CA3192690A1 - Pharmaceutical composition for treating nonalcoholic steatohepatitis and liver fibrosis - Google Patents
Pharmaceutical composition for treating nonalcoholic steatohepatitis and liver fibrosisInfo
- Publication number
- CA3192690A1 CA3192690A1 CA3192690A CA3192690A CA3192690A1 CA 3192690 A1 CA3192690 A1 CA 3192690A1 CA 3192690 A CA3192690 A CA 3192690A CA 3192690 A CA3192690 A CA 3192690A CA 3192690 A1 CA3192690 A1 CA 3192690A1
- Authority
- CA
- Canada
- Prior art keywords
- pharmaceutical composition
- composition according
- disease
- nonalcoholic steatohepatitis
- metabolic disease
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a pharmaceutical composition for preventing and treating metabolic diseases, and more specifically, for treating nonalcoholic steatohepatitis (NASH) or liver fibrosis through the pharmaceutical composition comprising sodium taurodeoxycholate (Na-TDC), a solvate thereof or a pharmaceutically acceptable salt thereof.
Description
[Description]
[Title of Invention]
PHARMACEUTICAL COMPOSITION FOR TREATMENT OF
NONALCOHOLIC STEATOHEPATITIS AND LIVER FIBROSIS
[Technical Field]
The present invention relates to a pharmaceutical composition for the treatment of nonalcoholic steatohepatitis (NASH) and liver fibrosis, particularly to a pharmaceutical composition comprising sodium taurodeoxycholate (Na-TDC), a solvate thereof, or a pharmaceutically acceptable salt thereof.
[Background Art]
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is a disease closely related to obesity, diabetes, and metabolic syndrome.
This refers to liver disease in a broad sense, ranging from simple steatosis, in which triglycerides are excessively accumulated in the liver, to cirrhosis, which is the aggravated form of the disease.
Nonalcoholic steatohepatitis (NASH) is a type of nonalcoholic fatty liver disease, and refers to a disease that exhibits pathological phenomena such as expansive degeneration, apoptosis, and inflammatory infiltration, and furthermore, fibrosis. Not all nonalcoholic fatty liver disease progresses to nonalcoholic steatohepatitis.
It takes about 7 years to progress from nonalcoholic fatty liver to nonalcoholic steatohepatitis and more than 50% of patients with nonalcoholic steatohepatitis are asymptomatic, making it difficult to diagnose nonalcoholic steatohepatitis. In this regard, the accuracy of liver damage indicators such as ALT and AST
and the measurement by imaging equipment and the like is not high, so the possibility of death from complications is high. It is reported that 10% to 29% of patients with nonalcoholic steatohepatitis undergo cirrhosis within 10 years, and 4% to 27% of patients with cirrhosis further undergo liver cancer.
Although the cause of nonalcoholic steatohepatitis is not known directly, it is presumed that nonalcoholic steatohepatitis is related to metabolic imbalance such as oxidative stress, lipid peroxidation, cytokine damage, lipid metabolism abnormality, and insulin resistance.
Efforts to treat nonalcoholic steatohepatitis are being made in various fields at home and abroad. In the United States, the FDA have recently issued guidelines to promote the development of new drugs for NASH, and multinational pharmaceutical companies such as Intercept Pharmaceuticals, Gilead, Allergan, and NGM
Biopharmaceuticals are making efforts to treat nonalcoholic steatohepatitis through clinical trials. In this regard, fibrates that activate PPARa and PPARy glitazones have been known as drugs for improving lipid metabolism abnormalities. Korean Patent Publication No.
10-2018-0124123 discloses a therapeutic agent for NASH
comprising obeticholic acid or a pharmaceutically acceptable salt thereof, and US Patent No. 10457703 discloses a use of a pharmaceutical composition comprising a bile acid derivative to treat FXR or TGR5-mediated diseases.
However, there is an urgent need to develop a therapeutic agent for nonalcoholic fatty liver disease since no therapeutic agent exerting a significant effect has been developed so far although the use of various substances to treat nonalcoholic fatty liver disease is known. The use of sodium taurodeoxycholate for the
[Title of Invention]
PHARMACEUTICAL COMPOSITION FOR TREATMENT OF
NONALCOHOLIC STEATOHEPATITIS AND LIVER FIBROSIS
[Technical Field]
The present invention relates to a pharmaceutical composition for the treatment of nonalcoholic steatohepatitis (NASH) and liver fibrosis, particularly to a pharmaceutical composition comprising sodium taurodeoxycholate (Na-TDC), a solvate thereof, or a pharmaceutically acceptable salt thereof.
[Background Art]
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is a disease closely related to obesity, diabetes, and metabolic syndrome.
This refers to liver disease in a broad sense, ranging from simple steatosis, in which triglycerides are excessively accumulated in the liver, to cirrhosis, which is the aggravated form of the disease.
Nonalcoholic steatohepatitis (NASH) is a type of nonalcoholic fatty liver disease, and refers to a disease that exhibits pathological phenomena such as expansive degeneration, apoptosis, and inflammatory infiltration, and furthermore, fibrosis. Not all nonalcoholic fatty liver disease progresses to nonalcoholic steatohepatitis.
It takes about 7 years to progress from nonalcoholic fatty liver to nonalcoholic steatohepatitis and more than 50% of patients with nonalcoholic steatohepatitis are asymptomatic, making it difficult to diagnose nonalcoholic steatohepatitis. In this regard, the accuracy of liver damage indicators such as ALT and AST
and the measurement by imaging equipment and the like is not high, so the possibility of death from complications is high. It is reported that 10% to 29% of patients with nonalcoholic steatohepatitis undergo cirrhosis within 10 years, and 4% to 27% of patients with cirrhosis further undergo liver cancer.
Although the cause of nonalcoholic steatohepatitis is not known directly, it is presumed that nonalcoholic steatohepatitis is related to metabolic imbalance such as oxidative stress, lipid peroxidation, cytokine damage, lipid metabolism abnormality, and insulin resistance.
Efforts to treat nonalcoholic steatohepatitis are being made in various fields at home and abroad. In the United States, the FDA have recently issued guidelines to promote the development of new drugs for NASH, and multinational pharmaceutical companies such as Intercept Pharmaceuticals, Gilead, Allergan, and NGM
Biopharmaceuticals are making efforts to treat nonalcoholic steatohepatitis through clinical trials. In this regard, fibrates that activate PPARa and PPARy glitazones have been known as drugs for improving lipid metabolism abnormalities. Korean Patent Publication No.
