Composition for preventing or treating pulmonary fibrosis containing taurodeoxycholic acid or pharmaceutically acceptable salt thereof as active ingredient

Abstract

The present invention relates to a composition for preventing or treating pulmonary fibrosis, which contains, as an active ingredient, a pharmaceutically acceptable salt of taurodeoxycholic acid, and more specifically, has been confirmed to have a prophylactic or therapeutic effect on pulmonary fibrosis in an idiopathic pulmonary fibrosis animal model and a pulmonary fibrosis cell model in which the pharmaceutically acceptable salt of taurodeoxycholic acid is administered. The taurodeoxycholic acid or the pharmaceutically acceptable salt thereof can be used as an active ingredient of a composition for preventing or treating pulmonary fibrosis because the expression of the taurodeoxycholic acid or the pharmaceutically acceptable salt thereof is reduced.

Description

Technical Field

[0001] The present invention relates to a composition for preventing or treating pulmonary fibrosis, which contains taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an effective ingredient. Background Art

[0002] Known causes of inflammation are pathogen-associated molecular patterns (PAMPs, Pathogen-associated molecular patterns) caused by pathogen infection and molecular patterns (DAMPs, Damage-associated molecular patterns) associated with damage caused by non-infectious tissue damage. Failure to regulate the protective response or inflammatory response in vivo involving immune cells, blood vessels and inflammatory mediators caused thereby can lead to inflammatory diseases. In addition, steroids, non-steroidal anti-inflammatory drugs (NSAIDs, Non-steroidal anti-inflammatory drugs), antibody therapeutics, JAK inhibitors, etc. are currently used as therapeutic agents for inflammatory diseases, but steroid drugs cause systemic side effects, so they can only be used in the short term, and NSAIDs do not show enough efficacy in the clinical stage. In addition, the response rate of antibody therapeutics is fast and can be used for a long time, but it has injection side effects, and its efficacy gradually decreases due to the generation of neutralizing antibodies in the body, and the cost burden of patients is high. In addition, JAK inhibitors have excellent anti-inflammatory effects, but are likely to aggravate severe infections, and have been confirmed in clinical trials to have cardiovascular side effects and carcinogenic risks. The recurrence rate of intractable inflammation is high, and long-term medication is required. However, the therapeutic agents developed so far cannot meet this market demand, so there is a need to develop a new therapeutic agent.

[0003] The formation of NLRP3 inflammasome is the core of the inflammatory response in the body. It mediates the activation of caspase-1 and the secretion of pro-inflammatory cytokines IL-1β / IL-18 caused by the response to microbial infection and cell damage, and is one of the important components of innate immunity. Inflammasomes are cytosolic multiprotein oligomers of the innate immune system that are responsible for activating inflammatory responses. The activation of inflammasomes not only promotes the cleavage of gasdermin-D by caspase-1, but also promotes the protein degradation, maturation and secretion of IL-1β and IL-18 into pro-inflammatory cytokines pro-IL-1β and pro-IL-18. In addition, when the activation regulation of these inflammasomes is impaired, various diseases such as cancer, metabolic diseases, degenerative diseases, and inflammatory diseases can be induced. Specifically, abnormal activation of NLRP3 inflammasomes is associated with the occurrence and worsening of symptoms of various inflammatory diseases, such as ulcerative colitis, gout, multiple sclerosis, arthritis, sepsis, inflammatory nervous system diseases, etc. This NLRP3 inflammasome is also activated by PAMPs of pathogens such as viruses and bacteria, as well as DAMPs such as calcium influx, mitochondrial reactive oxygen species, and extracellular APT.

[0004] In addition, the P2X7 receptor is an ion channel receptor composed of a complex belonging to the P2Xn purine receptor group, and its role is to promote the release of potassium ions to the extracellular and the rapid movement of calcium ions and sodium ions into the cell when estrogen stimulates P2X7. In the diseased state caused by the occurrence of inflammatory factors in vivo and in vitro, the extracellular ATP concentration increases significantly, thereby activating the P2X7 receptor, which triggers the release of potassium ions (which promotes the NLRP3 inflammasome) and intracellular ion imbalance. In addition, through the activation of the NLRP3 inflammasome and the resulting activation of pro-IL-1β / pro-IL-18, cell death is carried out and the inflammatory response of the surrounding tissue is aggravated. As mentioned above, the P2X7 receptor plays an important role in the progression of the inflammatory response. It is widely expressed in various immune cells, epidermal cells or nerve cells, and the P2X7 receptor signaling activates both the classical and non-classical pathways of NLRP3 activation, so it can be said that the ATP-P2X7 interaction is very important in the activation of the NLRP3 inflammasome. For example, high concentrations of ATP released by necrotic cells act as pro-inflammatory DAMPs, thereby binding to the P2X7 receptor and activating the NLRP3 inflammasome.

[0005] In the past, there have been many attempts to develop new drugs targeting the NLRP3 inflammasome, which is a major regulator of inflammatory responses. In recent years, with the discovery that inflammasomes are activated through classical and non-classical pathways consisting of pro-caspase, dermatocin D, ASC, NLR proteins, AIM2, IF116, pyrin, etc., and that if inflammasome regulation disorders occur in this process, various diseases will be induced, drug development for proteins involved in inflammasome-related signals has become active since 2010. Representative inflammasome regulators that have been developed include P2X7 receptor antagonists, NLRP3 inhibitors, and caspase-1 inhibitors. Specifically, multinational pharmaceutical companies such as Pfizer, AstraZeneca, and Janssen have developed rheumatoid arthritis, Crohn's disease, depression, etc. as indications, but most of them have been discontinued due to lack of efficacy in clinical trials. Caspase-1 inhibitors were discontinued in 2020 due to failure to achieve the target efficacy in clinical trials and safety issues, so there is no global R&D pipeline yet. NLRP3 inhibitors are being developed by venture capital companies such as OLATEC, IMFLAZOME, IFM THERAPETICS, NODTHERA, and AC Immune for indications such as osteoarthritis, systolic heart failure, Parkinson's disease, inflammatory bowel disease, and Alzheimer's disease. As mentioned above, most of these new inflammasome-modulating drugs have failed in clinical trials, and the known reason is that the new drug targets alone cannot effectively inhibit the diversity of proinflammatory pathways that activate NLRP3 inflammasomes. That is, the currently known new inflammasome-modulating drugs, such as P2X7 receptor antagonists, NLRP3 inhibitors, and caspase-1 inhibitors, selectively inhibit inflammatory cytokines triggered by inflammatory activity such as IL-1β and IL-18, but they cannot inhibit TNF-α, which is an inflammatory cytokine caused at the initial stage of inflammation. This is the basic limitation of new drugs that selectively target only NLRP3 or P2X7. It can be said that the pharmacological mechanism of selectively blocking the activation stage of inflammation alone cannot inhibit inflammatory responses through various bypass pathways. That is, most clinical reports indicate that the drug response rate and anti-inflammatory effect in patients treated with current novel drugs targeting inflammasome regulation are unsatisfactory as a result of alternative activation of compensatory alternative pathways.

