KR20210095249A - Combination formulation containing colchicine for treatment or enhancing the therapy of liver disease - Google Patents

Abstract

The present invention relates to a combination formulation for treating liver disease or enhancing a treatment effect. More specifically, the present invention relates to a combination formulation prepared by comprising colchicine, metformin, and carnitine as main active ingredients. The composition according to the present invention can be used as a treatment agent for liver diseases, which is effective for treating or preventing liver fibrosis, hepatocirrhosis, liver cancer, hepatitis and the like by reducing an amount of fat accumulated in liver tissues and lowering sugar resistance and insulin resistance, based on a synergetic effect of colchicine, metformin, and carnitine. Also, the composition can be used as an excellent medicine which can replace ursodeoxycholic acid, which has been widely used up to now as a liver disease treatment agent.

Description

Colchicine combination formulation containing colchicine for treatment or enhancing the therapy of liver disease

The present invention relates to a combination preparation for the treatment of liver disease or for enhancing the therapeutic effect, and the combination preparation is formed by including colchicine, metformin and carnitine as main active ingredients. More specifically, when administered by mixing colchicine, the drug known to have a hepatoprotective effect, with metformin, which is mainly used for diabetic diseases, and carnitine, which is known to have the effect of promoting lipolysis, it is superior to the conventional drug administered alone. It relates to a pharmaceutical composition exhibiting a pharmacological effect, and relates to a pharmaceutical composition for enhancing the therapeutic effect of liver disease prepared by specifically limiting the content of the drugs.

The liver plays a central role in the metabolism of substances and the body from outside the body, and is a living organ in which enzymatic reactions and energy metabolism occur continuously. Currently, hepatitis, liver cirrhosis and liver cancer account for the highest proportion of chronic diseases in Korea along with circulatory system diseases, and they account for a large proportion of the causes of death due to diseases. In particular, as the drinking population is relatively high compared to developed countries, and the cause of liver damage due to binge drinking is high, interest in it is high. Continuous damage to liver tissue due to viral infection or drinking is characteristic of a disease that develops into liver cirrhosis or liver cancer. Treatment and prevention of liver disease is very important in consideration of the physiological characteristics and importance of liver tissue, and the development of a pharmaceutical composition capable of reducing liver tissue damage and ultimately enhancing the therapeutic effect is required.

In particular, liver fibrosis refers to a state in which damaged liver tissue is transformed into fibrous tissue such as collagen, rather than being restored to normal hepatocytes, as part of a bioadaptation reaction accompanying chronic liver disease such as hepatitis. Although hepatic fibrosis is a bioadaptation reaction that occurs during the repair process of tissue damage, a decrease in liver function is inevitable in that the liver is replaced with fibrous tissue that cannot perform the inherent functions of the liver such as metabolism and bile secretion in the living body. The development of an appropriate therapeutic agent has been performed as an important task in drug development in that, when the liver fibrosis phenomenon is continuously repeated, it develops into cirrhosis and leads to death. However, until now, the mechanism of liver fibrosis itself has not been clearly elucidated, and thus, an appropriate therapeutic drug has not been developed.

Meanwhile, colchicine has already been widely used as a treatment for gout-related arthritis, and cases of acute gout and recurrent gout have also been reported. In addition, the pharmacokinetic properties of colchicine have also been reported, and it is characterized by oral administration. For more than 10 years, colchicine has been reported on various indications and mechanistic studies have been conducted. It is reported that there is

Ursodeoxycholic acid (UDCA), which has been extensively used as a treatment for liver disease in the past, is a major component of bile duct, and contains strong detoxification ability. It is known to prevent accumulation.

Ursodeoxycholic acid (UDCA) is imported from China because almost all of the raw materials used in Korea are imported from China. There is a limit to the quantity and price. Accordingly, there is an urgent need to develop a drug that can replace the UDCA in order to treat liver disease and the like.

Republic of Korea Patent Publication No. 10-2015-0102969 Republic of Korea Patent Publication No. 10-2015-0143725

The present invention has been developed to solve the above problems, and the present inventors have developed colchicine, a treatment for gouty arthritis, metformin, which is previously used as a treatment for metabolic diseases such as cardiovascular disease and diabetes, and increase blood flow in vivo to reduce fat degradation. It was confirmed that the therapeutic effect of liver fibrosis or inflammatory liver disease, such as liver fibrosis or inflammatory liver disease, was enhanced when a complex prepared by mixing carnitine, which is known to promote, as a main active ingredient was prepared and administered, and based on this, the present invention was completed.