10-2018-0124123 discloses a therapeutic agent for NASH
comprising obeticholic acid or a pharmaceutically acceptable salt thereof, and US Patent No. 10457703 discloses a use of a pharmaceutical composition comprising a bile acid derivative to treat FXR or TGR5-mediated diseases.
However, there is an urgent need to develop a therapeutic agent for nonalcoholic fatty liver disease since no therapeutic agent exerting a significant effect has been developed so far although the use of various substances to treat nonalcoholic fatty liver disease is known. The use of sodium taurodeoxycholate for the
2 treatment of nonalcoholic fatty liver disease is not known. Accordingly, the present inventors have attempted to reveal the use of sodium taurodeoxycholate to treat nonalcoholic fatty liver disease and liver fibrosis, and as a result, completed the present invention by finding the therapeutic use of a pharmaceutical composition comprising sodium taurodeoxycholate, a solvate thereof, or a pharmaceutically acceptable salt thereof.
[Summary of Invention]
[Technical Problem]
An object of the present invention is to provide a pharmaceutical composition comprising sodium taurodeoxycholate (Na-TDC), a solvate thereof, or a pharmaceutically acceptable salt thereof for the prevention and treatment of metabolic disease, more particularly the prevention and treatment of nonalcoholic steatohepatitis (NASH) and liver fibrosis.
[Solution to Problem]
In order to achieve the object, the present invention provides a pharmaceutical composition for prevention and treatment of metabolic disease comprising sodium taurodeoxycholate, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
In an aspect of the present invention, the metabolic disease is one or more selected from nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, obesity, diabetes or hyperlipidemia.
In an aspect of the present invention, the metabolic disease is nonalcoholic steatohepatitis (NASH).
In an aspect of the present invention, the metabolic
[Summary of Invention]
[Technical Problem]
An object of the present invention is to provide a pharmaceutical composition comprising sodium taurodeoxycholate (Na-TDC), a solvate thereof, or a pharmaceutically acceptable salt thereof for the prevention and treatment of metabolic disease, more particularly the prevention and treatment of nonalcoholic steatohepatitis (NASH) and liver fibrosis.
[Solution to Problem]
In order to achieve the object, the present invention provides a pharmaceutical composition for prevention and treatment of metabolic disease comprising sodium taurodeoxycholate, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
In an aspect of the present invention, the metabolic disease is one or more selected from nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, obesity, diabetes or hyperlipidemia.
In an aspect of the present invention, the metabolic disease is nonalcoholic steatohepatitis (NASH).
In an aspect of the present invention, the metabolic
3 disease is liver fibrosis.
In an aspect of the present invention, the composition is to reduce steatosis, inflammation or ballooning.
In an aspect of the present invention, the composition is to reduce fibrosis or cirrhosis.
The present invention also provides an oral preparation comprising the pharmaceutical composition for prevention and treatment of metabolic disease. In a specific aspect of the present invention, the oral preparation is selected from the group consisting of tablets, granules, pills, powders, capsules and liquids.
The present invention also provides an injectable preparation comprising the pharmaceutical composition for prevention or treatment of metabolic disease.
The composition of the present invention may be administered in combination with a therapeutic agent for nonalcoholic fatty liver disease (NAFLD). The composition of the present invention may be administered in combination with a therapeutic agent for nonalcoholic steatohepatitis (NASH).
In an aspect of the present invention, the therapeutic agent for nonalcoholic fatty liver disease is one or more selected from the group consisting of OCA
(obeticholic acid), thiazolidinediones, vitamin E, metformin, statins, ursodeoxycholic acid, unsaturated fatty acids, angiotensin receptor blockers, pentoxifylline, GLP-1 receptor agonists (glucagon-like peptide 1 receptor agonists), DPP-4 inhibitors (dipeptidyl peptidase-4 inhibitors), SGLT2 inhibitors (sodium/glucose cotransporter 2 inhibitors), elafibranor, and telmisartan.
The present invention also provides a food composition for prevention or improvement of metabolic
In an aspect of the present invention, the composition is to reduce steatosis, inflammation or ballooning.
In an aspect of the present invention, the composition is to reduce fibrosis or cirrhosis.
The present invention also provides an oral preparation comprising the pharmaceutical composition for prevention and treatment of metabolic disease. In a specific aspect of the present invention, the oral preparation is selected from the group consisting of tablets, granules, pills, powders, capsules and liquids.
The present invention also provides an injectable preparation comprising the pharmaceutical composition for prevention or treatment of metabolic disease.
The composition of the present invention may be administered in combination with a therapeutic agent for nonalcoholic fatty liver disease (NAFLD). The composition of the present invention may be administered in combination with a therapeutic agent for nonalcoholic steatohepatitis (NASH).
In an aspect of the present invention, the therapeutic agent for nonalcoholic fatty liver disease is one or more selected from the group consisting of OCA
(obeticholic acid), thiazolidinediones, vitamin E, metformin, statins, ursodeoxycholic acid, unsaturated fatty acids, angiotensin receptor blockers, pentoxifylline, GLP-1 receptor agonists (glucagon-like peptide 1 receptor agonists), DPP-4 inhibitors (dipeptidyl peptidase-4 inhibitors), SGLT2 inhibitors (sodium/glucose cotransporter 2 inhibitors), elafibranor, and telmisartan.
The present invention also provides a food composition for prevention or improvement of metabolic
4 disease comprising sodium taurodeoxycholate, a solvate thereof, or a sitologically acceptable salt thereof.
The present invention also provides a method for treating metabolic disease, the method comprising sodium taurodeoxycholate, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
[Advantageous Effects of Invention]
In the present invention, nonalcoholic steatohepatitis and liver fibrosis can be treated using a pharmaceutical composition comprising sodium taurodeoxycholate (Na-TDC), a solvate thereof, or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition has few side effects and thus can be used as a pharmaceutical.
[Brief Description of Drawings]
FIGS. lA to 10 are diagrams illustrating the effect of TDCA in the STAN model.
FIGS. 2A and 2B are diagrams confirming the effect of TDCA through histological analysis of liver.
FIGS. 3A and 3B are diagrams confirming the therapeutic effect of TDCA on fibrosis.
FIGS. 4A and 4B are diagrams confirming the anti-inflammatory effect of TDCA.
[Description of Embodiments]
The present invention relates to a pharmaceutical composition for prevention or treatment of metabolic disease, more particularly nonalcoholic steatohepatitis (NASH), comprising sodium taurodeoxycholate, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
[Embodiments]
Hereinafter, the present invention will be described in detail.