[0006] In addition, it has been found that due to the inherent genetic redundancy and polymorphism of NLRP3 and P2X7, the current new inflammasome regulating drugs do not produce the desired drug response rate in actual clinical practice. Specifically, it is known that it exists in a similar NLRP inflammasome group with the same protein domain as the NLPR3 inflammasome, so it causes the new drugs for regulating inflammasomes to have off-target side effects. Hundreds to thousands of single nucleotide polymorphisms (SNPs, Single nucleotide polymorphisms) have been identified in P2X7 protein and NLRP3 protein. Due to the high individual genetic diversity, it often leads to large individual differences in drug response rate and effectiveness. Therefore, it can be said that the new drugs for it are low in the possibility of becoming therapeutic agents with no individual differences and wide efficacy. As described above, the inflammasome-targeted new drugs, P2X7 receptor antagonists, NLRP3 inhibitors and caspase-1 inhibitors developed so far have many limitations in achieving the desired clinical efficacy.

[0007] In addition, in order to overcome the shortcomings of existing inflammasome-targeted new drugs, therapeutic agents targeting GPCR19 that regulate inflammasome upstream signals are being developed in recent years. Specifically, representative examples are TUDCA, INT-747 (Obeticholicacid, OCA) and INT-777 (S-EMCA). Currently, TUDCA is undergoing clinical trials for diseases such as type 2 diabetes, ulcerative colitis and Lou Gehrig's disease, and INT-747 is undergoing clinical trials for diseases such as biliary cirrhosis, non-alcoholic fatty hepatitis, and cirrhosis. These are all bile acid derivatives, and they are currently under study as agonists of GPCR19. In particular, GPCR19 is specifically and highly expressed mainly in immune cells, and because it selectively induces immune cell-mediated anti-inflammatory effects, it has low nonspecific side effects that affect normal cells. Considering that there are reports that the drug targets of existing anti-inflammatory drugs, such as steroids and JAK inhibitors, are distributed throughout the body outside the site of inflammation, in addition to the pharmacological effects on the targets, they also induce widespread systemic effects, thereby causing systemic metabolic side effects, increased risk of infection, and highly carcinogenic side effects. Therefore, it can be considered that new drugs targeting GPCR19 have great advantages in terms of safety.

[0008] As far as the GPCR19 targeted therapeutics developed so far are concerned, no new drugs have been proven to be effective in clinical trials. Taking the earliest developed GPCR19 targeted therapeutic as an example, it failed in a Phase 3 clinical trial for inflammatory diseases due to its low anti-inflammatory effect. In fact, early GPCR19 targeted therapeutics were new drugs derived from cell lines that artificially overexpressed GPCR19 without accurately considering the anti-inflammatory mechanism of GPCR19. They were new drugs developed in a system that did not accurately reflect the initiation and activation stages of inflammation through GPCR19 in the body, and this research and development environment led to clinical failure cases. Therefore, there is still a need to develop a new drug with a broad anti-inflammatory effect that can block the initiation and activation of inflammation through GPCR19 targeted therapy.

[0009] In addition, bile acids are the latest compounds studied as GPCR19 regulators in recent years. Bile acids are amphiphilic molecules with hydrophobic and hydrophilic regions. The production process of bile acids is that cholesterol is used as a precursor, and the cytochrome P450 enzyme in the liver produces primary bile acids in the form of cholic acid and chenodeoxycholic acid, which are combined with taurine and glycine by hepatocytes to have higher hydrophilicity and move to the intestines, and then converted into secondary bile acids by microorganisms in the intestines. Secondary bile acids are reabsorbed into the liver through the enterohepatic circulation, and after moving to various tissues through blood vessels, they exert various physiological functions. Specifically, their functions include digesting fats through their amphiphilic properties, inhibiting the excessive proliferation of harmful microorganisms in the intestines through acidity, and excreting cholesterol during the intestinal circulation process. In addition, it is known that it transmits signals through receptors such as farnesoid X receptor (FXR) which is a nuclear receptor and G protein-coupled bile acid receptor 1 (GPBAR1, GPCR19) which is a cell membrane G protein-coupled receptor. Specifically, bile acid bound to farnesoid X receptor inhibits gluconeogenesis and lipogenesis in the liver by inhibiting gluconeogenesis genes and lipogenesis genes, and binding to G protein-coupled bile acid receptor 1 plays a role in promoting metabolism in the body, promoting insulin secretion, inhibiting cytokine secretion, etc. In particular, binding to G protein-coupled bile acid receptor 1 inhibits inflammatory reactions, so research on the use of bile acid as a therapeutic agent for skin, nerve, stomach, intestine, liver, joint and other diseases related to inflammation and autoimmune diseases is very active.

[0010] Fibrosis can be defined as the abnormal or excessive accumulation of the extracellular matrix, especially fibrillar collagen, and refers to the abnormal accumulation of collagen matrix caused by damage or inflammation that changes the structure and function of various tissues. Inflammation is at the core of the development of fibrosis in the lungs, and inflammatory cells such as mast cells are present in large numbers in pulmonary fibrosis.

