WO2023101441A1 - Use of microsomal triglyceride transfer protein inhibitor in treatment of fibrosis disease - Google Patents
Use of microsomal triglyceride transfer protein inhibitor in treatment of fibrosis disease Download PDFInfo
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- WO2023101441A1 WO2023101441A1 PCT/KR2022/019267 KR2022019267W WO2023101441A1 WO 2023101441 A1 WO2023101441 A1 WO 2023101441A1 KR 2022019267 W KR2022019267 W KR 2022019267W WO 2023101441 A1 WO2023101441 A1 WO 2023101441A1
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- mtp
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- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/33—Heterocyclic compounds
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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Definitions
- the present invention relates to the use of a microsomal triglyceride transfer protein (MTP) inhibitor for the treatment of fibrotic diseases, and more particularly, as a novel use of an MTP inhibitor exhibiting an inhibitory effect on collagen accumulation associated with fibrosis, fibrosis It relates to disease prevention or treatment use.
- MTP microsomal triglyceride transfer protein
- Fibrosis is a disease in which extracellular matrix is abnormally produced, accumulated, and deposited by fibroblasts, and is caused by fibrosis of organs or tissues. Fibrosis is a very fatal disease that causes organ damage. For example, idiopathic pulmonary fibrosis (IPF) occurs as a result of recurrent alveolar epithelial cell damage associated with fibroblast accumulation and myofibroblast differentiation, resulting in irreversible destruction of lung parenchyma tissue and extracellular matrix (ECM).
- IPF idiopathic pulmonary fibrosis
- ECM extracellular matrix
- Fibrosis develops as a result of various underlying diseases. Chronic inflammation or tissue damage/remodeling is a typical fibrosis-induced event. Specific disease examples include idiopathic pulmonary fibrosis (IPF), liver fibrosis associated with alcoholic and non-alcoholic liver cirrhosis, renal fibrosis, cardiac fibrosis, and keloid formation resulting from abnormal wound healing [Wynn, T. A. (2004) Nature Reviews. Immunology. 4: 583-594; Friedman, S.L. (2013) Science Translation Medicine. 5(167):1-17].
- IPF idiopathic pulmonary fibrosis
- liver fibrosis associated with alcoholic and non-alcoholic liver cirrhosis include idiopathic pulmonary fibrosis (IPF), liver fibrosis associated with alcoholic and non-alcoholic liver cirrhosis, renal fibrosis, cardiac fibrosis, and keloid formation resulting from abnormal wound healing [Wynn, T. A. (2004) Nature Reviews. Immunology
- fibrosis is a key pathological feature associated with chronic autoimmune diseases including rheumatoid arthritis, Crohn's disease, systemic lupus erythematosus and scleroderma.
- Diseases that present a significant unmet medical need include idiopathic pulmonary fibrosis (IPF), scleroderma and nonalcoholic steatohepatitis (NASH) associated liver fibrosis.
- IPF idiopathic pulmonary fibrosis
- NASH nonalcoholic steatohepatitis
- hepatic fibrosis liver cirrhosis or hepatic fibrosis
- liver cirrhosis liver cirrhosis
- liver cirrhosis liver cirrhosis
- liver cirrhosis liver cirrhosis
- ECM extracellular matrix
- Liver fibrosis is difficult to restore to a normal liver once fibrosis progresses, and it progresses to liver cirrhosis or liver cancer, resulting in a continuously increasing mortality rate.
- Liver cirrhosis refers to deterioration of liver function by changing normal liver tissue into fibrotic tissue such as regenerative nodules (a phenomenon in which small lumps are formed) due to chronic inflammation. So far, there is no specific treatment for these diseases.
- the present inventors have conducted extensive research to develop a therapeutic agent that can effectively and safely treat fibrotic diseases. It was found that it was further improved through combined use, and the present invention was completed.
- an object of the present invention is to provide a pharmaceutical composition for preventing or treating fibrotic disease, comprising a microsomal triglyceride transfer protein (MTP) inhibitor as an active ingredient.
