KR0137602B1 - Pharmaceutical composition for prevention and treatment of hepatic diseases - Google Patents

Abstract

The present invention relates to a pharmaceutical composition useful for the treatment and prevention of liver disease. The pharmaceutical composition of the present invention contains biphenyldimethyldicarboxylate (PMC) and garlic oil as active ingredients and, if necessary, contains a vitamin component and a pharmaceutically acceptable carrier. In the composition of the present invention, biphenyldimethyldicarboxylate (PMC) and garlic oil are preferably in a weight ratio of 1-5: 0.01-30, more preferably in a weight ratio of 2-5: 1-30, especially 2.5 -3: 5-20 weight ratio. The pharmaceutical composition of the present invention configured as described above is a safe drug that provides an excellent synergistic treatment effect of liver disease and preventive effect of protecting the liver from drug-induced liver damage as compared with the use of each component alone.

Description

Pharmaceutical composition for the treatment and prevention of liver disease

The present invention relates to a galvanic ring dentition and a preventive pharmaceutical composition. In particular, the present invention contains two drugs with different mechanisms for the liver, biphenyldimethyldicarboxylate (PMC) and garlic oil (garlic oil), both showing a synergistic effect against liver disease caused by various causes A pharmaceutical composition for treating and preventing diseases.

Modern people are exposed to various liver diseases due to excessive stress, drinking, smoking, and environmental pollution caused by various pollutions. Representative liver diseases include cirrhosis, alcoholic cirrhosis, fatty liver, addictive liver disease, and various forms of hepatitis such as acute and chronic viral hepatitis. Among them, especially in recent years, serious social problems have emerged as a type of viral hepatitis B that is highly contagious and has a high morbidity rate for chronic hepatitis, cirrhosis and liver cancer. Moreover, liver diseases such as hepatitis often cause serious liver damage and complications, which poses a great threat to modern people living in a collective society. Therefore, there is an urgent need for the development of a method that can cure hepatitis disease fundamentally with little relapse by restoring impaired liver function while effectively treating acute and active hepatitis disease including hepatitis B.

The treatment methods of liver disease, which are generally used in modern times, are largely divided into dietary therapy and pharmaceutical therapy, and in most cases, these two methods are used in combination. Among these methods, a wide variety of drugs are used in the pharmacotherapy for liver disease, but in reality, few drugs have a fundamental therapeutic concept by the etiological approach of liver disease. In the therapy of liver disease, drugs with various mechanisms of action may be used depending on the cause and type of liver disease, for example, urousdeoxycholine acid, silymarin, glutathione, glycyrrhizine, hepahydrate, multivitamins, etc. Hepatocellular rejuvenating agents and liver function aids, antiviral agents such as Acyclovir (ACV), immunosuppressive agents such as corticosteroids, 6-mercaptopurine (6-MP), azathioprine, D-penicillamine and Agents such as fibrosis inhibitors, biphenyldimethyldicarboxylate (PMC) and interferon are generally used. However, in most cases, hepatic disease is not caused by only one cause but is caused by a complex action of several factors, and thus, in his treatment, it is sufficiently satisfactory for all cases made by drugs having any one mechanism of action. High therapeutic effects could not be expected.

Accordingly, the present inventors have appropriately combined and administered drugs having different therapeutic routes among the above-mentioned drugs, and various combinations can be effectively treated if the liver function damaged by liver disease is simultaneously restored through various routes. I looked at the effect on. As a result, biphenyldimethyldicarboxylate (PMC), which exhibits excellent therapeutic and prophylactic effects on drug-induced hepatitis as well as chronic viral hepatitis, including active hepatitis and cirrhosis, can be used for chemically induced hepatotoxicity and hepatocellular destruction. When combined with garlic oil, which provides a preventive effect, it is confirmed that the present invention provides not only an excellent synergistic therapeutic effect but also a prophylactic effect for various liver diseases including hepatitis.

Biphenyldimethyldicarboxylate (chemical names: dimethyl-4 ', 4'-dimethoxy-5,6,5', 6'-dimethylenedioxybiphenyl-2,2'-dicarboxylate, PMC) was long ago It is a synthetic compound similar to Schizandrin C, an active ingredient of Schizandra chinensis, which has been used for folk medicine.