[0011] Pulmonary fibrosis is a chronic disease that causes swelling and scarring of the alveoli and interstitial tissues of the lungs. This scar tissue replaces healthy tissue, causing inflammation, which can be considered a precursor to fibrosis. This damage to lung tissue causes the lungs to become stiff, making it difficult for an individual to breathe on their own.

[0012] Among them, idiopathic pulmonary fibrosis (IPF) is defined as a special form of chronic, progressive, unexplained and irreversible fibrotic interstitial pneumonia, which mainly occurs in the elderly. In the United States, 100,000 people suffer from idiopathic pulmonary fibrosis, and the risk of death within a few years after diagnosis is high and the prognosis is poor. Treatment options are limited to stopping disease progression and supplementing oxygen to improve symptoms and organ function. The clinical course of IPF usually includes acute exacerbations leading to hospitalization.

[0013] For patients with idiopathic pulmonary fibrosis, drugs with anti-fibrotic effects such as pirfenidone and nintedanib are usually used. The pharmacological mechanism of these drugs is that pirfenidone exerts its anti-fibrotic effect by inhibiting the proliferation of fibroblasts and collagen synthesis, and nintedanib is a small molecule tyrosine kinase inhibitor targeting fibroblast growth factor receptors. Its main target receptors are platelet-derived growth factor receptors (PDGFRα, β), fibroblast growth factor receptors (FGFR1, 2, 3), and vascular endothelial growth factor receptors (VEGFR1, 2, 3). It has a pathological mechanism of blocking the intracellular neurotransmission process by competitively binding to the target receptors. These drugs have been proven to be effective in delaying the progression of the disease, but they cannot cure the disease from the source. Taking pirfenidone as an example, more than 10% of users experience side effects such as digestive system (indigestion, loss of appetite, nausea, diarrhea, etc.), fatigue, headache, rash, etc., 1% to 10% of users experience side effects such as central nervous system (insomnia, dizziness, drowsiness, etc.), skin (photosensitivity, itching, etc.), digestive system (abnormal taste, abdominal pain, bloating, etc.), weight loss, increased liver function, chest pain, joint pain, weakness, etc., and less than 1% of users experience side effects such as angioedema and agranulocytosis. Taking nintedanib as an example, more than 10% of users experience gastrointestinal abnormalities (diarrhea , vomiting, nausea, abdominal pain), hepatobiliary abnormalities (elevated liver enzymes, increased alanine aminotransferase (ALT)), metabolic and nutritional abnormalities, decreased appetite, 1% to 10% of users experience hepatobiliary abnormalities (drug-induced liver injury, increased aspartate aminotransferase (AST), increased alkaline phosphatase (ALKP), increased gamma-glutamyl transferase (GGT)), vascular abnormalities (hypertension, bleeding), metabolic and nutritional abnormalities (weight loss), neurotic system abnormalities (headache), less than 1% of users experience gastrointestinal system abnormalities (pancreatitis), hepatobiliary abnormalities (hyperbilirubinemia), blood and lymphatic system abnormalities (thrombocytopenia), skin and subcutaneous tissue abnormalities (hair loss) and other side effects. In addition, currently developed drugs for the treatment of idiopathic pulmonary fibrosis include pentraxin-2, CTGF (connective tissue growth factor) inhibitors, autotaxin inhibitors, PI3 kinase / mTOR inhibitors, galectin-3 inhibitors, etc., and many clinical studies are underway, but there is no drug that can completely cure this disease, and patients who progress to a certain extent may need lung transplantation. Therefore, there is an urgent need to develop a therapeutic agent that can show a therapeutic effect on this idiopathic pulmonary fibrosis.

[0014] In addition, taking the traditional pharmaceutical composition for treating idiopathic pulmonary fibrosis including this prior art as an example, it provides partial therapeutic effect or the effect provided is insufficient and not significant, and thus cannot provide a fundamental effect of delaying the onset or progression of pulmonary fibrosis or treating it.

[0015] Furthermore, taking conventional pharmaceutical compositions for treating idiopathic pulmonary fibrosis including the prior art as an example, formulations based on chemical components have low biocompatibility, high incidence of side effects, and encounter difficulties in mass production and quality control based on productivity.

[0016] Therefore, the present inventors have devoted themselves to developing a therapeutic agent that exhibits excellent therapeutic effects on pulmonary fibrosis and has few side effects. Ultimately, they found that pulmonary fibrosis and the expression of fibrosis-related factors were reduced in an animal model of idiopathic pulmonary fibrosis to which a pharmaceutically acceptable salt of taurodeoxycholic acid was administered. This confirmed that the pharmaceutically acceptable salt of taurodeoxycholic acid can be used as an active ingredient in a composition for preventing or treating pulmonary fibrosis, thereby completing the present application.

[0017] [Prior art literature]

[0018] [Patent Document]

[0019] WO 2019-139956 (2019.07.18)

[0020] WO 2015-189401 (2015.12.17)

[0021] WO 2017-152048 (2017.09.08)

[0022] WO 2019-126089 (2019.06.27)

[0023] [Non-patent literature]

[0024] Won-Il Choi, Current and future treatment for idiopathic pulmonaryfibrosis, J Korean Med Assoc. 2021;64(4):256-263 Summary of the invention

[0025] Technical issues

[0026] The object of the present invention is to provide a composition for preventing, treating or improving pulmonary fibrosis, which has excellent effects and low side effects and contains taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

[0027] Technical Solution

[0028] To achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating pulmonary fibrosis, which contains taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0029] In addition, the present invention provides a health functional food composition for preventing or improving pulmonary fibrosis, which contains taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0030] In addition, the present invention provides a food composition for preventing or improving pulmonary fibrosis, which contains taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0031] In addition, the present invention provides a method for preventing or treating pulmonary fibrosis, which comprises administering taurodeoxycholic acid or a pharmaceutically acceptable salt thereof to an individual.

[0032] In addition, the present invention provides a use of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof in a pharmaceutical composition for preventing or treating pulmonary fibrosis.

[0033] In addition, the present invention provides a use of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof in a health functional food composition for preventing or improving pulmonary fibrosis.