- MTP microsomal triglyceride transfer protein
- Another object of the present invention is to provide a pharmaceutical composition for preventing or treating fibrotic disease comprising a microsomal triglyceride transfer protein (MTP) inhibitor.
- MTP microsomal triglyceride transfer protein
- an object of the present invention is to provide a pharmaceutical composition for preventing or treating fibrotic disease consisting essentially of a microsomal triglyceride transfer protein (MTP) inhibitor.
- MTP microsomal triglyceride transfer protein
- an object of the present invention is to provide a use of a microsomal triglyceride transfer protein (MTP) inhibitor for preparing a composition for treating fibrotic disease.
- MTP microsomal triglyceride transfer protein
- an object of the present invention is to provide a method for treating fibrotic disease comprising administering an effective amount of a composition comprising a microsomal triglyceride transfer protein (MTP) inhibitor as an active ingredient to a subject in need thereof. is to provide
- MTP microsomal triglyceride transfer protein
- the present invention provides a pharmaceutical composition for preventing or treating fibrotic disease comprising a microsomal triglyceride transfer protein (MTP) inhibitor as an active ingredient.
- MTP microsomal triglyceride transfer protein
- the present invention provides a pharmaceutical composition for preventing or treating fibrotic disease comprising a microsomal triglyceride transfer protein (MTP) inhibitor.
- MTP microsomal triglyceride transfer protein
- the present invention provides a pharmaceutical composition for preventing or treating fibrotic disease, essentially consisting of a microsomal triglyceride transfer protein (MTP) inhibitor.
- MTP microsomal triglyceride transfer protein
- the present invention provides a use of a microsomal triglyceride transfer protein (MTP) inhibitor for preparing a composition for treating fibrotic disease.
- MTP microsomal triglyceride transfer protein
- the present invention comprises administering an effective amount of a composition comprising a microsomal triglyceride transfer protein (MTP) inhibitor as an active ingredient to a subject in need thereof.
- MTP microsomal triglyceride transfer protein
- treatment refers to the application or administration of a therapeutic agent, that is, a compound of the present invention (alone or in combination with other pharmaceutical agents) to a patient or HBV infection
- HBV infection Treatment cure, alleviation, alleviation, alteration, resolution, amelioration, improvement or outbreak of HBV infection, symptoms of HBV infection, or HBV infection from patients at risk of developing symptoms or HBV infection (e.g., diagnosis or ex vivo application)
- a therapeutic agent Treatment
- cure alleviation, alleviation, alteration, resolution, amelioration, improvement or outbreak of HBV infection, symptoms of HBV infection, or HBV infection from patients at risk of developing symptoms or HBV infection (e.g., diagnosis or ex vivo application)
- Such treatment can be tailored and modified based on knowledge obtained, inter alia, from the field of genomic pharmacology.
- prevent means that, if nothing has happened, there is no development of the disorder or disease, or if there has already been the development of the disorder or disease, there is no further development of the disorder or disease. Also contemplated is one's ability to prevent some or all of the symptoms associated with a disorder or disease.
- the term "patient”, “individual” or “subject” refers to a human or a non-human mammal.
- non-human mammals include livestock and pets such as ovine, bovine, porcine, canine, feline and murine mammals.
- the patient, subject or individual is a human.
- the terms "effective amount”, “pharmaceutically effective amount” and “therapeutically effective amount” refer to a non-toxic sufficient amount of an agent to provide a desired biological result.
- the result may be a reduction and/or attenuation of a signal, symptom or cause of a disease, or any other desired change in a biological system.
- An appropriate therapeutic amount for any individual can be determined by one skilled in the art using routine experimentation.
- the term "pharmaceutically acceptable” means that it does not interfere with the biological activity or properties of a compound and is relatively non-toxic, that is, a substance has an undesirable biological effect or any component of a composition it contains. Refers to a substance, such as a carrier or diluent, that can be administered to an individual without interacting in a detrimental way with the component.