This biphenyldimethyldicarboxylate (PMC) is currently being applied in clinic as it has been demonstrated to have excellent effects on various chronic and viral hepatitis by animal and clinical trials. For example, in animal studies, biphenyldimethyldicarboxylate (PMC) has been shown to be safe in pharmacological and toxicological studies, as well as inhibiting liver damage caused by carbon tetrachloride. [Yu HuiQin: Diphenyl-dimethyl-dicarboxylate in treating and preventing hepatitis due to drug poisoning, Chinese Medical Journal, 100 (2): 122, 1987]. Also, biphenyldimethyldicarboxylate (PMC) has been shown to reduce serum alanine aminotransferase in patients with chronic active hepatitis and active cirrhosis. A prospective randomized controlled study of the effect of Biphenyl-Dimethyl-Dicarboxylate on Serum Alanine Aminotran sferase Levels in Patients with Chronic Active Liver Diseases, Lee Hyo-suk, et al. 40, No. 2, 1991]. Moreover, recently, the effects of biphenyldimethyldicarboxylate (PMC) on carbon tetrachloride-administered immunobiological responses have been examined, which suggests that biphenyldimethyldicarboxylate (PMC) has been shown to affect humoral immunity, cellular immunity and It has been reported to enhance apoptotic function such as specific immunity [Effect of Biphenyl Dimethyl Dicarboxylate on the immunobiological response of mice administered with carbon tetrachloride, the 41st Korean Society of Pharmaceutical Spring Conference 1992].

Garlic oil contains about 1% of allicin and includes its reducing agent diallyl disulfide. This substance has a bactericidal action in aqueous solution, is extremely stable when combined with vitamin B1, and rapidly changes to alithiamine to facilitate digestive tract absorption. According to an open study using 20 patients with high cholesterol, blood glucose, triglyceride, and high-density lipoprotein levels were significantly lower in the four-week Q-dose group than garlic-only group. . In addition to lipid lowering effects, in vitro studies using garlic extracts containing allicin as the main ingredient have reported antifungal, antimycobacterium tuberculosis and antiviral effects. Diallyl sulfide (DAS) and allicin defend against colon epithelial nuclear aberration in mice using mice as an aromatic component of garlic oil. DAS suppressed the development of cancer caused by 1,2-dimethylhydrazine (DMH) in rats, and has been shown to protect against hepatotoxicity induced by DMH, as well as N-nitrosodimethylbenzyl as another carcinogen. Esophageal cancer caused by amines was also suppressed. However, unlike biphenyldimethyldicarboxylate (PMC), garlic oil is known to have no effect on liver damage caused by carbon tetrachloride. The mechanism of the protective effect of garlic oil against these chemicals or carcinogens has not been fully understood, but the activity of cytochrome P450 2E1 in addition to the modest increase in the activity of glutathione S-transferase in the liver when DAS is administered And it is assumed that blocking the early metabolic activation of DMH by inhibiting expression is a mechanism of action, but until now there has been no specific report that garlic oil improves liver function by inhibiting abnormal increase of GOT, GPT and the like. Accordingly, the inventors of the present invention performed repeated experiments on the liver function improvement effect of garlic oil, and confirmed that garlic oil exhibited an excellent liver function improvement effect and was selected as a drug of the present invention.

Therefore, the present inventors have experimented by combining garlic oil with biphenyldimethyldicarboxylate (PMC), which can act on liver disease by a completely different mechanism of action, resulting in a surprising synergistic treatment of the liver by the complementary action of the two drugs. And it was confirmed that the preventive effect is provided to complete the present invention.

That is, the present invention relates to a pharmaceutical composition for treating and preventing liver disease, characterized by containing biphenyldimethyldicarboxylate (PMC) and garlic oil.

In the pharmaceutical composition according to the present invention, biphenyldimethyldicarboxylate (PMC) and garlic oil are preferably in a ratio of 1-5: 0.01-30, more preferably in a ratio of 2-5: 1-30, by weight. , In particular, in a ratio of 2.5-3: 5-20.