[0034] In addition, the present invention provides a use of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof in preparing a pharmaceutical composition for preventing or treating pulmonary fibrosis.

[0035] In addition, the present invention provides a use of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof in preparing a health functional food composition for preventing or improving pulmonary fibrosis.

[0036] Effects of the Invention

[0037] The present inventors administered a pharmaceutically acceptable salt of taurodeoxycholic acid to an animal model of idiopathic pulmonary fibrosis induced by bleomycin and a cell model of pulmonary fibrosis induced by TGF-β. The results confirmed that pulmonary fibrosis and the expression of pulmonary fibrosis-related factors decreased. Therefore, the taurodeoxycholic acid or a pharmaceutically acceptable salt thereof can be used as an active ingredient of a composition for preventing or treating pulmonary fibrosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 The figure is a schematic diagram of a method of preparing an animal model of idiopathic pulmonary fibrosis induced by bleomycin and then administering sodium taurodeoxycholate (hereinafter referred to as "HY209") which is a sodium salt of taurodeoxycholic acid to the animal model.

[0039] Figure 2This graph examines changes in body weight after administration of HY209 in an animal model of idiopathic pulmonary fibrosis induced by bleomycin.

[0040] Figure 3 The graph shows changes in lung weight after administration of HY209 in an animal model of idiopathic pulmonary fibrosis induced by bleomycin (*P<0.05 relative to the hydroxyethylcellulose administration group, #P<0.05 relative to the pulmonary fibrosis group).

[0041] Figure 4 The graph shows histopathological changes after administration of HY209 in an animal model of idiopathic pulmonary fibrosis induced by bleomycin (# vs. control group P<0.05, * vs. hydroxyethylcellulose administration group P<0.05, ** vs. pulmonary fibrosis group P<0.05).

[0042] Figure 5 The graph shows changes in α-SMA expression distribution after administration of HY209 in an animal model of idiopathic pulmonary fibrosis induced by bleomycin (*P<0.05 relative to the hydroxyethylcellulose administration group, #P<0.05 relative to the pulmonary fibrosis group).

[0043] Figure 6 The graph shows changes in the expression of Col1α1, α-SMA, or PAI-1 after HY209 or TUDCA was treated simultaneously with TGF-β-induced fibrosis in the human lung fibroblast MRC5 cell line (*P<0.05 relative to the group treated with TGF-β alone, **P<0.01 relative to the group treated with TGF-β alone).

[0044] Figure 7a This graph shows the inhibitory effect of HY209 or TUDCA treatment on the production of the inflammatory cytokine IL-1β after differentiating human monocyte U937 cell line into macrophages with PMA (phorbol 12-myristate 13-acetate) and inducing inflammatory response with BzATP (2'(3')-O-(4-Benzoylbenzoyl)adenosine 5'-triphosphate).

[0045] Figure 7b The graph shows the inhibitory effect of HY209 or TUDCA treatment on the production of the inflammatory cytokine TNF-α after U937 cells were differentiated into macrophages with PMA (phorbol 12-myristate 13-acetate) and inflammatory response was induced with Pam2CSK4 (Pam2CysSerLys4). DETAILED DESCRIPTION

[0046] Hereinafter, the present invention is described in detail.

[0047] In the present invention, the term "prevention" refers to all actions that inhibit or delay the occurrence, spread and recurrence of the disease by administering the composition of the present invention, and "treatment" refers to all actions that improve or favorably change the symptoms of the disease by administering the composition of the present invention.

[0048] In the present invention, the term "administer" refers to providing a predetermined substance to a patient by any appropriate method, and the composition of the present invention can be administered orally or parenterally by all conventional routes as long as it can reach the target tissue. In addition, the composition can be administered by any device that can move the active substance to the target cells.

[0049] The present invention provides a pharmaceutical composition for preventing or treating pulmonary fibrosis, which contains taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0050] In addition, the present invention provides a method for preventing or treating pulmonary fibrosis, which comprises administering taurodeoxycholic acid or a pharmaceutically acceptable salt thereof to an individual.

[0051] In addition, the present invention provides a use of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof in a pharmaceutical composition for preventing or treating pulmonary fibrosis.

[0052] In addition, the present invention provides a use of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof in preparing a pharmaceutical composition for preventing or treating pulmonary fibrosis.

[0053] In the present invention, the taurodeoxycholic acid is a bile acid and is a taurine-conjugated deoxycholic acid form, which has the chemical structure described in the following [Chemical Formula 1], more specifically, has the chemical structure described in the following [Chemical Formula 2]:

[0054] [Chemical formula 1]

[0055]

[0056] [Chemical formula 2]

[0057]

[0058] In addition, the taurodeoxycholic acid may be any taurodeoxycholic acid isolated from the bodies of animals such as cows, pigs, sheep, dogs, goats or rabbits, commercially available taurodeoxycholic acid, or synthetic taurodeoxycholic acid without limitation.

[0059] In the present invention, pulmonary fibrosis refers to the development of scar (fibrotic) tissue due to excessive formation or development (fibrosis) of fibrous connective tissue in the lungs. Specifically, pulmonary fibrosis is a chronic disease that causes swelling and scarring of the alveoli and interstitial tissue of the lungs. This scar tissue replaces healthy tissue, causing inflammation, and chronic inflammation can be considered a precursor to fibrosis. This lung tissue damage causes the lungs to become stiff, thereby making it difficult for an individual to breathe on their own.

[0060] In addition, the pulmonary fibrosis can specifically be idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, acute interstitial pneumonia, cryptogenic organizing pneumonia, respiratory bronchiolitis associated interstitial lung disease, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, interstitial pulmonary fibrosis or diffuse pulmonary fibrosis, more specifically, it can be idiopathic pulmonary fibrosis, but is not limited to this.