Another object of the present invention is to provide a dose that exhibits the most suitable efficacy when the colchicine, metformin and carnitine are administered to the human body.

The technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

In order to solve the above problems, the present invention provides a pharmaceutical composition for treating liver disease comprising colchicine, metformin and carnitine as main active ingredients.

In addition, the present invention provides a pharmaceutical composition for enhancing the therapeutic effect of liver disease comprising colchicine, metformin and carnitine as main active ingredients. The pharmaceutical composition for enhancing the therapeutic effect is the same concept as a therapeutic adjuvant for preventing and treating liver disease, which is the target disease of the present invention.

In one embodiment of the present invention, the liver disease may be one or more selected from liver fibrosis, liver cirrhosis, liver cancer, and inflammatory liver disease.

In one embodiment of the present invention, the co-administration may be in the form of administering the composition simultaneously (simultaneous), separately (separate) or sequentially (sequential) with the hepatoprotective agent.

In one embodiment of the present invention, the inflammatory liver disease is hepatitis, acute hepatitis, chronic hepatitis, alcoholic hepatitis, nonalcoholic hepatitis, subacute hepatitis, viral hepatitis, toxic liver disease, liver abscess, granulomatous hepatitis, autoimmune hepatitis and It may be selected from lupus-like hepatitis.

The composition according to the present invention is a combination preparation formed by including colchicine, metformin and carnitine as main active ingredients, and the combination preparation provided in the present invention is a combination of drugs showing a synergistic effect to treat liver fibrosis or inflammatory liver disease effect can be enhanced.

The combination preparation according to the present invention can be usefully used as a pharmaceutical composition for enhancing the therapeutic effect of liver diseases such as inflammatory liver disease including liver fibrosis, liver cirrhosis, liver cancer or hepatitis even when administered at a low dose.

1 is a summary of the process of carrying out an embodiment of the present invention.
Figure 2 shows the results of anatomical observation of the liver cross section of rats when colchicine alone and colchicine/metformin/carnitine were co-administered to obesity-induced rats using H&E staining.
Figure 3 shows the fat accumulated in the liver cross section of the rat that appears when colchicine alone and colchicine/metformin/carnitine are co-administered to obese-induced rats, stained with oil red O technique.
4 is a result of measuring the activation of AMPK and ACC metabolite in the liver tissue of rats when colchicine alone and colchicine/metformin/carnitine are co-administered to obesity-induced rats using mass spectrometry.
5 is a result confirming whether colchicine alone and colchicine/metformin/carnitine have an effect on AMPK and ACC activation of the hepatocyte AML12 cell line induced in the rat liver when co-administered.
6 is a result of measuring glucose resistance (Glusoce tolerance test: GTT) and insulin resistance (Insulin tolerance test: ITT) appearing when colchicine alone and colchicine/metformin/carnitine are co-administered to obesity-induced mice.
7 is a result of measuring the levels of liver triglyceride (Liver triglyceride) and plasma triglyceride (Plasma triglyceride) appearing when colchicine alone and colchicine/metformin/carnitine are co-administered to obesity-induced rats.
8 is a result of measuring the cholesterol (Cholesterol) level appearing when the colchicine alone and colchicine / metformin / carnitine co-administered to obesity-induced rats.
9 is a result of collagen staining using Masson's trichrome staining method in order to confirm sclerosis (Fibrosis) of the colon tissue of mice that appears when colchicine alone and colchicine/metformin/carnitine are co-administered to obesity-induced mice.
10 is a result of measuring the albumin content that appears when colchicine alone and colchicine/metformin/carnitine are co-administered to obesity-induced rats.
11 is a result of measuring ALT that appears when colchicine alone and colchicine/metformin/carnitine are co-administered to obesity-induced rats.
12 is a result of measuring AST appearing when colchicine alone and colchicine/metformin/carnitine are co-administered to obesity-induced rats.
13 is a result of measuring the total amount of protein that appears when colchicine alone and colchicine/metformin/carnitine are co-administered to obesity-induced rats.
14 is a result of measuring hydroxyproline that appears when colchicine alone and colchicine/metformin/carnitine are co-administered to obesity-induced rats.