Throughout the specification of the present invention, when a part "includes" a certain component, this means that the part does not exclude other components but may further include other components unless otherwise stated.
As used herein, the term "sodium taurodeoxycholate"
refers to a compound having the following chemical structure.
11 5 , 0....
J.--- "
Na+
HN
H C
3 .e,õ 0 OH ....., ,-.
CH3 11111011111, HO"' H
=
H
Sodium taurodeoxycholate may be named the same as 2-([3a,12a-dihydroxy-24-oxo-53-cholan-24-yl]amino)ethanesulfonic acid, taurodeoxycholic acid sodium salt hydrate, and CAS number 207737-97-1.
In the present invention, sodium taurodeoxycholate may exist in all forms, and may exist, for example, in a crystalline form, an amorphous form, and the form of a solvate.
As used herein, the term "solvate" refers to a form formed by adding a solvent to a compound, and includes monohydrate, dihydrate, and the like.
As used herein, the term "pharmaceutically acceptable" means that the contained ingredients do not significantly stimulate living organisms and do not impair biological activity and properties.
As used herein, the term "pharmaceutically acceptable salt" refers to a salt having desirable biological activity, and includes, but is not limited to, salts of inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid), salts of organic acids (acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, benzoic acid, ascorbic acid, tannic acid, pamoic acid, alginic acid, triethylamine, cyclohexylamine, and pyridine), alkali metal salts (sodium salt, potassium salt), alkaline earth metal salts (calcium salt), ammonium salt, or addition salts thereof.
As used herein, the term "prevention" refers to any action that suppresses the symptoms or delays the progression of a specific disease (for example, nonalcoholic steatohepatitis) by injecting the composition of the present invention into the body.
As used herein, the term "treatment" refers to any action that improves or beneficially changes the symptoms of a specific disease (for example, nonalcoholic steatohepatitis) by injecting the composition of the present invention into the body.
Compounds described herein refer to commonly recognized compounds unless otherwise defined.
The present invention relates to a pharmaceutical composition for prevention or treatment of metabolic disease comprising sodium taurodeoxycholate, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
In the present invention, metabolic disease refers to any disease that occurs by an abnormality in the pathway of chemical reactions taking place in the body, and non-limiting examples of metabolic disease include the following diseases. Metabolic disease includes, but is not limited to, for example, type 1 diabetes, type 2 diabetes, hyperlipidemia, hypertension, insulin resistance, obesity, abnormal glucose metabolism, diabetic retinopathy, diabetic nephritis, diabetic neuropathy, increase in body mass, hypercholesterolemia, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, polycystic ovary syndrome (PCOS), cirrhosis, hepatitis C, alcoholic liver disease, primary sclerosing cholangitis, and primary biliary cholangitis.
In an aspect of the present invention, the pharmaceutical composition of the present invention exhibits the effect of preventing or treating one or more selected from the group consisting of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, obesity, diabetes and hyperlipidemia.
In a specific aspect of the present invention, the pharmaceutical composition of the present invention exhibits the effect of preventing or treating nonalcoholic steatohepatitis (NASH).
In a specific aspect of the present invention, the pharmaceutical composition of the present invention exhibits the effect of preventing or treating liver fibrosis.
In an aspect of the present invention, the composition is to reduce steatosis, inflammation or ballooning.
In an aspect of the present invention, the composition is to reduce fibrosis or cirrhosis.
The pharmaceutical composition of the present invention may be administered orally or parenterally according to the desired method, and the dosage thereof may vary depending on the patient's weight, age, health status, and diet, time of administration, method of administration, type of disease, severity of disease and the like. When the pharmaceutical composition of the present invention is administered, the daily dosage is about 0.01 to 1000 mg/kg, more specifically 0.1 to 100 mg/kg, and the pharmaceutical composition may be administered one time to several times a day.
In an aspect of the present invention, there is also provided an oral preparation comprising the pharmaceutical composition for prevention and treatment of metabolic disease described above. In a specific aspect of the present invention, the oral preparation is selected from the group consisting of tablets, granules, pills, powders, capsules and liquids.
The present invention also provides an injectable preparation comprising the pharmaceutical composition for prevention or treatment of metabolic disease described above.
In an aspect of the present invention, the pharmaceutical preparation for oral administration may exist, for example, in the form of dosage units such as tablets, granules, pills, powders, capsules or liquids, and in the form of ampoules. These are prepared by methods known per se, for example by a common mixing, granulation, conserve preparation, dissolution or lyophilization method.
Other orally administrable pharmaceutical preparations include capsules, and capsules include dry-filled capsules made of gelatin, and sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Dry-filled capsules may contain the active ingredient in the form of particles, for example, in the form of a mixture with a filler such as lactose, a binder such as starch, and/or a glidant such as talc or magnesium stearate, and if appropriate, a stabilizing agent. In soft capsules, the active ingredient is dissolved or suspended in a suitable liquid such as fatty oil, paraffin oil or liquid polyethylene glycol, to which a stabilizing agent may be added.
When the formulation of the present invention is a liquid formulation, a solvent, solubilizer, or emulsifier is used as a carrier ingredient, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, glycerol-based aliphatic esters, fatty acid esters with polyethylene glycol or sorbitan.
In an aspect of the present invention, parenteral administration may be applied, for example, but not limited to, intravenously, subcutaneously, intradermally, intraperitoneally or topically. Pharmaceutical preparations for parenteral administration may be sterilized and/or contain additives such as preservatives, stabilizing agents, wetting agents and/or emulsifying agents, solubilizing agents, salts for adjusting the osmotic pressure and/or buffers.
The pharmaceutical composition of the present invention may be administered in combination with a therapeutic agent for nonalcoholic fatty liver disease (NAFLD).
The pharmaceutical composition of the present invention may be administered in combination with a therapeutic agent for nonalcoholic steatohepatitis (NASH).
In an aspect of the present invention, the therapeutic agent for nonalcoholic fatty liver disease is one or more selected from the group consisting of OCA
(obeticholic acid), thiazolidinediones, vitamin E, metformin, statins, ursodeoxycholic acid, unsaturated fatty acids, angiotensin receptor blockers, pentoxifylline, GLP-1 receptor agonists (glucagon-like peptide 1 receptor agonists), DPP-4 inhibitors (dipeptidyl peptidase-4 inhibitors), SGLT2 inhibitors (sodium/glucose cotransporter 2 inhibitors), elafibranor, and telmisartan.