- the term "pharmaceutically acceptable salt” refers to a salt of a compound to be administered prepared from non-toxic acids including pharmaceutically acceptable inorganic acids, organic acids, solvates, hydrates or clathrates thereof.
- inorganic acids are hydrochloric acid, hydrobromic acid, iodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, hexafluorophosphoric acid, citric acid, gluconic acid, benzoic acid, propionic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid.
- Suitable organic acids may be selected, for example, from the aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, such as formic acid, acetic acid, propionic acid, succinic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, isethionic acid, Lactic acid, malic acid, mucous acid, tartaric acid, para-toluenesulfonic acid, glycolic acid, glucuronic acid, maleic acid, furoic acid, glutamic acid, benzoic acid, atranilic acid, salicylic acid, phenylacetic acid, mandelic acid, emphonic acid (pam acid), Examples include methanesulfonic acid, ethanesulfonic acid, pantothenic acid, benzenesulfonic acid (pam acid), Examples include methanesulfonic acid, ethanesulfonic acid, pantothenic acid, benzenesulfonic acid
- the term "pharmaceutically acceptable carrier” refers to a liquid or solid filler, stabilizer, A pharmaceutically acceptable substance, composition or carrier such as a dispersing agent, suspending agent, diluent, additive, thickening agent, solvent or encapsulating material. Typically, these components are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formula, including compounds useful within the present invention, and not injurious to the patient.
- materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose used in pharmaceutical formulations; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc; additives such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; Surfactants; alginic acid; pyrogen-free water; isotonic solution; Ringer's solution; ethyl alcohol; phosphat
- pharmaceutically acceptable carrier is compatible with the activity of compounds useful within the present invention, and is physiologically acceptable to patients in part or in whole coating agent, antiviral and antibacterial agent, and absorption delaying agent. Include etc. Supplementary active compounds may also be incorporated into the compositions. Further “pharmaceutically acceptable carriers” may further include pharmaceutically acceptable salts of compounds useful within the present invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of this invention are known in the art.
- composition refers to a mixture of at least one compound useful within the present invention with a pharmaceutically acceptable carrier.
- a pharmaceutical composition facilitates administration of the compound to a patient or subject.
- a variety of techniques exist in the art for administering compounds including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary and topical administration.
- the terms "combination therapy” or “in combination” refer to the administration of two or more therapeutic agents to treat the conditions or disorders described herein (ie, metabolic diseases and fibrotic diseases). Such administration includes co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed proportion of the active ingredients. Alternatively, such administration includes co-administration in multiple or separate containers (eg, capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to the desired dosage prior to administration. In addition, such administration includes sequential use of each type of therapeutic agent at about the same time or at different times. In either case, the treatment regimen will provide beneficial effects of the drug combination in the treatment of the conditions or disorders described herein.
- Combination therapy can provide a "synergistic effect" and can prove to be “synergistic.” That is, the effect achieved when the active ingredients are used together is greater than the sum of the effects produced by using the compounds individually.
- a synergistic effect occurs when the active ingredients are (1) co-formulated and administered or delivered simultaneously in a combined unit dosage form; (2) when delivered alternately or in parallel as separate dosage forms; or (3) when delivered by some other initiative.
- a synergistic effect can be obtained when the compounds are administered or delivered sequentially, eg by different injections in separate syringes.
- effective doses of each active ingredient are administered sequentially, i.e.
- Synergistic effect refers to the action of two therapeutic agents to produce an effect greater than the simple sum of the effects of each drug administered alone.
- the synergistic effect can be calculated using suitable methods such as, for example, the Sigmoid-Emax equation, the Loewe additive equation, and the median effect equation.
- Sigmoid-Emax equation the Sigmoid-Emax equation
- Loewe additive equation the median effect equation.
- the present invention provides a pharmaceutical composition for preventing or treating fibrotic disease comprising a microsomal triglyceride transfer protein (MTP) inhibitor as an active ingredient.
- MTP microsomal triglyceride transfer protein
- MTP is the protein encoded by the MTTP gene in humans, which completes the heterodimeric microsomal triaglyceride transporter protein, which plays a central role in lipoprotein assembly.