In the case of administration of a combination formulation comprising all of colchicine, metformin and carnitine provided in the present invention, it was confirmed that liver function was improved in patients with severe chronic active hepatitis and early liver cirrhosis with severe disease activity, and hepatoprotective agent and When it was confirmed that there is an effect of enhancing treatment when colchicine is administered in combination or in combination, the present invention has been completed based on this.

Hereinafter, the present invention will be described in detail.

Among the terms used in the present invention, "inflammatory liver disease" is generally called hepatitis, and refers to a general disease caused by inflammation of hepatocytes and liver tissues. Inflammatory liver disease according to the present invention is hepatitis, acute hepatitis, chronic hepatitis, alcoholic hepatitis, non-alcoholic hepatitis, subacute hepatitis, viral hepatitis, toxic liver disease, liver abscess, granulomatous hepatitis, autoimmune hepatitis, lupus-like hepatitis, etc. may include, but is not limited thereto.

Among the terms used in the present invention, "treatment" refers to any action in which liver fibrosis or inflammatory liver disease is improved or is advantageously changed by administration of the pharmaceutical composition according to the present invention.

Colchicine, the main active ingredient used in the present invention, is a substance extracted from a plant of the genus Colchicum, and is mainly used as an alternative drug for gout when non-steroidal anti-inflammatory drugs do not show a smooth therapeutic effect on gout. It is a drug and is also used in the treatment of familial Mediterranean fever, pericarditis, and Behcet's disease.

Another active ingredient used in the present invention, metformin, is a biguanide drug and is mainly used as a treatment for diabetes because it has an effect on improving blood sugar. Although the mechanism of action of metformin is not precise, it is known that it inhibits cellular respiration that occurs in mitochondria and activates AMPK to prevent glucagon-induced cAMP concentration increase, and consequently inhibits PKA activity to inhibit glucose production.

Another active ingredient used in the present invention, carnitine, is a component contained in soybeans, red meat, avocado, etc., and is known as a substance that accelerates fat burning by accelerating glycogen consumption in the living body and consequently decomposing fatty acids.

The present inventors confirmed through various experiments that when colchicine, metformin, and carnitine are administered in a combined form, the liver disease treatment efficacy is enhanced.

In one embodiment of the present invention, as a result of confirming the therapeutic effect of administering the combination drug of colchicine, metformin and carnitine through blood biochemical test, compared with the single administration of colchicine, the recovery of albumin levels and total protein concentration was confirmed, , it was confirmed that the activation of AMPK (AMP-activated protein kinase) and ACC (acetyl-CoA carboxylase) was further increased.

In addition, in one embodiment of the present invention, as a result of confirming the fibrin level when colchicine, metformin, and carnitine are administered in a combined form through Hydroxyproline assay, the level of fibrin is reduced in the combined administration compared to when colchicine is administered alone The mode of making was confirmed.

In addition, in one embodiment of the present invention, when colchicine, metformin, and carnitine are administered in a combined form through H&E staining, which is a histopathological examination, changes in liver function and liver tissue were confirmed, compared to when colchicine was administered alone. Thus, it was confirmed that the pathological findings were further improved in combination administration.

The contents of colchicine, metformin and carnitine included in the combined preparation of colchicine, metformin and carnitine provided in the present invention are as follows.

In administering the combination formulation provided by the present invention, the colchicine is preferably 10 to 200 μg/kg, more preferably 50 to 100 μg/kg.

The metformin is preferably added in an amount of 50 to 400 mg/kg, more preferably 100 to 200 mg/kg.

The carnitine is preferably 50 to 500 mg/kg, more preferably 100 to 200 mg/kg.

When the content of colchicine is less than 10 μg/kg, the efficacy of colchicine is hardly exhibited, and when the content exceeds 200 μg/kg, there is a side effect of causing gastrointestinal disorders when taken.

When the content of metformin is less than 50 mg/kg, the efficacy is not exhibited, and when the content exceeds 400 mg/kg, there is a possibility that side effects such as abdominal pain, diarrhea, and vomiting may occur.

When the content of carnitine is less than 50 mg/kg, the synergistic effect of the components is not so great, and when the content exceeds 500 mg/kg, the synergistic effect continues at a certain level, and in the present invention, the synergistic effect by carnitine is It can be inferred that the maximum is about 500 mg/kg.