[0061] The pulmonary fibrosis can be caused by a variety of reasons, such as microscopic damage to the lungs induced by inhalation of fine particles (asbestos, stone powder, metal dust, particles in cigarette smoke, silica dust, etc.). In addition, pulmonary fibrosis can be caused by the secondary effects of other diseases (autoimmune diseases, viral or bacterial infections), and can be induced by specific drugs such as cytotoxic agents (bleomycin, busulfan and methotrexate, etc.), antibiotics (nitrofurantoin and sulfasalazine, etc.), arrhythmia therapeutic agents (amiodarone and tocainide, etc.), anti-inflammatory drugs (gold, penicillamine, etc.), illegal drugs (ice, cocaine and heroin, etc.). The idiopathic pulmonary fibrosis can be caused by other unknown reasons other than the above reasons.

[0062] In the present invention, the composition can prevent or treat pulmonary fibrosis by inhibiting the expression of pulmonary fibrosis-related factors (eg, Col1α1, α-SMA, or PAI-1).

[0063] In a specific embodiment of the present invention, the inventors applied a pharmaceutically acceptable salt of taurodeoxycholic acid to an animal model of idiopathic pulmonary fibrosis induced by bleomycin, and the results confirmed that pulmonary fibrosis and the expression of α-SMA, a factor associated with pulmonary fibrosis, decreased. In addition, a pharmaceutically acceptable salt of taurodeoxycholic acid was applied to a cell model of pulmonary fibrosis induced by TGF-β, and the results confirmed that the expression of Col1α1, α-SMA, and PAI-1, factors associated with pulmonary fibrosis, decreased. Therefore, the taurodeoxycholic acid or a pharmaceutically acceptable salt thereof can be used as an active ingredient of a pharmaceutical composition for preventing or treating pulmonary fibrosis.

[0064] The taurodeoxycholic acid of the present invention includes pharmaceutically acceptable salts, solvates, hydrates, racemates, or stereoisomers that can be prepared therefrom.

[0065] The taurodeoxycholic acid of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed from a pharmaceutically acceptable free acid can be effectively used as the salt. Acid addition salts are obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and non-toxic organic acids such as aliphatic monomers and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, decanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, 1,4-butyrates diol, 1,6-diacid hexane, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, or mandelate.

[0066] The acid addition salt according to the present invention can be prepared by conventional methods, for example, by dissolving the taurodeoxycholic acid of the present invention in an excess of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. In addition, it can also be prepared by drying by evaporating the solvent or excess acid in the mixture, or by suction filtering the precipitated salt.

[0067] In addition, a pharmaceutically acceptable metal salt can be prepared using a base. Alkali metal or alkaline earth metal salts can be obtained, for example, by dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare a sodium salt, a potassium salt or a calcium salt as a metal salt, and more specifically, taking taurodeoxycholic acid as an example, it is suitable to prepare a sodium salt. In addition, the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with an appropriate silver salt (e.g., silver nitrate).

[0068] The content of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof of the present invention can be included in a therapeutically effective amount, and may include a pharmaceutically acceptable carrier.

[0069] The "effective amount or effective amount" in the present specification refers to an amount sufficient to alleviate or minimize a disease, or provide a therapeutic benefit in the process of treating or controlling a disease by the compound of the present invention.

[0070] The pharmaceutically acceptable carrier can use, for example, a carrier for oral administration or a carrier for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. In addition, carriers for parenteral administration may include water, appropriate oil, physiological saline, aqueous glucose solution, ethylene glycol, etc., and may further include stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl parahydroxybenzoate or propyl parahydroxybenzoate and chlorobutanol. Other pharmaceutically acceptable carriers may refer to the following literature content (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).

[0071] The pharmaceutical composition of the present invention can be administered to mammals including humans via any administration route. It can be administered orally or parenterally.

[0072] Parenteral administration methods may include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, percutaneous, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal administration. For example, the pharmaceutical composition of the present invention can be administered by a method of preparing an injection preparation and then gently piercing the skin with a 30-gauge fine injection needle, or by directly applying or attaching to the skin.

[0073] The pharmaceutical composition of the present invention can be formulated into preparations for oral administration or parenteral administration via the administration routes described above.

[0074] Taking the preparation for oral administration as an example, the composition of the present invention can be configured into powder, granules, tablets, pills, sugar-coated tablets, capsules, solutions, gels, syrups, slurries, suspensions, etc. by methods known in the art. For example, it can be ground after mixing the active ingredient and solid excipients, and then processed into a granular mixture after adding appropriate adjuvants to obtain the oral preparation of tablets. Suitable excipient examples can include sugars such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol, starches such as corn starch, wheat starch, rice starch and potato starch, celluloses including cellulose, methylcellulose, sodium carboxymethylcellulose and hydroxypropyl methylcellulose, and fillers such as gelatin and polyvinyl pyrrolidone. In addition, cross-linked polyvinyl pyrrolidone, agar, alginic acid or sodium alginate, etc. can be added as disintegrants, depending on the specific circumstances. In addition, the pharmaceutical composition of the present invention can further include anti-aggregants, lubricants, wetting agents, spices, emulsifiers and preservatives, etc.

[0075] Preparations for parenteral administration can be formulated into injections, creams, emulsions, external ointments, oils, moisturizers, gels, patches, aerosols, and nasal inhalers by methods known in the art. These dosage forms are described in all prescription texts known in the field of pharmaceutical chemistry (Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour).

[0076] The total dose of the pharmaceutical composition of the present invention can be applied to the patient in the form of a single dose, or can be applied by a fractionated treatment protocol that is applied for a long time in multiple doses. The pharmaceutical composition of the present invention can change the content of the active ingredient according to the symptoms of the disease. Specifically, the total dose of the composition of the present invention can be about 0.01 μg to 1000 mg per day, per kilogram of patient body weight, more specifically, 0.1 μg to 100 mg. However, the dosage of the pharmaceutical composition of the present invention can be determined by a technician in the field of the invention after considering the route of administration and the number of treatments and the patient's age, weight, health status, sex, severity of the disease, diet, excretion rate and other factors to determine the appropriate effective dose. The dosage form, route of administration and method of administration of the pharmaceutical composition of the present invention are not particularly limited, as long as the effect of the present invention can be shown.