The composition of the present invention may also contain vitamins, which are adjuvant commonly used for treating liver disease, if necessary. These vitamin components are rarely used for the purpose of treating liver disease because they have little therapeutic effect on liver disease when used alone, but when included in the composition of the present invention, garlic oil may be easily absorbed to increase the effect. In addition, the vitamin deficiency caused by poor absorption of water-soluble and fat-soluble vitamins, decreased storage amount, and activating disorders that may occur in the liver of patients with liver disease, can be compensated, and the liver disease treatment and liver function improvement effect by the composition of the present invention Can be improved. The vitamin component which can be used in the composition of the present invention is not particularly limited, but preferably, vitamin B ₁ and B ₂ components such as thiamine hydrochloride, thiamine nitrate, riboflavin, riboflavin tetrabutyrate and the like are used. When the vitamin component is included in the composition of the present invention, the vitamin component is preferably used in a ratio of 0.01 to 2 parts by weight per 1 part by weight of biphenyldimethyldicarboxylate (PMC).

The pharmaceutical composition of the present invention is administered in actual use, preferably formulated in a unit dosage form suitable for oral administration according to methods conventional in the pharmaceutical art. Formulations for oral administration suitable for this purpose include tablets, hard and soft capsules, and the like. Such oral preparations include, in addition to two pharmacologically active ingredients, one or more pharmaceutically inert conventional carriers such as excipients such as starch, lactose, carboxymethylcellulose, kaolin, water, gelatin, alcohols, glucose Additional additive components such as binders such as gum arabic, tragaganta rubber, disintegrants such as starch, dextrin, sodium alginate, and suspending agents such as talc stearic acid, magnesium stearate, liquid paraffin, and the like may be included.

The daily dosage of the composition according to the present invention will vary depending on various factors such as the severity of the liver disease, the state of liver function, age, and complications of the subject to be administered. 900 mg, preferably 125 to 750 mg is administered orally in 1 to 3 divided doses per day. However, in case of severe liver disease such as active cirrhosis, the composition of the present invention may be administered by increasing the composition to a large amount outside the above-mentioned range. Most preferably, a unit dose containing 25 mg of biphenyldimethyldicarboxylate (PMC) and 50 mg or 100 mg of garlic oil is administered orally three times a day.

The pharmaceutical composition according to the present invention is a biphenyl dimethyl dicarboxylate (PMC) which has an excellent effect of treating liver disease, and has an effect of inhibiting hepatotoxicity and hepatocellular destruction by chemicals, and a mechanism different from this to chemical compounds. The excellent preventive effect of garlic oil, which suppresses the hepatotoxicity caused by it, is optimally harmonized to provide an excellent synergistic treatment and prevention of synergistic liver disease that was never expected, and there is almost no toxicity and side effects thereby. It is a drug that can be used with confidence even when taking a long time, especially for prophylactic purposes.

The present invention is explained in more detail by the following examples and experimental examples, but the present invention is not limited in any way by these examples.

Composition example

Example 1 (Drug)

Component Content (100. Party)

Biphenyldimethyldicarboxylate (PMC) ......................... 2.5g

Garlic oil ... ............... 10.0g

Lactose ... ............... 12.0g

Corn Starch ... ......... 8.5g

Calcium Carboxymethylcellulose ....................... 2.5g

Magnesium Stearate ......................................... 0.5g

Hydroxypropyl Cellulose ................................. 2.5g

Arabian rubber ... ........ 0.3g

Talc ... 0.8 g

Ash ash titanium ... ............... 0.075g

Gelatin ... 0.05 g

Per bag ... 19.4 g

Hydroxypropylmethylcellulose ............. 0.3g

Polyethyleneglycol 6000 .......................................... 0.075g

Precipitated Calcium Carbonate ... ........... 4.0g

2.5 g of biphenyldimethyldicarboxylate (PMC) was added to 10.0 g of garlic oil, stirred for 1 hour while maintaining the temperature at 30 to 60 ° C., and then cooled to room temperature, and the respective amounts of the ingredients specified above were added to uniformity. After compounding, the tablets were compressed according to a conventional method for preparing tablets to prepare 100 tablets each containing 635 mg of the composition in one tablet.