The term 'complex formulation' used in the present invention refers to the pharmaceutical composition provided by the present invention.

The composition of the present invention may further include suitable carriers, excipients and diluents commonly used in the preparation of pharmaceutical compositions. In addition, according to a conventional method, it can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injection solutions, preferably oral It may be formulated into a unit dosage form suitable for administration and used.

Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose , microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate and mineral oil. When formulating the composition, it is usually prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the composition, for example, starch, calcium carbonate, sucrose, lactose, It is prepared by mixing gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral administration include suspensions, solutions, emulsions, syrups, etc. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. In addition, as the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.

In addition, an antioxidant may be further added to the composition for treating liver disease, etc. provided by the present invention. As the antioxidant, thiamin (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pantothenic acid (vitamin B5), pyridoxine (vitamin B6) and cobalamin (cobalamin, Vitamin B group compounds such as vitamin B12), vitamin C, vitamin D, vitamin E, N-acetylcysteine (NAC), and the like may be used.

The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type, severity, and drug activity of the patient. , sensitivity to drugs, administration time, administration route and excretion rate, duration of treatment, factors including concurrent drugs, and other factors well known in the medical field. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.

The pharmaceutical composition of the present invention may be administered to an individual by various routes. Any mode of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebrovascular injection. The pharmaceutical composition of the present invention is determined according to the type of drug as an active ingredient, along with several related factors such as the disease to be treated, the route of administration, the age, sex and weight of the patient, and the severity of the disease.

Hereinafter, preferred examples are presented to help the understanding of the present invention. However, the following examples are only provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.

Example

1. Experimental animal preparation and experimental method

Six-week-old C57BL/6J male rats were ingested for 6 weeks through a normal diet (ND) or High Fat diet (HFD) diet, after which colchicine (10 μg/kg) alone or colchicine (10 μg/kg) was administered. μg/kg)/metformin (50 mg/kg)/carnitine (50 mg/kg) were co-administered, and the drug was administered with a high-fat diet for a total of 6 weeks and was administered orally 3 times a week (oral gavage).

1 is a summary of the process of preparing the animal and the test process for the administration of colchicine alone and colchicine/metformin/carnitine in combination.

2-1. Pathological examination of liver tissue when colchicine alone and colchicine/metformin/carnitine co-administration in obesity-induced rats

In order to perform pathological examination of liver tissue in rats following colchicine administration alone and co-administration of colchicine, metformin and carnitine, Microvesicular steatosis, Macrovesicular steatosis, portal inflammation, According to the histologic findings of ballooning degeneration, there is no disease (NAD) that can distinguish pathological characteristics according to severity, 0 points, mild symptoms (mild) 1 point, moderate symptoms (Moderate) 2 Point and severe symptoms (Severe) were evaluated by giving 3 points, and the results are presented in Tables 1 and 2, respectively. In Table 2, the content of colchicine is 100 μg/kg, and the content of metformin is 200 mg/kg.

Group
Fatty necrosis Ballooning degeneration Portal inflammation Fibrosis Total score Normal 0 0 0 0 0 Vehicle 0 0 0 0 0 HFD 3 2 3 3 11 HFD + Colchicine (10 μg/kg) 3 2 2 3 10 HFD + Colchicine (50 μg/kg) 2 2 2 2 8 HFD + Colchicine (100 μg/kg) 2 One One One 5 HFD + Colchicine (200 μg/kg) 2 2 2 One 7

Group
Fatty necrosis Ballooning degeneration Portal inflammation Fibrosis Total score Normal 0 0 0 0 0 Vehicle 0 0 0 0 0 HFD 3 3 3 3 12 HFD + Colchicine 2 One 2 One 6 HFD + Colchicine + Metformin One One One One 4 HFD+Colchicine+Metformin+Carnitine (50 mg/kg) One One One One 4 HFD+Colchicine+Metformin+Carnitine (100 mg/kg) One One 0 One 3 HFD+Colchicine+Metformin+Carnitine (200 mg/kg) 0 0 0 One One HFD+Colchicine+Metformin+Carnitine (500 mg/kg) One One One One 4

2-2. Examination of anatomical changes in liver cross-section when colchicine alone and colchicine/metformin/carnitine co-administration in obese-induced rats

For anatomical examination of the rat liver cross section, H&E staining was applied, and the results are shown in FIG. 2 .