- MTP is a lipid transport protein required for the assembly and secretion of very-low-density lipoproteins (LDL) in the liver and chylomicrons in the intestine.
- the MTP inhibitor may include those that inhibit the expression of a gene encoding an MTP protein or the activity of a protein.
- antisense nucleotides for example, antisense nucleotides, aptamers, small interfering RNA (siRNA), short hairpin RNA (shRNA), micro RNA (miRNA) or RNA interference (RNAi) against MTTP mRNA encoding the MTP protein, and the like, and It may include, but is not limited to, natural products, organic compounds, poorly differentiated compounds, antibodies, proteins, etc. capable of inhibiting expression and/or activity.
- the MTP inhibitor has a very excellent activity of inhibiting collagen accumulation by inflammatory factors in human lung fibroblasts, and can exhibit an effect of preventing or treating fibrotic disease in each tissue in the body.
- the fibrotic disease is also called fibrosis, and is a chronic and progressive disease characterized by excessive accumulation of extracellular matrix (ECM) leading to hardening and/or scarring of related tissues. It develops through complex interactions of cells, extracellular matrix, cytokines, and growth factors.
- ECM extracellular matrix
- Other cell types include resident mesenchymal cells (fibroblasts and myofibroblasts) and ECM-producing cells derived from epithelial and endothelial cells (through a process called epithelial- and endothelial-mesenchymal transition), and local or bone marrow-derived stem cells (fibroblasts). ), etc.
- Fibroblasts have long been considered as the major cell type involved in normal wound healing and as important effector cells in fibrogenesis.
- ⁇ -smooth muscle actin ⁇ -smooth muscle actin
- the type of fibrotic disease is not particularly limited, and is caused by chronic inflammation or tissue damage/remodeling, etc., and is a progressive disease that leads to hardening and/or scarring of related tissues due to excessive accumulation of extracellular matrix (ECM). Any disease can be included.
- Non-limiting examples of the fibrotic disease may include pulmonary fibrosis, liver fibrosis, skin fibrosis, renal fibrosis, pancreatic fibrosis, systemic sclerosis and cardiac fibrosis.
- the lung fibrosis is a serious medical condition involving scarring of lung tissue. These symptoms occur when the alveoli and interstitial tissue of the lungs become inflamed and develop scars in the tissue in an attempt to repair itself. Pulmonary fibrosis involves progressive exchange of fibrotic tissue (fibrous scar) with normal lung parenchyma.
- Pulmonary fibrosis is characterized by chronic inflammatory processes (sarcomatosis, Wegener's granulomatous disease), infections, environmental agents (exposure to asbestos, silica, certain gases), exposure to ionizing radiation (e.g. radiation therapy to treat tumors in the chest), and chronic conditions. (lupus), and certain medications (eg amiodarone, bleomycin, pingyangmycin, busulfan, methotrexate, and nitrofurantoin).
- fibrosis of the lungs may develop after a high immune response to inhaled organic dust or industrial chemicals. These symptoms mostly result from inhalation of dust contaminated with bacteria, fungi, or animal products.
- liver fibrosis or hepatic fibrosis is a process of excessive accumulation of extracellular matrix proteins (including collagen) and subsequent scar formation that occurs in most chronic liver diseases. Liver fibrosis that progresses over time results in cirrhosis. Cirrhosis is the final stage of chronic liver disease and is generally irreversible with poor long-term prognosis. At an advanced stage, the only option is a liver transplant. The risk of liver cancer is significantly increased with cirrhosis, and cirrhosis can be seen as a precancerous condition (hepatocellular carcinoma). In fact, cirrhosis and liver cancer are among the top 10 causes of death worldwide. Thus, there is a need for effective treatment of liver fibrosis and subsequent cirrhosis. Unfortunately, there are few treatment options available, and most treatment consists of addressing the causes and/or symptoms of cirrhosis.
- NASH non-alcoholic steatohepatitis
- the skin fibrosis or epidermal fibrosis is excessive scarring of the skin and results from a pathological wound healing response.