The present invention also relates to a food composition for prevention or improvement of metabolic disease comprising sodium taurodeoxycholate, a solvate thereof, or a sitologically acceptable salt thereof.
The present invention also provides a method for treating metabolic disease, the method comprising sodium taurodeoxycholate, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
[Examples]
Hereinafter, the present invention will be described in detail by way of Examples and Experimental Examples.
However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the contents of the present invention are not limited to the following Examples and Experimental Examples.
<Example 1> Preparation of sample Sodium taurodeoxycholate was purchased from New Zealand Pharmaceuticals Ltd. (Palmerston North, New Zealand). Telmisartan (Micardis10) was purchased from Boehringer Ingelheim GmbH (Germany) and dissolved in purified water. DPBS (Dulbecco's phosphate-buffered saline) was purchased from WelGene Inc. (LB001-02, Korea) and used as a vehicle compound.
<Experimental Example 1> Animal model of nonalcoholic steatohepatitis and test design <1-1> Animal model of nonalcoholic steatohepatitis In order to confirm the therapeutic effect of sodium taurodeoxycholate on nonalcoholic steatohepatitis, a mouse STAN model was prepared.
The STAN model was induced using C57BL/6 mice through the combination of a high-fat diet and a chemical, streptozotocin. C57BL/6 mice (14-day pregnant female) were procured from Japan SLC, Inc. (Japan), and the STAN model was prepared at SMC Laboratories, Inc.
(Tokyo, Japan) using 136 C57BL/6 male mice. All animals used in the study were housed and managed in conformity with the Animal Use Guidelines of the Japanese Pharmacological Association. Specifically, nonalcoholic steatohepatitis (NASH) was induced by giving single subcutaneous injection of 200 pg streptozotocin (STZ, Sigma-Aldrich, USA) solution 2 days after birth and providing ad libitum feeding of a high-fat diet (HFD, 57 kcal% fat, CLEA Japan, Cat# HFD32, Japan) after 4 weeks of age. Mice were randomly assigned, and the specific study design is illustrated in FIG. 1A.
At 6 weeks of age, vehicle compound DPBS, taurodeoxycholic acid (TDCA) and telmisartan were each orally administered every day, and the treatment was performed until 9 weeks of age. Body weight was measured prior to each treatment. Then, 9-week-old mice were euthanized by exsanguination by direct cardiac puncture under isoflurane (Pfizer Inc., USA) anesthesia.
<1-2> Histological analysis 1-2-1. For H&E staining, sections were cut from paraffin blocks of liver tissue fixed with Bouin's solution, and stained with Lillie-Mayer's Hematoxylin (Muto Pure Chemicals Co., Ltd., Japan) and eosin solution (FUJIFILM Wako Pure Chemical Corporation, Japan).
1-2-2. NAFLD activity score (NAS) was calculated according to the Kleiner criteria.
1-2-3. For visualization of collagen deposition, liver sections fixed with Bouin's solution were stained using picro-Sirius Red solution (Waldeck, Germany).
1-2-4. For quantitative analysis of fibrosis regions, sections stained with Sirius Red were captured around the central vein using a 200x magnification digital camera (DFC295; Leica, Germany). Positive regions in 5 fields/section were measured using Image J software (National Institute of Health, USA).
1-2-5. For immunohistochemistry, sections were cut from frozen liver tissue fixed in Tissue-Tek 0.C.T
compound and fixed in acetone. Endogenous peroxidase activity was blocked using 0.03% H202 for 10 minutes, and then the sections were incubated with Block Ace (DS
pharma Biomedical Co., Ltd., Japan) for 10 minutes. The sections were incubated with reticular fibroblast antibodies (BMA Biomedicals Inc., Cat#: T-2109, Clone:
ER-TR7, Switzerland) at room temperature for 1 hour.
Subsequently, the sections were incubated with a biotin-conjugated secondary antibody (VECTASTAIN Elite ABC kit, Vector Laboratories, Cat#: PK-4004, USA), and then incubated with ABC reagent at room temperature for 30 minutes.
The enzyme substrate reaction was conducted using a 3,3'-diaminobenzidine/H202 solution (Nichirei Bioscience inc., Japan).
1-2-6. For quantitative analysis of ER-TR7 positive regions, bright field images of ER-TR7 immunostained sections were captured around the central vein using a 200x magnification digital camera (DFC295; Leica).
Positive regions in 5 fields/section were measured using Image J software (National Institute of Health, USA).
<1-3> Quantitative RT-PCR (real time polymerase chain reaction) Total RNA was extracted from liver samples using RNAiso (Takara Bio, Japan) according to the manufacturer's instructions. Specifically, 1 pg of RNA
was reverse transcribed using 20 pL of a reaction mixture. The reaction mixture contains 4.4 mM MgCl2 (F.
Hoffmann-La Roche, Switzerland), 40 U RNase inhibitor (Toyobo, Japan), 0.5 mM dNTP (Proemga, USA), 6.28 pM
random hexamer (Promega, USA), 5x first strand buffer (Promega, USA), 10 mM dithiothreitol (Invitrogen, USA), and 200 U MMLV-RT (Invitrogen, USA). The reaction was conducted at 37 C for 1 hour and then at 99 C for 5 minutes.
Specific gene expression was quantified through real-time PCR using PowerUpTM SYBRTM Green Master Mix (Applied Biosystems Inc., USA, Cat# A25779), and the real-time PCR was performed using the QuantStudio 6 Flex System Instrument (Applied Biosystems Inc., USA).
60S acidic ribosomal protein PO (RPLPO) RNA
expression was measured as an internal control.
Relative expression levels of target genes were normalized to RPLPO and compared. Relative quantification was performed using the ACt method.
The primer sequence is as follows: CCL2(MCP1) (Forward: 5'- AAACTGCATCTGCCCTAAGG-35 / Reverse: 55-AGAAGTGCTTGAGGTGGTTG-35).
<1-4> ELISA
TNF-a in the mouse plasma was analyzed using a mouse TNF-a uncoated ELISA Kit (Invitrogen, Cat# 88-7324, USA) and TIMP1 was analyzed using a mouse TIMP1 ELSIA Kit (abcam, Cat# ab196265, Cambridge, UK), and the kits were used according to the manufacturer's instructions.
<1-5> Data and statistical analysis Data are presented as mean SD, all data including two or more groups were analyzed by one-way ANOVA, then analyzed by Dunnett or Tukey multiple comparison test, or Kruskal Wallis test, and then analyzed by Dunn multiple comparison test. Asterisks in the figures mean *: p <
0.05, **: p < 0.01, ***: p < 0.001 and ****: p < 0.0001, respectively. Analysis was performed using GraphPad Prism 8.3.1 (San Diego, CA, USA).