As shown in FIG. 2 , a high-fat diet induced steatosis in liver tissue, and it was confirmed that colchicine was reduced by administration alone. Furthermore, when colchicine, metformin and carnitine were administered in combination, steatosis was caused by the synergistic effect of the drugs. It can be seen that the reduction effect of

In addition, in order to examine the quantitative change of the fat accumulated in the liver tissue of the rat, the fat was confirmed by staining using the oil red O technique, and the results are shown in FIG. 3 .

According to FIG. 3 , a high-fat diet induced fat accumulation in liver tissue, which was confirmed to be reduced by colchicine alone administration. The effect of reducing fat accumulation by colchicine alone administration was synergistic by colchicine/metformin/carnitine combination It was confirmed that an effect could occur.

2-3. Activation of AMPK and ACC metabolite in rat liver tissue when colchicine alone and colchicine/metformin/carnitine co-administration were administered to obese-induced rats

To confirm the above results, mass spectrometry was applied, and the results are presented in FIG. 4 .

According to FIG. 4, the AMPK and ACC activation decreased by the high-fat diet was partially restored by colchicine administration, and the activation of AMPK and ACC was a combination of colchicine (100 μg/kg)/metformin (200 mg/kg)/carnitine. It was confirmed that AMPK and ACC were more activated by the synergistic effect of the components prepared by the present invention by showing that it was significantly increased by administration.

In addition, when colchicine alone and colchicine (100 μg/kg)/metformin (200 mg/kg)/carnitine were administered in combination, the results of further confirming the effect on AMPK and ACC activation in the hepatocyte AML12 cell line induced in the rat liver were further confirmed. It is presented in FIG. 5 .

As shown in FIG. 5 , the activation of AMPK and ACC increased by colchicine alone (drug treatment for 7 hours) in the murine AML12 liver cell line was increased by colchicine/metformin/carnitine combination treatment (drug treatment for 7 hours). It can be seen that the activated activation is further increased.

2-4. Glucose tolerance test (GTT) and insulin resistance (Insulin tolerance test: ITT) occurring when colchicine alone or colchicine (100 μg/kg)/metformin (200 mg/kg)/carnitine combination was administered to obesity-induced rats ) of the contrast result

As shown in FIG. 6 , it was found that the blood glucose resistance and insulin resistance of obese rats were significantly reduced by the co-administration of colchicine/metformin/carnitine rather than colchicine alone.

In addition, as can be confirmed by FIGS. 7 and 8, the levels of liver triglyceride, plasma triglyceride and cholesterol were higher in mice when colchicine/metformin/carnitine was administered in combination than colchicine alone. It was confirmed that it was significantly reduced, and by the above results, the level of glucose resistance, insulin resistance, triglyceride and cholesterol was significantly reduced by the synergistic effect between the drugs when colchicine / metformin / carnitine was administered in combination than colchicine alone. it can be seen that

2-5. Colchicine alone and colchicine (100 μg/kg)/metformin (200 mg/kg)/carnitine co-administration in obese-induced mice

Masson's trichrome staining method was applied to confirm the difference in sclerosis of the colon tissue, and as shown in FIG. 9, when colchicine/metformin/carnitine was administered in combination, it was confirmed that sclerosis of the colon tissue of mice was significantly reduced. there is.

2-6. Changes in albumin, ALT, AST and total protein amount in liver tissue during the week when obesity was induced when colchicine alone and colchicine (100 μg/kg)/metformin (200 mg/kg)/carnitine were administered in combination

The activities of proteins such as albumin, ALT, and AST appearing when colchicine alone and colchicine/metformin/carnitine were administered in combination with obesity-induced mice were measured. 11 , 12 and 13 .

Table 3 below presents changes in values for a total of four items, such as albumin levels, ALT (alanine aminotransferase), AST (aspartate aminotransferase), and total protein concentration, which occur when colchicine is administered alone in the experiment.