- fibrotic skin diseases There are a wide range of fibrotic skin diseases: scleroderma, nephrogenic dermatosis, mixed connective tissue disease, sclerosing myxedema, sclerotic hydrocele, and eosinophilic fasciitis. Exposure to chemical or physical agents (mechanical trauma, burns) is also a potential cause of fibrotic skin disease. Skin fibrosis can be driven by immune, autoimmune and inflammatory mechanisms. The balance of collagen production and degradation in fibroblasts plays an important role in the pathophysiological process of skin fibrosis.
- cytokines such as transforming growth factor- ⁇ (TGB- ⁇ ) and interleukin-4 (IL-4) promote wound healing and fibrosis, while interferon- ⁇ (IFN- ⁇ ) and tumor necrosis factor- ⁇ ( Others, such as TNF- ⁇ ), are anti-fibrotic.
- Fibroblasts in normal skin are quiescent. They control the amount of connective tissue proteins and have low proliferative activity. After skin injury, these cells are activated, ie they express ⁇ -smooth muscle actin ( ⁇ -SMA) and synthesize large amounts of connective tissue proteins. Activated cells are often called myofibroblasts.
- dermal fibrosis can have a significant impact on health outcomes, particularly when it is part of systemic scleroderma.
- the latter refers to connective tissue diseases of autoimmune etiology. Restricted cutaneous scleroderma is limited to the skin of the face and feet, whereas diffuse cutaneous scleroderma covers more skin and may progress to the visceral organs.
- the renal fibrosis means excessive proliferation of cells, hardening of tissues and scars. Renal fibrosis can result from renal failure and catheterization, eg dialysis following peritoneal and vascular access fibrosis. Renal fibrosis can also result from nephropathy such as glomerular disease (eg glomerulosclerosis, glomerulonephritis), chronic renal failure, acute renal failure, end-stage renal disease and renal failure. Regardless of etiology, all patients with chronic kidney disease exhibit a gradual decline in renal function over time. Fibrosis, so-called scarring, is a major cause of the pathophysiology.
- Fibrosis involves excessive accumulation of extracellular matrix (composed primarily of collagen), usually resulting in loss of function when normal tissue is replaced by scar tissue. This process is often irreversible and essentially leads to end-stage renal failure, a condition requiring lifelong dialysis or kidney transplantation.
- cardiac fibrosis a hallmark of heart disease, is thought to contribute to sudden cardiac death, ventricular arrhythmias, left ventricular (LV) dysfunction, and cardiac disorders.
- Cardiac fibrosis is characterized by disproportionate accumulation of fibrotic collagen, inflammation, increased workload, hypertrophy, and stimulation by a number of hormones, cytokines, and growth factors that occur after cardiomyocyte death.
- Cardiac fibrosis can also refer to abnormal thickening of heart valves due to disproportionate proliferation of cardiac fibroblasts, but more generally refers to proliferation of fibroblasts in the heart muscle.
- Fibrous cells normally secrete collagen and function to provide structural support for the heart. When overly activated, this process causes thickening and fibrosis of the valves, at which time white tissue not only builds the tricuspid valve, but also occurs in the pulmonary valve. Concentration and loss of flexibility can eventually lead to valve failure and right-sided heart failure.
- CP Chronic pancreatitis
- pancreas which causes pancreatic fibrosis
- CP is a progressive inflammatory disease of the pancreas characterized by irreversible morphological changes and progressive fibrotic replacement of the gland.
- parenchymal fibrosis loss of exocrine and endocrine function occurs.
- the main symptoms of CP are abdominal pain and indigestion.
- the pancreas may be enlarged or atrophied with or without cysts or calcifications or tumors.
- the tube may be dilated, irregular or constricted.
- the major pathological features include irregular and non-uniform loss of lobular tissue, chronic inflammation, ductal changes and fibrosis.
