was observed until death and final autopsy was performed on day 10. The virus titer, histopathological examination, and immunohistochemical observation were performed in the following manner. Table 7 shows.

[How to measure]

1. Virus titer: Virus titer in blood was inoculated into SR-CDF1-DBT (DBT) cells by centrifugation to measure plasma titer by plaque assay.

2. Histopathological examination: After blood collection and bleeding at the time of death or slaughter, the liver was subjected to normal paraffin embedding to prepare 5 μm thick tissue sections, and then stained with Hematoxylin-Eosin (H & E) for optical analysis. It was observed under a microscope.

3. Immunohistochemical observation: Hepatic livers were removed from the mice that died during the experiment or autopsied at 10 days of inoculation, followed by visual observation. After immobilization in Bouin solution, the cells were embedded in paraffin according to a conventional method to make slides. Eosin staining and immunohistochemical staining with anti-MHV serum were performed to observe the optical microscopy of virus in liver tissue.

division MHV + D.W. MHV-2 + Gepix MHV-2 + UDCA MHV-2 + BDD MHV-2 + AH MHV-2 + AD MHV-2 + ADU D.W. 100 mg / kg 40 mg / kg 40 mg / kg 40 mg / kg 80 mg / kg 100 mg / kg Test 13 13 13 13 13 13 13 13 Survival 0 One 0 0 2 5 4 13 Survival rate (%) 0 7.7 0 0 15.4 38.4 30.8 100 The test was stopped on day 10 and slaughtered autopsies were performed on the new mouse.

As shown in Table 5, all of the UDCA-administered group and BDD-administered group died after the virus inoculation, but showed a slight survival rate in the Gepix-administered group and the AH-administered group, and the ADU (AH + BDD + UDCA complex) and ADU (AH + BDD + UDCA complexes). ) Significantly increased survival rate in the administration group.

division MHV1 + D.W. MHV-2 + Gepix MHV-2 + UDCA MHV-2 + BDD MHV-2 + AH MHV-2 + AD MHV-2 + ADU D.W. 100 mg / kg 40 mg / kg 40 mg / kg 40 mg / kg 80 mg / kg 100 mg / kg Deaths (survival) One 0/13 0/13 0/13 0/13 0/13 0/13 0/13 0/13 2 0/13 0/13 0/13 0/13 0/13 0/13 0/13 0/13 3 5/8 4/9 6/7 5/8 4/9 2/11 3/10 0/13 4 7/1 6/3 4/3 6/2 5/47 3/8 4/6 0/13 5 1/0 2/1 3/0 1/1 1/3 1/7 -/ 6 0/13 6 0/0 0/1 0/0 1/0 1/2 1/6 1/5 0/13 7 0/0 0/1 0/0 0/0 0/2 1/5 1/4 0/13 8 0/0 0/1 0/0 0/0 0/2 1/4 0/4 0/13 9 0/0 0/1 0/0 0/0 0/2 0/4 0/4 0/13 10 0/0 0/1 0/0 0/0 0/2 0/4 0/4 0/13 Average number of deaths (days) 3.69 3.83 3.77 3.85 3.91 4.88 4.2 Average number of deaths = (number of deaths × number of deaths) / total number of deaths * The test was discontinued on day 10 and slaughtered autopsies were performed on surviving mice.

As shown in Table 6, the AD (AH + BDD complex) administration group and the ADU (AH + BDD + UDCA complex) administration group according to the present invention was confirmed that the number of days until the average death is longer than the other drug administration group.

division MHV + D.W. MHV-2 + Gepix MHV-2 + UDCA MHV-2 + BDD MHV-2 + AH MHV-2 + AD MHV-2 + ADU D.W. 100 mg / kg 40 mg / kg 40 mg / kg 40 mg / kg 80 mg / kg 100 mg / kg Virus Count (PFU) 3 × 10 ⁷ 1.3 × 10 ⁷ 2.6 × 10 ⁷ 3.1 × 10 ⁷ 7.6 × 10 ⁷ 1.4 × 10 ⁷ 1.7 × 10 ⁷ 0

Table 7 showing the virus titers in each mouse on day 3 of the virus inoculation, showed that the AD (AH + BDD complex) administration group and the ADU (AH + BDD + UDCA combination) administration group had lower blood serum concentrations than the other drug administration groups. It was confirmed that the virus proliferation slightly.

In addition, as a result of examining the effects of each drug on the hepatitis virus induced by mouse hepatitis virus, most of the drugs showed severe cell necrosis showing eosinophilic fused necrosis due to disruption and fusion of liver cells throughout the liver. Normal hepatocytes were rarely observed. However, in the group administered with AH, AD, and ADU, necrosis over the liver was slightly weakened, and some normal liver tissues were observed, especially in the group treated with ADU. Furthermore, in the surviving mouse group, many nuclear fission and dinuclei were observed throughout the whole liver cells, and regeneration of hepatocytes was remarkably observed.

In summary, the AD and ADU according to the present invention was confirmed to show an excellent effect than the conventional drug against the hepatitis virus caused by mouse hepatitis virus.

Test Example 2: HBV inhibitory activity using an in vitro cellline assay.

HepG2-2.2.15 cells, a cell line producing human hepatitis B virus, were prepared in a T25 flask with 10% FeBS (Fetal Bovine Serum), 1% ABAM (GIBCO BRL. # 15240-013), and G418 at a final concentration of 200 mg / ml. After 6 days of incubation in a DMEM medium containing a dilution and aliquot to 1.0 ~ 1.2 × 10 ⁵ cell / ml / well in a 24 well microplate and incubated for about 3 hours in a 5% CO ₂ incubator. After confirming that the cells adhered well to the bottom of the plate, each sample was treated by diluting 1/10 by 1 nM at a final concentration of 10 μM.