<Experimental Example 2> Confirmation of effect of treating nonalcoholic steatohepatitis <2-1> Confirmation of changes in body weight and liver weight The effect of TDCA in the STAN model of nonalcoholic steatohepatitis by the experimental method according to <Experimental Example 1> was investigated. Telmisartan, an angiotensin II receptor antagonist and peroxisome proliferator-activated receptor-y agonist, has the property of improving NASH by reducing fibrosis and inflammation. In the experiment of the present invention, telmisartan was used as a reference drug.
It has been confirmed that TDCA and telmisartan have therapeutic effects in the STAN model (FIG. 1A).
A significant difference in the body weight between the treatment group (TDCA) and the vehicle group (DPBS) has not been observed, and it has been thus confirmed that there is no weight loss due to general drug toxicity. However, it has been confirmed that a remarkable decrease occurs in the telmisartan group compared to the vehicle group (FIG. 1B).
A significant difference in the liver to body weight ratio between the treatment group (TDCA) and the vehicle group (DPBS) has not been observed. However, it has been confirmed that a remarkable decrease occurs in the telmisartan group compared to the vehicle group (FIG.
10). The telmisartan group decreased the liver to body weight ratio in the animal group as previously reported.
<2-2> Histological analysis of liver Compared to the normal group, hepatocyte steatosis, ballooning, and inflammatory cell infiltration occurred in the STAN model group (FIG. 2A).
Compared to the vehicle group (DPBS), a significant decrease in total NAS has been confirmed in the TDCA 1.25 mg/kg treatment group and the telmisartan group, and the improvement in NAS lesion index, an important clinical symptom measure of NASH, has been thus confirmed (FIG.
2B).
<Experimental Example 3> Confirmation of therapeutic effect on fibrosis Compared to normal mice, an increase in collagen deposition in the hepatic lobule region has been observed in the liver sections stained with Sirius Red and liver sections stained with anti-fibroblast antibody ER-TR7 in the STAN mice (FIG. 3A).
Compared to the vehicle group (DPBS), a significant decrease in the area of fibrosis in the seropositive region has been observed in the TDCA 2.5 mg/kg treatment group and the telmisartan group, and the therapeutic effect on fibrosis, an important clinical treatment measure of NASH drugs, has been thus confirmed (FIG. 3B).
Compared to the vehicle group (DPBS), a significant decrease in the ER-TR7 positive region has been confirmed in the TDCA 10 mpk group, and it has been thus confirmed that the improvement of fibrosis is correlated with the effect of inhibiting fibroblasts in the liver tissue (FIG. 3B).
<Experimental Example 4> Gene and protein expression of inflammatory collagen/fibrosis marker The mRNA expression levels of mouse liver tissue genes related to inflammation and fibrosis in NASH were analyzed according to the experimental example described above. The inflammatory marker analyzed was MCP-1 (monocyte chemoattractant protein-1). As a result of the analysis, a remarkable decrease in MCP-1 was observed in the TDCA 2.5 mg/kg treatment group compared to the vehicle group (DPBS), and the anti-inflammatory effect has been thus confirmed (FIG. 4A).
Protein expression levels of the inflammatory cytokine TNF-a and the fibrosis marker TIMP1 in mouse plasma were analyzed by ELISA. As a result of the analysis, a remarkable decrease in TNF-a was observed in the TDCA 2.5 mg/kg treatment group compared to the vehicle group (DPBS), and it has been thus confirmed that there is an anti-inflammatory effect of inhibiting important inflammatory cytokines (FIG. 4B).
[Industrial Applicability]
The present invention can be usefully utilized for the prevention or treatment of metabolic disease, more specifically the prevention or treatment of nonalcoholic steatohepatitis (NASH).
The present invention also provides a method for treating metabolic disease, the method comprising sodium taurodeoxycholate, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
[Advantageous Effects of Invention]
In the present invention, nonalcoholic steatohepatitis and liver fibrosis can be treated using a pharmaceutical composition comprising sodium taurodeoxycholate (Na-TDC), a solvate thereof, or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition has few side effects and thus can be used as a pharmaceutical.
[Brief Description of Drawings]
FIGS. lA to 10 are diagrams illustrating the effect of TDCA in the STAN model.
FIGS. 2A and 2B are diagrams confirming the effect of TDCA through histological analysis of liver.
FIGS. 3A and 3B are diagrams confirming the therapeutic effect of TDCA on fibrosis.
FIGS. 4A and 4B are diagrams confirming the anti-inflammatory effect of TDCA.
[Description of Embodiments]
The present invention relates to a pharmaceutical composition for prevention or treatment of metabolic disease, more particularly nonalcoholic steatohepatitis (NASH), comprising sodium taurodeoxycholate, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
[Embodiments]
Hereinafter, the present invention will be described in detail.
Throughout the specification of the present invention, when a part "includes" a certain component, this means that the part does not exclude other components but may further include other components unless otherwise stated.
As used herein, the term "sodium taurodeoxycholate"
refers to a compound having the following chemical structure.
11 5 , 0....
J.--- "
Na+
HN
H C
3 .e,õ 0 OH ....., ,-.
CH3 11111011111, HO"' H
=
H
Sodium taurodeoxycholate may be named the same as 2-([3a,12a-dihydroxy-24-oxo-53-cholan-24-yl]amino)ethanesulfonic acid, taurodeoxycholic acid sodium salt hydrate, and CAS number 207737-97-1.
In the present invention, sodium taurodeoxycholate may exist in all forms, and may exist, for example, in a crystalline form, an amorphous form, and the form of a solvate.
As used herein, the term "solvate" refers to a form formed by adding a solvent to a compound, and includes monohydrate, dihydrate, and the like.
As used herein, the term "pharmaceutically acceptable" means that the contained ingredients do not significantly stimulate living organisms and do not impair biological activity and properties.
As used herein, the term "pharmaceutically acceptable salt" refers to a salt having desirable biological activity, and includes, but is not limited to, salts of inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid), salts of organic acids (acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, benzoic acid, ascorbic acid, tannic acid, pamoic acid, alginic acid, triethylamine, cyclohexylamine, and pyridine), alkali metal salts (sodium salt, potassium salt), alkaline earth metal salts (calcium salt), ammonium salt, or addition salts thereof.
As used herein, the term "prevention" refers to any action that suppresses the symptoms or delays the progression of a specific disease (for example, nonalcoholic steatohepatitis) by injecting the composition of the present invention into the body.