Group
albumin
(g/dl) ALT
(U/L) AST
(U/L) total protein
(g/dl) Normal 2.33±0.04 39.80±2.65 88.46±4.58 6.56±0.83 Vehicle 2.32±0.02 37.36±3.05 88.58±6.36 6.82±0.68 HFD 1.84±0.02 1775.28±27.68 1802.21±75.28 5.07±0.29 HFD + Colchicine (10 μg/kg) 1.85±0.01 1742.57±102.71 1766.90±90.48 5.07±0.30 HFD + Colchicine (50 μg/kg) 1.98±0.02 1602.38±61.31 1759.49±61.71 5.21±0.33 HFD + Colchicine (100 μg/kg) 2.12±0.04 1466.48±49.34 1614.70±78.28 5.24±0.13 HFD + Colchicine (200 μg/kg) 1.94±0.04 1735.40±86.49 1833.70±131.74 5.09±0.32

Table 4 below shows the changes in values for a total of four items, such as albumin levels, ALT, AST, and total protein concentration, that occur when colchicine/metformin/carnitine are co-administered in the above experiment. In Table 4, the content of colchicine is 100 μg/kg, and the content of metformin is 200 mg/kg.

Group
albumin
(g/dl) ALT
(U/L) AST
(U/L) total protein
(g/dl) Normal 2.39±0.05 40.37±4.28 86.79±10.24 6.95±0.10 Vehicle 2.39±0.07 39.36±3.03 81.76±7.95 6.62±0.29 HFD 1.81±0.02 1902.90±72.72 1870.81±80.89 4.68±0.37 HFD + Colchicine (100 μg/kg) 2.08±0.04 1541.13±96.29 1646.87±52.72 5.19±0.20 HFD+Colchicine+Metformin+Carnitine (50 mg/kg) 2.26±0.08 1270.76±79.91 1079.36±69.34 5.35±0.20 HFD+Colchicine+Metformin+Carnitine (100 mg/kg) 2.34±0.04 1179.71±97.04 923.73±40.47 5.68±0.27 HFD+Colchicine+Metformin+Carnitine (200 mg/kg) 2.41±0.05 950.51±82.55 768.00±54.37 6.19±0.50 HFD+Colchicine+Metformin+Carnitine (400 mg/kg) 2.32±0.05 1182.53±101.15 897.77±155.72 5.35±0.28

As can be seen from Tables 3 and 4 as well as FIGS. 10 to 13, when colchicine/metformin/carnitine was co-administered to obesity-induced rats, the synergistic effect of the above components compared to colchicine alone. It can be seen that the activity is maximized.

Hydroxyproline assay was used to determine the change in the level of liver fibrin accumulation in obesity-induced rats that occurred when colchicine alone and colchicine (100 μg/kg)/metformin (200 mg/kg)/carnitine were co-administered. was measured, and the results are shown in Tables 5 and 6 below.

Table 5 shows the changes in the hydroxyproline values when colchicine is administered alone, and Table 6 shows the changes in the hydroxyproline values when co-administered with colchicine, metformin and carnitine.

Group Hydroxyproline (μg/g of liver) Normal 248.00±24.01 Vehicle 252.89±20.89 HFD 355.94±14.21 HFD + Colchicine (10 mg/kg) 345.28±8.14 HFD + Colchicine (50 mg/kg) 326.46±14.55 HFD + Colchicine (100 mg/kg) 308.13±5.04 HFD + Colchicine (200 mg/kg) 324.83±20.81

Group Hydroxyproline (μg/g of liver) Normal 238.17±8.97 Vehicle 242.93±5.62 HFD 362.02±13.45 HFD + Colchicine (100 μg/kg) 316.30±10.29 HFD + Colchicine + Metformin + Carnitine (50 mg/kg) 261.16±10.00 HFD + Colchicine + Metformin + Carnitine (100 mg/kg) 248.34±12.68 HFD + Colchicine + Metformin + Carnitine (200 mg/kg) 242.00±10.55 HFD + Colchicine + Metformin + Carnitine (500 mg/kg) 268.31±22.04

As can be seen from the above-described examples, the combination agent of colchicine/metformin/carnitine provided in the present invention prevents the accumulation of adipose tissue in vivo by the synergistic effect of the components, and reduces glucose resistance and insulin resistance, thereby causing liver disease , hepatitis, can be applied as an excellent pharmaceutical composition that can treat various liver diseases such as cirrhosis.

In addition, since the pharmaceutical composition provided in the present invention does not use ursodeoxycholic acid, which has been mainly used conventionally for the treatment and prevention of liver diseases, etc., almost all of the raw material of ursodeoxycholic acid is imported from China. It can be a useful pharmaceutical composition that can replace it.

The above description of the present invention is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

The present invention is industrially applicable.