Example 1 (made by capsule)

Component Content (per 100 capsules)

Biphenyldimethyldicarboxylate (PMC) ... 5.0 g

Garlic oil ... 4.0 g

Corn Starch ... .......... 15.0g

Lactose ... 12.0 g

Magnesium Stearate ......................................... 0.5g

According to the conventional capsule preparation method, the above-mentioned ingredients were combined in a predetermined amount, and then filled with hard gelatin capsules of appropriate size to contain a blend of 365 mg per capsule, thereby preparing a desired capsule.

Example 3 (soft capsule)

Component Content (per 100 capsules)

Biphenyldimethyldicarboxylate (PMC) ....................... 2.5g

Garlic oil ... 20.0 g

Soybean oil ... 50.0 g

Paraoxymethylbenzoate ..................................... 0.024g

Paraoxypropylbenzoate .................................... 0.006 g

Glycerin ... .............. 0.5g

Gelatin ... 0.5 g

Sorbitol ..................... 1.5 g

After blending the above components in a specified amount, a soft capsule containing 750.3 mg of the compound per capsule was prepared according to a conventional soft capsule preparation method.

Example 4 (made of capsule)

Component Content (per 100 capsules)

Biphenyldimethyldicarboxylate (PMC) ......... 2.5 g

Garlic oil ... 5.0 g

Vitamin B1 ... ........... 0.2g

Vitamin B2 ... ........... 0.2g

Corn Starch ... ......... 15.0g

Lactose ... 14.0 g

Magnesium Stearate ......................................... 0.7g

According to the conventional capsule preparation method, the above-mentioned ingredients were combined in a predetermined amount, and then filled with hard gelatin capsules of appropriate size to contain 376 mg of each compound.

Experimental Example

Experimental Example 1

The following experiments were performed to compare the effects of the pharmaceutical compositions according to the invention on drug-induced liver damage with the effects of administering each combination component alone.

As a test animal, 36 male Sprague-Dawley rats weighing 200-250 g were used. The carbon tetrachloride as a 50% solution mixed with corn oil was administered to experimental animals twice a week (Tue, Fri) for 4 weeks at a dose of 0.75 ml / kg body weight. Eight of the carbon tetrachloride-treated groups were used as the first group without treatment of the therapeutic drug, and the second group (8 rats) was given biphenyldimethyldicarboxylate (PMC) 50 kg / kg to the rats simultaneously with carbon tetrachloride. The formula was administered once a day, six days a week. In the third group (8 rats), rats were administered 100 mg of garlic oil per kilogram of body weight once a day and 6 days a week. In the fourth group (8 rats), 50 mg of biphenyldimethyldicarboxylate (PMC) and 100 mg of garlic oil per kg of body weight were administered to rats simultaneously with carbon tetrachloride. The other group 1 (4 rats) was used as a drug-untreated group which was not treated with any drug. After the drug administration was continued for 4 weeks, the animals were killed and serum was obtained to measure the ALT concentration in the serum. The results are shown in Table 1 below.

TABLE 1

Effect of the pharmaceutical composition according to the invention on CCl ₄ -induced liver injury

Note) 1. Each of the above figures is the mean ± standard deviation of the measured ALT values in each group.

2. Group 1: Control group treated with carbon tetrachloride only

Group 2: The group which received biphenyl dimethyl dicarboxylate (PMC) after carbon tetrachloride treatment

Group 3: garlic oil treated after carbon tetrachloride

Group 4: A group administered with a mixture of biphenyldimethyldicarboxylate (PMC) and garlic oil (composition of the present invention) after carbon tetrachloride treatment

Group 5: Untreated group not treated with any drug

As can be seen from the results shown in Table 1 above, after treatment with carbon tetrachloride, only biphenyldimethyldicarboxylate (PMC) was administered at a dose of 50 mg / kg / day, followed by CCl ₄ − Although it was effective in reducing the induced increase in ALT activity by 28%, the group receiving 100 mg / kg garlic oil daily showed no therapeutic effect on CCl ₄ -induced liver damage. On the contrary, in the group administered with a 1: 2 dose ratio mixture of biphenyldimethyldicarboxylate (PMC) and garlic oil, the pharmaceutical composition according to the present invention, a 64% decrease in CCl ₄ -induced ALT was shown, resulting in a biphenyldimethyldicarboxylate. It can be seen that there is a more than twofold increase in efficacy compared to the group treated with (PMC) alone.