[0077] In addition, the pharmaceutical composition of the present invention can be used as a separate therapeutic agent, or can be used in combination with other therapeutic agents. When used in combination with other therapeutic agents, the composition of the present invention and other therapeutic agents can be used simultaneously, individually or sequentially. At this time, other therapeutic agents can be substances known to have a therapeutic or ameliorative effect on pulmonary fibrosis. When the pharmaceutical composition of the present invention is used in combination with other therapeutic agents, the composition of the present invention and other therapeutic agents can be separated and configured in separate containers, or can be configured in combination in the same dosage form.

[0078] In addition, the present invention provides a health functional food composition for preventing or improving pulmonary fibrosis, which contains taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0079] In addition, the present invention provides a use of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof in a health functional food composition for preventing or improving pulmonary fibrosis.

[0080] In addition, the present invention provides a use of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof in preparing a health functional food composition for preventing or improving pulmonary fibrosis.

[0081] In the present invention, the taurodeoxycholic acid or a pharmaceutically acceptable salt thereof is as described above, and the specific description is referred to the above content. The following only describes the unique composition of the health functional food composition.

[0082] In addition, the present inventors administered a pharmaceutically acceptable salt of taurodeoxycholic acid in an animal model of idiopathic pulmonary fibrosis induced by bleomycin and a cell model of pulmonary fibrosis induced by TGF-β. The results confirmed that pulmonary fibrosis and the expression of pulmonary fibrosis-related factors decreased. Therefore, the taurodeoxycholic acid or a pharmaceutically acceptable salt thereof can be used as an active ingredient of a health functional food composition for preventing or improving pulmonary fibrosis.

[0083] The health functional food composition of the present invention can be prepared into any dosage form selected from the group consisting of powder, granules, pills, tablets, capsules, candies, syrups and beverages, but is not limited thereto.

[0084] The health functional food composition is not particularly limited as long as it can be taken for the prevention or improvement of diseases. When the health functional food composition of the present invention is used as a food additive, the health functional food composition can be added as it is or used together with other foods or food ingredients, and can be used appropriately according to conventional methods. The active ingredient can be used appropriately according to the purpose of use (prevention or improvement). When food or beverage is usually manufactured, it can be added in an amount of less than or equal to 15 parts by weight relative to the health functional food composition of the present invention, preferably less than or equal to 10 parts by weight. However, when long-term intake is for the purpose of maintaining health, the amount can be less than or equal to the above range, and since there are no safety issues, the amount of the active ingredient used can be greater than or equal to the above range. The food type is not particularly limited. Examples of foods to which the health functional food composition can be added include meat, sausage, bread, chocolate, candy, snacks, biscuits, pizza, instant noodles, other noodles, chewing gum, dairy products including ice cream, various soups, beverages, tea beverages, alcoholic beverages, vitamin complexes, etc., and include all conventional health foods. In addition, the health functional food composition of the present invention can be made into food, particularly functional food.

[0085] Functional food of the present invention includes the ingredients routinely added in the food manufacturing process, such as protein, carbohydrate, fat, nutrients and flavoring. For example, when beverage is made, in addition to effective ingredients, natural carbohydrate or flavoring can also be included as additional ingredients. The natural carbohydrate is preferably monosaccharide (such as glucose, fructose, etc.), disaccharide (such as maltose, sucrose, etc.), oligosaccharide, polysaccharide (such as dextrin, cyclodextrin, etc.), or sugar alcohol (such as xylitol, sorbitol, erythritol, etc.). The flavoring can be applied with natural flavoring (such as, thaumatin, stevia extract, etc.) or synthetic flavoring (such as, saccharin, aspartame, etc.). In addition to the above-mentioned health functional food composition, various nutrients, vitamins, electrolytes, flavoring, coloring agents, pectin acid and its salt, alginic acid and its salt, organic acid, protective colloid thickener, pH control agent, stabilizer, preservative, glycerol, alcohol, carbonating agent for carbonated beverage, etc. can be further contained.

[0086] Hereinafter, the present invention is described in detail by way of examples.

[0087] However, the following embodiments are merely for illustrating the present invention, and the contents of the present invention are not limited to the following embodiments.

[0088] <Example 1> Preparation of bleomycin-induced idiopathic pulmonary fibrosis animal model and experimental design

[0089] In order to confirm the efficacy of taurodeoxycholic acid (TDCA), an animal model of idiopathic pulmonary fibrosis induced by bleomycin was prepared, and sodium taurodeoxycholate (hereinafter referred to as "HY209"), which is the sodium salt of TDCA, was administered to the animal model.

[0090] Specifically, 9-week-old C57B / L6 mice were purchased and the experiment was conducted after a 1-week acclimatization period. The experimental animals were kept at a temperature of 22±2°C, a relative humidity of 55±10%, and a 12-hour light-dark cycle. Drinking water was free, and sterilized feed was provided and consumed freely.

[0091] Then, if Figure 1 As shown in the schematic diagram, after 1 mg / mL of bleomycin (BLM, Enzo Life Sciences, Inc., Cas. No. 9041-93-4) was administered intranasally to mice once, the mice were divided into 7 groups as shown in [Table 1] below, and the samples were administered in the fibrosis stage (day 7 to day 21) after the inflammation stage (day 0 to day 7). For the pulmonary fibrosis group, the vehicle (0.5% carboxymethylcellulose (CMC)) was orally administered as a sample twice a day at 10 mL / kg, and for the experimental group, HY209 was orally administered as a sample twice a day, and the HY209 was prepared by making the final concentration of 0.5% CMC solution to 10 mg / kg, 30 mg / kg, and 60 mg / kg, respectively. For the control group (nintedanib administration group), nintedanib was orally administered twice a day as a sample, and the nintedanib was prepared by making the final concentration of the vehicle (0.1% hydroxyethylcellulose solution) reach 60 mg / kg. For the pulmonary fibrosis group (hydroxyethylcellulose administration group) for comparison with the above-mentioned nintedanib administration group, 10 mL / kg of 0.1% hydroxyethylcellulose solution was orally administered twice a day. For the control group, physiological saline was administered instead of bleomycin, and 10 mL / kg of the vehicle (0.5% CMC solution) as a sample was orally administered twice a day.