Claims (16)

To a pharmaceutical composition for treating liver disease, wherein the pharmaceutical composition comprises all of colchicine, metformin and carnitine.
The method according to claim 1, wherein the content of colchicine contained in the pharmaceutical composition is 10-200 μg/kg, the content of metformin is 50-400 mg/kg, and the content of carnitine is 50-500 mg/kg Pharmaceutical composition for the treatment of liver disease, characterized in that
The method according to claim 1, wherein the content of colchicine included in the pharmaceutical composition is 50 to 100 μg/kg, the content of metformin is 100 to 200 mg/kg, and the content of carnitine is 100 to 200 mg/kg Pharmaceutical composition for the treatment of liver disease, characterized in that
The pharmaceutical composition for treating liver disease according to claim 1, wherein the liver disease is at least one selected from liver fibrosis, liver cirrhosis, liver cancer, and inflammatory liver disease.
5. The method of claim 4, wherein the inflammatory liver disease is hepatitis, acute hepatitis, chronic hepatitis, alcoholic hepatitis, nonalcoholic hepatitis, subacute hepatitis, viral hepatitis, toxic liver disease, liver abscess, granulomatous hepatitis, autoimmune hepatitis and lupus form. A pharmaceutical composition for treating liver disease, characterized in that at least one selected from hepatitis
The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition is any one selected from the group consisting of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and injection solutions. Pharmaceutical composition for the treatment of liver disease, characterized in that it is prepared in a dosage form
The method according to any one of claims 1 to 5, wherein the pharmaceutical composition is lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate , cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxy benzoate, propyl hydroxy benzoate, characterized in that it further comprises one or more components selected from the group consisting of talc and magnesium stearate A pharmaceutical composition for the treatment of liver disease
According to any one of claims 1 to 5, wherein the pharmaceutical composition is one selected from the group consisting of thiamine, riboflavin, niacin, pantophenic acid, pyridoxine, cobalamin, vitamin C, vitamin D, vitamin E and N-acetylcysteine. Pharmaceutical composition for treating liver disease, characterized in that it further comprises the above components
It relates to a pharmaceutical composition for enhancing the therapeutic effect of liver disease, wherein the pharmaceutical composition comprises all of colchicine, metformin and carnitine.
The method according to claim 9, wherein the content of colchicine included in the pharmaceutical composition is 10-200 μg/kg, the content of metformin is 50-400 mg/kg, and the content of carnitine is 50-500 mg/kg Pharmaceutical composition for enhancing the therapeutic effect of liver disease, characterized in that
The method according to claim 9, wherein the content of colchicine included in the pharmaceutical composition is 50 to 100 μg/kg, the content of metformin is 100 to 200 mg/kg, and the content of carnitine is 100 to 200 mg/kg A pharmaceutical composition for enhancing the therapeutic effect of liver disease, characterized in that
The pharmaceutical composition for enhancing the therapeutic effect of liver disease according to claim 9, wherein the liver disease is at least one selected from among liver fibrosis, liver cirrhosis, liver cancer, and inflammatory liver disease.
13. The method of claim 12, wherein the inflammatory liver disease is hepatitis, acute hepatitis, chronic hepatitis, alcoholic hepatitis, nonalcoholic hepatitis, subacute hepatitis, viral hepatitis, toxic liver disease, liver abscess, granulomatous hepatitis, autoimmune hepatitis and lupus form. A pharmaceutical composition for enhancing the therapeutic effect of liver disease, characterized in that at least one selected from hepatitis According to any one of claims 9 to 13, wherein the pharmaceutical composition is any one selected from the group consisting of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and injection solutions Pharmaceutical composition for enhancing the therapeutic effect of liver disease, characterized in that it is prepared in a dosage form
14. The method according to any one of claims 9 to 13, wherein the pharmaceutical composition is lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate. , cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxy benzoate, propyl hydroxy benzoate, characterized in that it further comprises one or more components selected from the group consisting of talc and magnesium stearate Pharmaceutical composition for enhancing the therapeutic effect of liver disease
The method according to any one of claims 9 to 13, wherein the pharmaceutical composition is one selected from the group consisting of thiamine, riboflavin, niacin, pantophenic acid, pyridoxine, cobalamin, vitamin C, vitamin D, vitamin E and N-acetylcysteine. Pharmaceutical composition for enhancing the therapeutic effect of liver disease, characterized in that it further comprises the above components

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