Therefore, from the above results, in the pharmaceutical composition of the present invention, biphenyldimethyldicarboxylate (PMC) is mixed with biphenyldimethyldicarboxylate (PMC) by combining garlic oil having no therapeutic effect against CCl ₄ -induced liver damage. It can be clearly seen that the synergistic effect is excellent compared to the case of administration alone.

Experimental Example 2

Since metabolism of carbon tetrachloride activates Cooper cells and releases toxic secretions, activation of Cooper cells and an increase in the number of Cooper cells is an important factor related to the death of hepatocytes. Therefore, the effect of the pharmaceutical composition according to the present invention, which inhibits invasion of Cooper cells and death of hepatocytes by CCl ₄ -induced liver injury, was compared with the effect of administering each of the compounding ingredients alone.

1) Rats inducing liver damage by carbon tetrachloride in Experimental Example 1 were killed, and livers were extracted from each animal group and used as experimental materials. After infiltrating 1% formaldehyde solution into the extracted liver tissue, staining with hematoxylin and eosin was performed to measure the infiltration rate of Cooper cells, phagocytes present in the liver, under a microscope. The results are shown in Table 2 below.

TABLE 2

Effect of the pharmaceutical composition according to the present invention for inhibiting infiltration of Cooper cells

Note: 1. Each of the above figures is the mean number ± standard deviation of infiltrated Cooper cells measured in each animal group.

2. The percentage change is a value calculated relative to the control at 100%.

3. Group 1: Control group treated with carbon tetrachloride only

Group 2: The group which received biphenyl dimethyl dicarboxylate (PMC) after carbon tetrachloride treatment

Group 3: garlic oil treated after carbon tetrachloride

Group 4: A group administered with a mixture of biphenyldimethyldicarboxylate (PMC) and garlic oil (composition of the present invention) after carbon tetrachloride treatment

Group 5: Untreated group not treated with any drug

As can be seen from the results of Table 2, the infiltration of Cooper cells induced by carbon tetrachloride was lower in the liver tissue of the biphenyldimethyldicarboxylate (PMC) -administered group than the garlic oil-administered group. The effect of inhibiting invasion of Cooper cells was significantly better in the group to which the composition of the present invention was administered compared to the group to which each drug was administered alone. Therefore, with respect to cirrhosis due to hepatic fibrosis in hepatic parenchyma, the effect of inhibiting Cooper cell invasion due to administration of the pharmaceutical composition according to the present invention will help to prevent the hardening of liver tissue that can occur in various ways. It is expected.

2) Excision of the abdomen was performed to expose the liver before the rats inducing liver injury in Experimental Example 1, and liver tissue was saturated with an oxygen / carbon dioxide (95: 5) mixture in a circulatory system (Krebs-). Henseleit) bicarbonate buffer (pH 7.6, 37 ° C). After removing blood, trypanblue (0.4 mM) was injected for 10 minutes, followed by 10 minutes of washing with Krebs-Hencelite buffer, followed by immobilization of 1% paraformaldehyde. Tissue sections were stored for histological analysis and stained with eosin. The number of dead hepatic parenchymal cells (blue nuclei) was measured in the range of 5 cell radius centered on the periventral vein. Results are expressed in trypan blue-positive cells / field.

TABLE 3

Inhibitory effect of the pharmaceutical composition according to the present invention on hepatocyte death

Note) 1. Each of the above values is the mean hepatocyte death rate ± standard deviation measured in any visible region (400 magnification) in each animal group (n = 10).

2.% inhibition is a value calculated relative to the control 100%.

3. Group 1: Control group treated with carbon tetrachloride only

Group 2: The group which received biphenyl dimethyl dicarboxylate (PMC) after carbon tetrachloride treatment

Group 3: garlic oil treated after carbon tetrachloride

Group 4: A group administered with a mixture of biphenyldimethyldicarboxylate (PMC) and garlic oil (composition of the present invention) after carbon tetrachloride treatment

Group 5: Untreated group not treated with any drug

As can be seen from the results shown in Table 3 above, when biphenyl dimethyl dicarboxylate (PMC) and garlic oil were used in combination according to the present invention, biphenyl dimethyl dicarboxylate (PMC) or garlic oil was respectively used. It clearly shows an elevated hepatoprotective effect compared to the case of use alone. In other words, when CCl ₄ rats were treated for 4 weeks, there was a clear overlook at the central periphery, but when biphenyldimethyldicarboxylate (PMC) was administered alone, the number of dead hepatocytes was reduced by 41%. Treatment with garlic oil reduced the number of dead hepatocytes by 34%. On the other hand, when treated with the composition according to the present invention showed an effect of reducing the number of dead hepatocytes by 80%. From the above results, it can be seen that the mixed composition of biphenyldimethyldicarboxylate (PMC) and garlic oil according to the present invention has a clearly elevated effect compared to the case of using each alone.