[0092] [Table 1]

[0093]

[0094] <Example 2> Confirmation of body weight changes by administration of HY209 in an animal model of bleomycin-induced idiopathic pulmonary fibrosis

[0095] The changes in body weight of each mouse in the above <Example 1> were confirmed.

[0096] Specifically, during the experiment of each group of mice in <Example 1>, the body weight was measured every day.

[0097] The results are as follows Figure 2 As shown, there was no significant difference in body weight change between the HY209-administered group and the control group.

[0098] <Example 3> Confirmation of changes in lung weight by administration of HY209 in an animal model of bleomycin-induced idiopathic pulmonary fibrosis

[0099] The change in lung weight per mouse in the above <Example 1> was confirmed.

[0100] Specifically, after the experiment, the mice in each group in the above <Example> were sacrificed and the lungs were removed. The weight of the lungs after removal was measured.

[0101] The results are as follows Figure 3 As shown, the lung weight was significantly increased in the pulmonary fibrosis group and the hydroxyethylcellulose administration group due to idiopathic pulmonary fibrosis induced by bleomycin compared to the control group. In contrast, the lung weight of the nintedanib administration group was significantly reduced compared to the hydroxyethylcellulose administration group. In addition, the lung weight was reduced by a statistically effective amount in the 10 mg / kg HY209 administration group and the 60 mg / kg HY209 administration group compared to the pulmonary fibrosis group.

[0102] <Example 4> Confirmation of histopathological changes in response to administration of HY209 in an animal model of bleomycin-induced idiopathic pulmonary fibrosis

[0103] Each mouse in the above-mentioned <Example 1> was evaluated for pulmonary fibrosis.

[0104] Specifically, after the experiment, the mice in each group in the above <Example> were sacrificed and the lungs were removed. For histopathological evaluation, the removed lungs were embedded in paraffin and stained by the Crossman trichrome method (Gray P. The Microtomist's Formulary and Guide. Published by Robert E. Krieger Publishing Co.). The Matsuse modification of the Ehrlich score in the following [Table 2] was used to evaluate lung histological changes (Ashcroft Het al. J Clin Pathol (1988) 41: 467-70; Matsuse T et al. Eur Respir J (1999) 13: 71-77).

[0105] [Table 2]

[0106] Ashcroft score Fraction Normal lung (no fibrosis) 1 Mild fibrosis and thickening of alveolar or bronchial walls (fine collagen fiber network) 2 Moderate fibrosis with wall thickening and no obvious damage to lung structure 3 Fibrosis with damage to lung structure (coarse fibrous bands or small fibrous clusters, collagen fibers within the alveoli) 4 Extensive fibrosis with severe distortion of lung architecture 5

[0107] The results are as follows Figure 4 As shown, the pulmonary fibrosis in the pulmonary fibrosis group and the hydroxyethylcellulose administration group was significantly increased compared with the control group. In contrast, the pulmonary fibrosis in the nintedanib administration group was significantly reduced compared with the hydroxyethylcellulose administration group. In addition, compared with the pulmonary fibrosis group, in the 10 mg / kg HY209 administration group and the 60 mg / kg HY209 administration group, pulmonary fibrosis was reduced by a statistically effective amount.

[0108] <Example 5> Confirmation of changes in the expression of pulmonary fibrosis-related factors using HY209 in an animal model of bleomycin-induced idiopathic pulmonary fibrosis

[0109] The expression distribution of fibrosis-related factors in the lung tissue of each mouse in the above-mentioned <Example 1> was confirmed.

[0110] Specifically, after the experiment, the mice in each group in the above <Example 1> were sacrificed and the lungs were removed. For histopathological evaluation, the removed lungs were embedded in paraffin, and the slices were obtained and attached to slides. Then, the expression distribution of α-SMA, a fibrosis-related factor, in each lung tissue was evaluated.

[0111] Immunohistochemical analysis of α-SMA was performed using anti-α-SMA antibody. Antigen detection was performed using target repair solution pH 6 (PT Linkmodul, DAKO). The slides were reacted with primary rabbit polyclonal anti-α-SMA antibody and then with the ImmPRESS detection kit (Autostainer Link48, DAKO). Digital image analysis software was used. The extent of de novo α-SMA accumulation was assessed. Results are shown as percentage (%) of α-SMA area.

[0112] The results are as follows Figure 5 As shown, the α-SMA area in the pulmonary fibrosis group and the hydroxyethylcellulose administration group increased significantly compared with the control group. No significant difference was shown between the pulmonary fibrosis group and the hydroxyethylcellulose administration group.

[0113] In contrast, the α-SMA area in the nintedanib administration group was significantly reduced compared with the pulmonary fibrosis group and the hydroxyethylcellulose administration group. In addition, the α-SMA area was significantly reduced in the 10 mg / kg HY209 administration group and the 60 mg / kg HY209 administration group compared with the pulmonary fibrosis group and the hydroxyethylcellulose administration group.

[0114] <Example 6> Comparison of the ability of HY209 and TUDCA to inhibit the expression of fibrosis-related factors

[0115] In order to compare the fibrosis inhibitory ability of HY209 and TUDCA in pulmonary fibrosis, TGF-β was used to induce fibrosis in the human lung fibroblast MRC5 cell line, and the inhibitory ability of HY209 and TUDCA on the expression of fibrosis-related factors was detected by qPCR.

[0116] Specifically, human lung fibroblast MRC5 cell line was inoculated with 2x10^5 cells in a 6-well plate and cultured overnight to allow the cells to adhere. Then, the culture medium was removed, HY209 was treated with 5ng / mL TGF-β1 or 0μM, 0.1μM, 1μM, 10μM TUDCA and cultured for 48 hours, and then the cells were collected. Then, RNA was extracted from the cells using RNeasy Mini Kit (QIAGEN) and Maxime TM cDNA was synthesized by RT PreMix (LiliF Diagnostic). TM qPCR was performed using Green PCR Master Mix (Thermo Fisher Scientific) according to the manufacturer's protocol. In addition, the expression of Col1α1, α-SMA, and PAI-1 was confirmed using primers, and GAPDH was confirmed as an internal standard.