As used herein, the term "treatment" refers to any action that improves or beneficially changes the symptoms of a specific disease (for example, nonalcoholic steatohepatitis) by injecting the composition of the present invention into the body.
Compounds described herein refer to commonly recognized compounds unless otherwise defined.
The present invention relates to a pharmaceutical composition for prevention or treatment of metabolic disease comprising sodium taurodeoxycholate, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
In the present invention, metabolic disease refers to any disease that occurs by an abnormality in the pathway of chemical reactions taking place in the body, and non-limiting examples of metabolic disease include the following diseases. Metabolic disease includes, but is not limited to, for example, type 1 diabetes, type 2 diabetes, hyperlipidemia, hypertension, insulin resistance, obesity, abnormal glucose metabolism, diabetic retinopathy, diabetic nephritis, diabetic neuropathy, increase in body mass, hypercholesterolemia, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, polycystic ovary syndrome (PCOS), cirrhosis, hepatitis C, alcoholic liver disease, primary sclerosing cholangitis, and primary biliary cholangitis.
In an aspect of the present invention, the pharmaceutical composition of the present invention exhibits the effect of preventing or treating one or more selected from the group consisting of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, obesity, diabetes and hyperlipidemia.
In a specific aspect of the present invention, the pharmaceutical composition of the present invention exhibits the effect of preventing or treating nonalcoholic steatohepatitis (NASH).
In a specific aspect of the present invention, the pharmaceutical composition of the present invention exhibits the effect of preventing or treating liver fibrosis.
In an aspect of the present invention, the composition is to reduce steatosis, inflammation or ballooning.
In an aspect of the present invention, the composition is to reduce fibrosis or cirrhosis.
The pharmaceutical composition of the present invention may be administered orally or parenterally according to the desired method, and the dosage thereof may vary depending on the patient's weight, age, health status, and diet, time of administration, method of administration, type of disease, severity of disease and the like. When the pharmaceutical composition of the present invention is administered, the daily dosage is about 0.01 to 1000 mg/kg, more specifically 0.1 to 100 mg/kg, and the pharmaceutical composition may be administered one time to several times a day.
In an aspect of the present invention, there is also provided an oral preparation comprising the pharmaceutical composition for prevention and treatment of metabolic disease described above. In a specific aspect of the present invention, the oral preparation is selected from the group consisting of tablets, granules, pills, powders, capsules and liquids.
The present invention also provides an injectable preparation comprising the pharmaceutical composition for prevention or treatment of metabolic disease described above.
In an aspect of the present invention, the pharmaceutical preparation for oral administration may exist, for example, in the form of dosage units such as tablets, granules, pills, powders, capsules or liquids, and in the form of ampoules. These are prepared by methods known per se, for example by a common mixing, granulation, conserve preparation, dissolution or lyophilization method.
Other orally administrable pharmaceutical preparations include capsules, and capsules include dry-filled capsules made of gelatin, and sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Dry-filled capsules may contain the active ingredient in the form of particles, for example, in the form of a mixture with a filler such as lactose, a binder such as starch, and/or a glidant such as talc or magnesium stearate, and if appropriate, a stabilizing agent. In soft capsules, the active ingredient is dissolved or suspended in a suitable liquid such as fatty oil, paraffin oil or liquid polyethylene glycol, to which a stabilizing agent may be added.
When the formulation of the present invention is a liquid formulation, a solvent, solubilizer, or emulsifier is used as a carrier ingredient, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, glycerol-based aliphatic esters, fatty acid esters with polyethylene glycol or sorbitan.
In an aspect of the present invention, parenteral administration may be applied, for example, but not limited to, intravenously, subcutaneously, intradermally, intraperitoneally or topically. Pharmaceutical preparations for parenteral administration may be sterilized and/or contain additives such as preservatives, stabilizing agents, wetting agents and/or emulsifying agents, solubilizing agents, salts for adjusting the osmotic pressure and/or buffers.
The pharmaceutical composition of the present invention may be administered in combination with a therapeutic agent for nonalcoholic fatty liver disease (NAFLD).
The pharmaceutical composition of the present invention may be administered in combination with a therapeutic agent for nonalcoholic steatohepatitis (NASH).
In an aspect of the present invention, the therapeutic agent for nonalcoholic fatty liver disease is one or more selected from the group consisting of OCA
(obeticholic acid), thiazolidinediones, vitamin E, metformin, statins, ursodeoxycholic acid, unsaturated fatty acids, angiotensin receptor blockers, pentoxifylline, GLP-1 receptor agonists (glucagon-like peptide 1 receptor agonists), DPP-4 inhibitors (dipeptidyl peptidase-4 inhibitors), SGLT2 inhibitors (sodium/glucose cotransporter 2 inhibitors), elafibranor, and telmisartan.
The present invention also relates to a food composition for prevention or improvement of metabolic disease comprising sodium taurodeoxycholate, a solvate thereof, or a sitologically acceptable salt thereof.
The present invention also provides a method for treating metabolic disease, the method comprising sodium taurodeoxycholate, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
[Examples]
Hereinafter, the present invention will be described in detail by way of Examples and Experimental Examples.
However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the contents of the present invention are not limited to the following Examples and Experimental Examples.
<Example 1> Preparation of sample Sodium taurodeoxycholate was purchased from New Zealand Pharmaceuticals Ltd. (Palmerston North, New Zealand). Telmisartan (Micardis10) was purchased from Boehringer Ingelheim GmbH (Germany) and dissolved in purified water. DPBS (Dulbecco's phosphate-buffered saline) was purchased from WelGene Inc. (LB001-02, Korea) and used as a vehicle compound.
<Experimental Example 1> Animal model of nonalcoholic steatohepatitis and test design <1-1> Animal model of nonalcoholic steatohepatitis In order to confirm the therapeutic effect of sodium taurodeoxycholate on nonalcoholic steatohepatitis, a mouse STAN model was prepared.
The STAN model was induced using C57BL/6 mice through the combination of a high-fat diet and a chemical, streptozotocin. C57BL/6 mice (14-day pregnant female) were procured from Japan SLC, Inc. (Japan), and the STAN model was prepared at SMC Laboratories, Inc.