Experimental Example 3 Effects of the Compositions of the Invention on CCl ₄ -Induced Fatty Liver

The following experiments were conducted to determine the effect on fatjiyun in the liver of the composition according to the present invention.

65 male ICR mice, each weighing about 20 to 30 g, were divided into 6 groups (groups 1 to 6) and 5 groups of 1 group (group 7), each of 10 rats and used for the experiment. Modified feed containing 0.007% biphenyldimethyldicarboxylate (PMC) in the first group, modified feed containing 0.14% biphenyldimethyldicarboxylate (PMC) in the second group, garlic oil in the third group Modified feed containing 0.07%, modified feed containing 0.14% garlic oil in group 4, modified feed containing 0.007% biphenyldimethyldicarboxylate (PMC) and 0.07% garlic oil in group 5 Was administered for 7 days, and the sixth and seventh groups received data without addition of any drugs for 7 days. Here, the content of each component is expressed based on the total weight of the feed, and the total amount of the feed fed to the mouse per day was adjusted to about 2 to 3 g. Therefore, administration of a feed containing 0.007% of biphenyldimethyldicarboxylate (PMC) and 0.07% of garlic oil, respectively, of 3 mg of biphenyldimethyldicarboxylate (PMC) and 30 mg of garlic oil per kilogram of body weight per day, respectively. It is equivalent to intake. After the feed was completed, each animal of the first to six groups except for the seventh group was intraperitoneally administered with carbon tetrachloride at a dose of 50 μg / kg body weight. Twenty four hours after treatment with carbon tetrachloride, the liver was excised and homogenized, and commercially available kits (TG Kit, Cholesterol-E Kit: Young Dong) were used to measure the concentrations of triglycerides and total cholesterol in liver homogenates (1:10, w / w). Drug). The seventh group measured the concentrations of triglyceride and total cholesterol in the liver as it was after feeding. The measured results are as described in Tables 4 and 5 below.

TABLE 4

Effect on the liver triglyceride concentration of the composition according to the present invention

Note) 1. All values are expressed as mean ± standard error.

2. The change rate (%) is a value obtained by calculating the concentration increase in the sixth group to 100% based on the concentration in the seventh group, which is the untreated group, and calculating the increase in each group relatively.

TABLE 5

Effect on the total hepatic cholesterol concentration of the composition of the present invention

Note) 1. All values are expressed as mean ± standard error.

2. The rate of change was expressed based on the cholesterol concentration of the seventh group, which was not treated.

As can be seen from the results described in Tables 4 and 5, in the case of the animal group inducing fatty liver with carbon tetrachloride after administration of a feed containing 0.007% or 0.014% biphenyldimethyldicarboxylate (PMC) Triglyceride concentrations increased by 87% and 63% in the liver triglyceride concentrations compared to the non-treated group, that is, the seventh group, and were treated with carbon tetrachloride after administration of feed containing 0.07% or 0.14% garlic oil. Fatty liver-derived animals showed only 68% and 41% increase, respectively, compared to the seventh bacterium, while biphenyldimethyldicarboxylate (PMC) (0.007%) and garlic oil (0.07) according to the present invention. %) Showed only a 38% increase over the untreated group 7. From these results, it can be seen that the composition of the present invention exhibits an excellent inhibitory effect of increasing the concentration of triglycerides in the liver compared to the case where the individual components are administered at twice the dose.