At this time, the control group was treated with the concentration of interferon alpha (1000 IU) and lamivudine (10 μg / ml) as the appropriate maximum dose.

Using the HepG2-2.2.15 cells, RT-PCR, Western blot, LDH cytotoxicity and NO assay were tested by the following method.

(1) RT-PCR: PCR kit-Taq Core Kit 10, Q-Bio gene, USA

division primer Amino acid sequence Annealing Temperature (℃) collection HBsA (380 bp) 5'primer 5'-gaa gca ccc aag tgt cct g-3 '(SEQ ID NO: 1) 57.8 30 3'primer 5'-aaa cgg act gag gcc cac t-3 '(SEQ ID NO: 2) HBcAg (423bp) 5'primer 5'-tcc gtg atc tgc tcg aca c-3 '(SEQ ID NO: 3) 56.8 3'primer 5'-acc ttc gtc tgc gag gcg a-3 '(SEQ ID NO: 4) 6-16 (553 bp) 5'primer 5-caa gct taa ccg ttt act cgc tgc tgt-3 '(SEQ ID NO: 5) 62 3'primer 5'-tgc ggc cgc tgc tgg cta ctc ctc acc t-3 '(SEQ ID NO: 6)

(2) Western Blot

20 μg of protein samples were boiled in SDS loading buffer at 90 ° C. for 5 minutes and loaded onto 12% SDS-polyacrylamide mini-gels. After the end of electrophoresis was transferred to a PVDF membrane (membrane) and washed with TBS-T buffer (buffer) and then blocked (blocking) for 1 hour with 5% skim milk (skim milk). After washing for 15-5-5 minutes, the probe was probed with primary antibody for 1 hour. After washing for 15-5-5 minutes, a secondary antibody (HRP-conjugated) was attached to the X-ray film under ECL system (Santa Cruz). It was exposed to light and exposed.

(3) LDH cytotoxicity

For this experiment, Promega Cytotox 96 Asaay kit (Cat. # G1781) was used, and the cytotoxicity of the drug was examined by observing the amount of LDH, a stable cellular enzyme. The experimental method was applied to the method provided by the manufacturer and the result was measured at 490 nm.

(4) NO assay

For this experiment, Promega's Griess reagent system kit (Cat. # G2930) was used, and the reaction of the cells by the drug was observed by observing nitric oxide produced and secreted from the cells. The experimental method was applied to the method provided by the manufacturer and the result was measured at 540 nm.

As shown in Figures 1, 2 and 3, the results of in vitro experiments can be seen that after about 72 hours, the effect is obvious, biphenyl dimethyl dicarboxylate (BDD) according to the present invention The combination of amantadine hydrochloride (AH) and / or ursodeoxycholic acid (UDCA) showed effective results, and the antiviral effect was confirmed from the activity of STAT1-alpha protein and 6-6 gene.

In addition, the expression of IL-1beta similar to IFN-alpha was observed when amantadine hydrochloride (AH) and ursodeoxycholic acid (UDCA) were administered, so antiviral synergistic effects could be expected when the two drugs were administered in combination. As shown in Figure 1 and 2, it was shown that the expression of HBsAg from the direct endpoint (endpoint) is inhibited in the combination of three people, HBcAg also showed this result.

4 is a result showing the change in LDH, from this result, it was determined that the cytotoxicity by the study drug compared to the conventional drug was found to be a safe drug, in Figure 5 nitric known to be associated with HBV virus proliferation As an experiment showing the production of oxide (NO), the quantitative change of NO is expected in the group containing UDCA, so additional synergistic effect can be expected in HBV virus proliferation by UDCA.

In other words, it is difficult to expect the inhibition of HBV expression with amantadine hydrochloride alone (AH), but the long-term and long-term effects of biphenyl dimethyl dicarboxylate (BDD) and ursodeoxycholic acid (UDCA) can be predicted. It was confirmed that there is.

As described above, the pharmaceutical composition according to the present invention comprises biphenyl dimethyl dicarboxylate (BDD) and amantadine hydrochloride (AH) and / or ursodeoxycholic acid (UDCA) as an active ingredient and is pharmaceutically acceptable. By using an appropriate amount of excipients in combination, it shows strong protection against hepatotoxicity due to the synergistic effect of the above components, and thus can be very useful as a therapeutic agent for hepatitis.

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Claims (4)

Next, 7.5 to 200 parts by weight of biphenyl dimethyl dicarboxylate (BDD) represented by Formula 1 and 50 to 200 parts by weight of amantadine hydrochloride (AH) represented by Formula 2 are included. . [Formula 1]

[Formula 2]

The method of claim 1, wherein 50 parts by weight of biphenyl dimethyl dicarboxylate (BDD) represented by Chemical Formula 1 and 50 parts by weight of amantadine hydrochloride (AH) represented by Chemical Formula 2 are contained. Pharmaceutical composition. The pharmaceutical composition for treating hepatitis according to claim 1, wherein 50 to 100 parts by weight of ursodeoxycholic acid (UDCA) represented by the following Chemical Formula 3 is additionally contained in the pharmaceutical composition. [Formula 3]

According to claim 3, Biphenyl dimethyl dicarboxylate (BDD) represented by Formula 1 15 parts by weight, Amantadine hydrochloride (AH) 50 parts by weight of the formula (2) and Ursode represented by the formula (3) Pharmaceutical composition for treating hepatitis, characterized in that it contains 50 parts by weight of oxycholine acid (UDCA).

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