(Tokyo, Japan) using 136 C57BL/6 male mice. All animals used in the study were housed and managed in conformity with the Animal Use Guidelines of the Japanese Pharmacological Association. Specifically, nonalcoholic steatohepatitis (NASH) was induced by giving single subcutaneous injection of 200 pg streptozotocin (STZ, Sigma-Aldrich, USA) solution 2 days after birth and providing ad libitum feeding of a high-fat diet (HFD, 57 kcal% fat, CLEA Japan, Cat# HFD32, Japan) after 4 weeks of age. Mice were randomly assigned, and the specific study design is illustrated in FIG. 1A.
At 6 weeks of age, vehicle compound DPBS, taurodeoxycholic acid (TDCA) and telmisartan were each orally administered every day, and the treatment was performed until 9 weeks of age. Body weight was measured prior to each treatment. Then, 9-week-old mice were euthanized by exsanguination by direct cardiac puncture under isoflurane (Pfizer Inc., USA) anesthesia.
<1-2> Histological analysis 1-2-1. For H&E staining, sections were cut from paraffin blocks of liver tissue fixed with Bouin's solution, and stained with Lillie-Mayer's Hematoxylin (Muto Pure Chemicals Co., Ltd., Japan) and eosin solution (FUJIFILM Wako Pure Chemical Corporation, Japan).
1-2-2. NAFLD activity score (NAS) was calculated according to the Kleiner criteria.
1-2-3. For visualization of collagen deposition, liver sections fixed with Bouin's solution were stained using picro-Sirius Red solution (Waldeck, Germany).
1-2-4. For quantitative analysis of fibrosis regions, sections stained with Sirius Red were captured around the central vein using a 200x magnification digital camera (DFC295; Leica, Germany). Positive regions in 5 fields/section were measured using Image J software (National Institute of Health, USA).
1-2-5. For immunohistochemistry, sections were cut from frozen liver tissue fixed in Tissue-Tek 0.C.T
compound and fixed in acetone. Endogenous peroxidase activity was blocked using 0.03% H202 for 10 minutes, and then the sections were incubated with Block Ace (DS
pharma Biomedical Co., Ltd., Japan) for 10 minutes. The sections were incubated with reticular fibroblast antibodies (BMA Biomedicals Inc., Cat#: T-2109, Clone:
ER-TR7, Switzerland) at room temperature for 1 hour.
Subsequently, the sections were incubated with a biotin-conjugated secondary antibody (VECTASTAIN Elite ABC kit, Vector Laboratories, Cat#: PK-4004, USA), and then incubated with ABC reagent at room temperature for 30 minutes.
The enzyme substrate reaction was conducted using a 3,3'-diaminobenzidine/H202 solution (Nichirei Bioscience inc., Japan).
1-2-6. For quantitative analysis of ER-TR7 positive regions, bright field images of ER-TR7 immunostained sections were captured around the central vein using a 200x magnification digital camera (DFC295; Leica).
Positive regions in 5 fields/section were measured using Image J software (National Institute of Health, USA).
<1-3> Quantitative RT-PCR (real time polymerase chain reaction) Total RNA was extracted from liver samples using RNAiso (Takara Bio, Japan) according to the manufacturer's instructions. Specifically, 1 pg of RNA
was reverse transcribed using 20 pL of a reaction mixture. The reaction mixture contains 4.4 mM MgCl2 (F.
Hoffmann-La Roche, Switzerland), 40 U RNase inhibitor (Toyobo, Japan), 0.5 mM dNTP (Proemga, USA), 6.28 pM
random hexamer (Promega, USA), 5x first strand buffer (Promega, USA), 10 mM dithiothreitol (Invitrogen, USA), and 200 U MMLV-RT (Invitrogen, USA). The reaction was conducted at 37 C for 1 hour and then at 99 C for 5 minutes.
Specific gene expression was quantified through real-time PCR using PowerUpTM SYBRTM Green Master Mix (Applied Biosystems Inc., USA, Cat# A25779), and the real-time PCR was performed using the QuantStudio 6 Flex System Instrument (Applied Biosystems Inc., USA).
60S acidic ribosomal protein PO (RPLPO) RNA
expression was measured as an internal control.
Relative expression levels of target genes were normalized to RPLPO and compared. Relative quantification was performed using the ACt method.
The primer sequence is as follows: CCL2(MCP1) (Forward: 5'- AAACTGCATCTGCCCTAAGG-35 / Reverse: 55-AGAAGTGCTTGAGGTGGTTG-35).
<1-4> ELISA
TNF-a in the mouse plasma was analyzed using a mouse TNF-a uncoated ELISA Kit (Invitrogen, Cat# 88-7324, USA) and TIMP1 was analyzed using a mouse TIMP1 ELSIA Kit (abcam, Cat# ab196265, Cambridge, UK), and the kits were used according to the manufacturer's instructions.
<1-5> Data and statistical analysis Data are presented as mean SD, all data including two or more groups were analyzed by one-way ANOVA, then analyzed by Dunnett or Tukey multiple comparison test, or Kruskal Wallis test, and then analyzed by Dunn multiple comparison test. Asterisks in the figures mean *: p <
0.05, **: p < 0.01, ***: p < 0.001 and ****: p < 0.0001, respectively. Analysis was performed using GraphPad Prism 8.3.1 (San Diego, CA, USA).
<Experimental Example 2> Confirmation of effect of treating nonalcoholic steatohepatitis <2-1> Confirmation of changes in body weight and liver weight The effect of TDCA in the STAN model of nonalcoholic steatohepatitis by the experimental method according to <Experimental Example 1> was investigated. Telmisartan, an angiotensin II receptor antagonist and peroxisome proliferator-activated receptor-y agonist, has the property of improving NASH by reducing fibrosis and inflammation. In the experiment of the present invention, telmisartan was used as a reference drug.
It has been confirmed that TDCA and telmisartan have therapeutic effects in the STAN model (FIG. 1A).
A significant difference in the body weight between the treatment group (TDCA) and the vehicle group (DPBS) has not been observed, and it has been thus confirmed that there is no weight loss due to general drug toxicity. However, it has been confirmed that a remarkable decrease occurs in the telmisartan group compared to the vehicle group (FIG. 1B).
A significant difference in the liver to body weight ratio between the treatment group (TDCA) and the vehicle group (DPBS) has not been observed. However, it has been confirmed that a remarkable decrease occurs in the telmisartan group compared to the vehicle group (FIG.
10). The telmisartan group decreased the liver to body weight ratio in the animal group as previously reported.
<2-2> Histological analysis of liver Compared to the normal group, hepatocyte steatosis, ballooning, and inflammatory cell infiltration occurred in the STAN model group (FIG. 2A).