In addition, the first, second and third groups inducing fatty liver with carbon tetrachloride after administration of a feed containing 0.007% or 0.14% biphenyldimethyldicarboxylate (PMC) or 0.07% garlic oil in the total cholesterol concentration In each group, the cholesterol concentration was 53%, 56% and 54% compared to the non-treated group 7, whereas the fifth group to which the composition according to the present invention was administered had a cholesterol concentration of 66% compared to the seventh group. It was. Therefore, it can be seen from the above results that the administration of a combination of biphenyldimethyldicarboxylate (PMC) and garlic oil increases the liver cholesterol concentration even more significantly than when the individual drug is administered at a double dose.

These results demonstrate that the combination of biphenyl dimethyl dicarboxylate (PMC) and garlic oil shows a significantly superior preventive effect against fatty liver caused by carbon tetrachloride compared to the case of using individual components alone.

Experimental Example 4: Acute Toxicity Test

In order to measure the acute toxicity of the pharmaceutical composition according to the present invention, Sprague-Dowley rats weighing 150-200 g were orally administered the composition according to the present invention to confirm their mortality.

The test agent is biphenyl dimethyl dicarboxylate (PMC) and garlic oil by weight 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 8, 1:10, 1 Pharmaceutical compositions containing the ratios of: 20 and 1:30 were administered orally in amounts of 0.1 g, 0.2 g, 0.5 g, 1 g and 3 g per kg body weight of the test animal. Ten rats were used for each test drug. The death rate was determined by counting the number of animals that died two weeks after drug administration. The results are shown in Table 6 below.

TABLE 6

Acute Toxicity of the Pharmaceutical Compositions of the Invention

Note) 1.PMC = biphenyldimethyldicarboxylate

GAL = Garlic Oil

2. The ratio of PMC and GAL is based on weight.

3. The number of test animals in each group is 10.

As shown in the results of Table 6, it can be seen that the pharmaceutical composition of the present invention is substantially very safe and non-toxic drugs.

From the results of the above experiments, the pharmaceutical composition according to the present invention exhibits a superior synergistic hepatic disease treatment effect compared to the case where each ingredient is used alone by a unique combination of biphenyldimethyldicarboxylate (PMC) and garlic oil. It also provides a clear advance in the art as it also exhibits a prophylactic effect of protecting the liver from drug-induced long injuries.

Claims (12)

A pharmaceutical composition for treating and preventing liver disease, characterized by containing biphenyldimethyldicarboxylate (PMC) and garlic oil. The pharmaceutical composition for treating and preventing liver disease according to claim 1, wherein biphenyldimethyldicarboxylate (PMC) and garlic oil are contained in a ratio of 1-5: 0.01-30 by weight. The pharmaceutical composition for treating and preventing liver disease according to claim 2, wherein biphenyldimethyldicarboxylate (PMC) and garlic oil are contained in a ratio of 2-5: 1-30 by weight. 4. The pharmaceutical composition for treating and preventing liver disease according to claim 3, wherein biphenyl dimethyl dicarboxylate (PMC) and garlic oil are contained in a ratio of 2.5-3: 5-20 by weight. The pharmaceutical composition for treating and preventing liver disease according to claim 4, wherein the pharmaceutical composition is in a unit dosage form containing 25 mg of biphenyldimethyldicarboxylate (PMC) and 50 mg or 100 mg of garlic oil. The pharmaceutical composition for treating and preventing liver disease according to claim 1, further comprising at least one vitamin component. The pharmaceutical composition for treating and preventing liver disease according to claim 6, wherein the vitamin component is contained in a ratio of 0.01 to 2 parts by weight per 1 part by weight of biphenyldimethyldicarboxylate (PMC). The pharmaceutical composition for treating and preventing liver disease according to claim 6, wherein the vitamin component is a vitamin B ₁ or a vitamin B ₂ component or a mixture thereof. The pharmaceutical composition for treating and preventing liver disease according to any one of claims 1 to 8, further comprising at least one pharmaceutically acceptable carrier. A method for preparing a pharmaceutical composition for treating and preventing liver disease according to any one of claims 1 to 9, characterized by mixing biphenyldimethyldicarboxylate (PMC) with garlic oil. The method of claim 10, wherein the mixture of biphenyldimethyldicarboxylate (PMC) and garlic oil is subsequently formulated into a pharmaceutical unit dosage form. The method of claim 11, wherein the pharmaceutical unit dosage form is a tablet, hard capsule, or soft capsule.