[0117] The results are as follows Figure 6 As shown, HY209 inhibited the expression of α-SMA and PAI-1 at 0.1 μM, 1 μM, and 10 μM, but TUDCA showed no inhibitory ability at concentrations of 0.1 μM and 1 μM, but only at 10 μM. In addition, HY209 reduced the expression of Col1α1 at 0.1 μM, 1 μM, and 10 μM, while TUDCA increased the expression at 0.1 μM and 1 μM concentrations.

[0118] The above results indicate that HY209 is significantly better than TUDCA in inhibiting the expression of fibrosis-related factors.

[0119] <Example 7> Evaluation of the Inflammation Suppression Efficacy of HY209 and TUDCA

[0120] To evaluate the anti-inflammatory effects of HY209 and TUDCA, human monocyte U937 cells were differentiated into macrophages by treating them with PMA (phobol12-myristate 13-acetate), and the inflammatory response was induced by BzATP or Pam2CSK4. Then, the inhibitory effects of HY209 or TUDCA on the production of inflammatory cytokines IL-1β and TNF-α were detected.

[0121] Specifically, human monocyte U937 cells were seeded at 70,000 cells per well in a 96-well plate and cultured in RPMI1640 medium containing 50 nM PMA (phobol 12-myristate 13-acetate) for 24 hours to differentiate macrophages. The medium of each well was removed, and HY209 or TUDCA was treated at each concentration (HY209: 1 μM, 0.5 μM, 0.25 μM, 0.125 μM, 0.0625 μM, 0.0312 μM, 0.0156 μM, 0.0078 μM, TUDCA: 1000 μM, 316 μM, 100 μM, 31.6 μM, 10 μM, 3.16 μM, 0.316 μM, 0.1 μM, 0.0316 μM, 0.01 μM, 0.00316 μM) for 12 hours. BzATP was added until the final concentration reached 300 μM, and then cultured for a further 12 hours. Then, the supernatant was collected and IL-1β ( Figure 7a ).

[0122] In addition, human monocyte U937 cells were seeded at 5x10^6 cells in a 100-pi culture dish and cultured in RPMI1640 medium containing 4nM PMA for 5 hours to differentiate macrophages. The differentiated macrophages were seeded at 50,000 cells per well in a 96-well plate and cultured for 24 hours, followed by a rest period. Then, the medium was replaced with a serum-free medium and cultured for 12 hours. The medium was removed from each well, and HY209 or TUDCA was treated with 50 ng / mL Pam2CSK4 at each concentration (HY209: 10 μM, 4 μM, 2 μM, 1 μM, 0.5 μM, 0.25 μM, 0.125 μM, 0.0625 μM, 0.03125 μM, TUDCA: 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.125 μM, 1.562 μM, 0.76 μM) for 4 hours, and the supernatant was collected. The collected supernatant was tested for TNF-α using a TNF-α ELISA kit (R&D Systems) according to the manufacturer's procedure. Figure 7b ).

[0123] The results are as follows Figure 7a and 7b As shown in Figure 2, HY209 and TUDCA showed IC values ​​of 0.044 μM and 1.496 μM, respectively, for the inhibition of IL-1β production. 50 value( Figure 7a ), and showed IC values ​​of 0.36μM and 13.1μM for TNF-α, respectively. 50 value( Figure 7b ).

[0124] The above results show that HY209 exhibits a 34-fold lower IL-1β IC compared to TUDCA 50 values ​​and 36-fold lower TNF-αIC 50 This indicates that the inflammation-inhibiting effect of HY209 is significantly superior to that of TUDCA.

[0125] Industrial Applicability

[0126] In the present invention, it was confirmed that a pharmaceutically acceptable salt of taurodeoxycholic acid reduces pulmonary fibrosis and the expression of pulmonary fibrosis-related factors in an animal model of idiopathic pulmonary fibrosis and a cell model of pulmonary fibrosis. Therefore, taurodeoxycholic acid or a pharmaceutically acceptable salt thereof of the present invention can be used as an active ingredient of a composition for preventing or treating pulmonary fibrosis.

Claims

1. A pharmaceutical composition for preventing or treating pulmonary fibrosis, comprising taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

2. The pharmaceutical composition for preventing or treating pulmonary fibrosis according to claim 1, wherein: The taurodeoxycholic acid is a compound represented by the following [Chemical Formula 2]: [Chemical formula 2] 3. The pharmaceutical composition for preventing or treating pulmonary fibrosis according to claim 1, wherein: The pharmaceutically acceptable salt is a sodium salt.

4. The pharmaceutical composition for preventing or treating pulmonary fibrosis according to claim 1, wherein: The composition reduces the expression of factors associated with pulmonary fibrosis.

5. The pharmaceutical composition for preventing or treating pulmonary fibrosis according to claim 4, wherein: The pulmonary fibrosis-related factor is COL1α1, α-SMA or PAI-1.

6. The pharmaceutical composition for preventing or treating pulmonary fibrosis according to claim 1, wherein: The pulmonary fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis, nonspecific interstitial lung, acute interstitial pneumonia, cryptogenic organizing pneumonia, respiratory bronchiolitis interstitial lung disease, desquamative interstitial pneumonia, lymphocytic interstitial pneumonia, interstitial pulmonary fibrosis and diffuse pulmonary fibrosis.

7. The pharmaceutical composition for preventing or treating pulmonary fibrosis according to claim 1, further comprising: One or more pharmaceutically acceptable carriers.

8. A health functional food composition for preventing or improving pulmonary fibrosis, comprising taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an effective ingredient.

9. A food composition for preventing or improving pulmonary fibrosis, comprising taurodeoxycholic acid or a pharmaceutically acceptable salt thereof as an effective ingredient.

10. A method for preventing or treating pulmonary fibrosis, comprising: Taurodeoxycholic acid or a pharmaceutically acceptable salt thereof is administered to the individual.

11. Use of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof in a pharmaceutical composition for preventing or treating pulmonary fibrosis.

12. Use of taurodeoxycholic acid or a pharmaceutically acceptable salt thereof in a health functional food composition for preventing or improving pulmonary fibrosis.

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