Compared to the vehicle group (DPBS), a significant decrease in total NAS has been confirmed in the TDCA 1.25 mg/kg treatment group and the telmisartan group, and the improvement in NAS lesion index, an important clinical symptom measure of NASH, has been thus confirmed (FIG.
2B).
<Experimental Example 3> Confirmation of therapeutic effect on fibrosis Compared to normal mice, an increase in collagen deposition in the hepatic lobule region has been observed in the liver sections stained with Sirius Red and liver sections stained with anti-fibroblast antibody ER-TR7 in the STAN mice (FIG. 3A).
Compared to the vehicle group (DPBS), a significant decrease in the area of fibrosis in the seropositive region has been observed in the TDCA 2.5 mg/kg treatment group and the telmisartan group, and the therapeutic effect on fibrosis, an important clinical treatment measure of NASH drugs, has been thus confirmed (FIG. 3B).
Compared to the vehicle group (DPBS), a significant decrease in the ER-TR7 positive region has been confirmed in the TDCA 10 mpk group, and it has been thus confirmed that the improvement of fibrosis is correlated with the effect of inhibiting fibroblasts in the liver tissue (FIG. 3B).
<Experimental Example 4> Gene and protein expression of inflammatory collagen/fibrosis marker The mRNA expression levels of mouse liver tissue genes related to inflammation and fibrosis in NASH were analyzed according to the experimental example described above. The inflammatory marker analyzed was MCP-1 (monocyte chemoattractant protein-1). As a result of the analysis, a remarkable decrease in MCP-1 was observed in the TDCA 2.5 mg/kg treatment group compared to the vehicle group (DPBS), and the anti-inflammatory effect has been thus confirmed (FIG. 4A).
Protein expression levels of the inflammatory cytokine TNF-a and the fibrosis marker TIMP1 in mouse plasma were analyzed by ELISA. As a result of the analysis, a remarkable decrease in TNF-a was observed in the TDCA 2.5 mg/kg treatment group compared to the vehicle group (DPBS), and it has been thus confirmed that there is an anti-inflammatory effect of inhibiting important inflammatory cytokines (FIG. 4B).
[Industrial Applicability]
The present invention can be usefully utilized for the prevention or treatment of metabolic disease, more specifically the prevention or treatment of nonalcoholic steatohepatitis (NASH).
Claims (14)
- [Claim 1]
A pharmaceutical composition for prevention and treatment of metabolic disease comprising sodium taurodeoxycholate, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. - [Claim 2]
The pharmaceutical composition according to claim 1, wherein the metabolic disease is one or more selected from the group consisting of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, obesity, diabetes and hyperlipidemia. - [Claim 3]
The pharmaceutical composition according to claim 1, wherein the metabolic disease is nonalcoholic steatohepatitis (NASH). - [Claim 4]
The pharmaceutical composition according to claim 1, wherein the metabolic disease is liver fibrosis. - [Claim 5]
The pharmaceutical composition according to claim 1, wherein the composition is to reduce steatosis, inflammation or ballooning. - [Claim 6]
The pharmaceutical composition according to claim 1, wherein the composition is to reduce fibrosis or cirrhosis. - [Claim 7]
An oral preparation comprising the pharmaceutical composition according to any one of claims 1 to 6. - [Claim 8]
The oral preparation according to claim 7, wherein the oral preparation is selected from the group consisting of tablets, granules, pills, powders, capsules and liquids. - [Claim 9]
An injectable preparation comprising the pharmaceutical composition according to any one of claims 1 to 6. - [Claim 10]
The pharmaceutical composition according to claim 1, wherein the composition is administered in combination with a therapeutic agent for nonalcoholic fatty liver disease (NAFLD). - [Claim 11]
The pharmaceutical composition according to claim 1, wherein the composition is administered in combination with a therapeutic agent for nonalcoholic steatohepatitis (NASH). - [Claim 12]
The pharmaceutical composition according to claim 10, wherein the therapeutic agent for nonalcoholic fatty liver disease is one or more selected from the group consisting of OCA (obeticholic acid), thiazolidinediones, vitamin E, metformin, statins, ursodeoxycholic acid, unsaturated fatty acids, angiotensin receptor blockers, pentoxifylline, GLP-1 receptor agonists (glucagon-like peptide 1 receptor agonists), DPP-4 inhibitors (dipeptidyl peptidase-4 inhibitors), SGLT2 inhibitors (sodium/glucose cotransporter 2 inhibitors), elafibranor, and telmisartan. - [Claim 13]
A food composition for prevention or improvement of metabolic disease comprising sodium taurodeoxycholate, a solvate thereof, or a sitologically acceptable salt thereof. - [Claim 14]
A method for treating metabolic disease, the method comprising sodium taurodeoxycholate, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US202063080112P | 2020-09-18 | 2020-09-18 | |
| US63/080,112 | 2020-09-18 | ||
| PCT/KR2021/011231 WO2022059946A1 (en) | 2020-09-18 | 2021-08-23 | Pharmaceutical composition for treating nonalcoholic steatohepatitis and liver fibrosis |
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| CA3192690A Pending CA3192690A1 (en) | 2020-09-18 | 2021-08-23 | Pharmaceutical composition for treating nonalcoholic steatohepatitis and liver fibrosis |
Country Status (3)
| Country | Link |
|---|---|
| KR (1) | KR20230079001A (en) |
| CA (1) | CA3192690A1 (en) |
| WO (1) | WO2022059946A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR100785656B1 (en) * | 2007-05-14 | 2007-12-17 | 재단법인서울대학교산학협력재단 | Sodium glycocholate or derivatives thereof used as anti-inflammatory agents |
| US10398717B2 (en) * | 2008-03-04 | 2019-09-03 | Alexander Vladimirovich Dikovskiy | Pharmaceutical composition based on a hepatoprotector and prebiotic, and method for administrating |
| EA202091464A1 (en) * | 2018-02-14 | 2020-12-07 | Люмос Фарма, Инк. | COMPOSITIONS FOR TREATMENT OF NON-ALCOHOLIC FAT LIVER DISEASE AND NON-ALCOHOLIC STEATOHEPATITIS |
| KR102204406B1 (en) * | 2019-01-23 | 2021-01-18 | (주)샤페론 | Composition for preventing or treating of inflammatory bowel disease comprising taurodeoxycholic acid or pharmaceutically acceptable salts thereof as an active ingredient |
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2021
- 2021-08-23 KR KR1020237005249A patent/KR20230079001A/en unknown
- 2021-08-23 CA CA3192690A patent/CA3192690A1/en active Pending
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| KR20230079001A (en) | 2023-06-05 |
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