- Gene mutations including but not limited to cystic fibrosis, cationic trypsinogen gene, CFTR gene mutation in idiopathic acute and chronic pancreatitis, pancreatic secretory trypsin inhibitor gene, chymotrypsinogen C gene, calcium sensing receptor gene, ⁇ - 1 including antitrypsin deficiency), metabolic (alcohol, tobacco smoking, hypercalcemia, hyperlipidemia, chronic renal failure), environmental factors (micronutrient deficiencies (nutritional factors such as zinc, copper and selenium; also post-irradiation exposure), obstructive ( tumor), ischemic (vascular disease)) and autoimmune diseases, or is the final manifestation of a complex pathogenic mechanism associated with primary sclerosing bile duct flames, Sjogren's syndrome, primary biliary disorders and type 1 diabetes mellitus.
- the composition containing the non-nucleoside reverse transcriptase inhibitor according to the present invention suppresses the fibrotic reaction by reducing the amount of procollagen alpha 1 in each tissue or cell, and this effect is (B-cell lymphoma 2) inhibitors, DPP-4 (Dipeptidyl peptidase-4) inhibitors, and niclosamide (Niclosamide) when used in combination with one or more drugs can show synergistic effects.
- the composition may further include at least one selected from the group consisting of parthenolide, digoxin, and pharmaceutically acceptable salts thereof. That is, an MTP inhibitor and parthenolide or digoxin can show a synergistic effect in the treatment of fibrotic disease as a combination therapy or as a combination agent.
- the combination therapy or combination preparation may show a synergistic effect in the treatment of fibrotic disease.
- each component included in the combination preparation may be formulated for use separately, simultaneously or sequentially. That is, in the case of sequential administration, the combination preparation may be administered in two or more administrations. Concomitant administration can include co-administration using separate formulations or a single pharmaceutical formulation, as well as sequential administration in either order.
- these combination drugs are used in a molar ratio of 1:0.01 to 1000, preferably in a molar ratio of 1:1 to 500, more preferably It may be administered in combination at a molar ratio of 1:50 to 500, more preferably at a molar ratio of 1:100 to 500, and most preferably at a molar ratio of 1:150 to 350.
- the MTP inhibitor and digoxin are used as a combination therapy or combination drug
- these combination drugs are used in a molar ratio of 1:0.1 to 100, preferably in a molar ratio of 1:0.1 to 50, and more preferably 1 : It may be co-administered at a molar ratio of 0.5 to 20, most preferably at a molar ratio of 1:1 to 10.
- the present invention also relates to lomitapide or a pharmaceutically acceptable salt thereof; And parthenolide (Parthenolide), digoxin (Dogoxin) and provides a pharmaceutical composition for preventing or treating fibrotic disease comprising at least one selected from the group consisting of pharmaceutically acceptable salts thereof as an active ingredient.
- the pharmaceutical composition according to the present invention may contain the MTP inhibitor alone or may be formulated in a suitable form together with a pharmaceutically acceptable carrier, and may further contain an excipient or diluent.
- 'pharmaceutically acceptable refers to a non-toxic composition that is physiologically acceptable and does not cause allergic reactions such as gastrointestinal disorders, dizziness, etc., or similar reactions when administered to humans.
- a pharmaceutically acceptable carrier may further include, 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 and the like.
- the carrier for parenteral administration may include water, suitable oil, saline, aqueous glucose and glycol, and the like, and may further include a stabilizer and a preservative.
- Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid.
- Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.
- the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifier, a suspending agent, and the like in addition to the above components.
- a lubricant e.g., a talc, a kaolin, a kaolin, a kaolin, a kaolin, a kaolin, a kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mann
- the content of the composition is not significantly limited depending on the purpose or aspect of use, for example, 0.01 to 99% by weight, preferably 0.5 to 50% by weight, more preferably 1 to 30% by weight based on the total weight of the composition. weight percent.
- the pharmaceutical composition according to the present invention may further include additives such as pharmaceutically acceptable carriers, excipients or diluents in addition to active ingredients.
- the pharmaceutical composition of the present invention may include 0.1 to 99.9% by weight of the composition containing the microsomal triglyceride transfer protein inhibitor and 99.9% to 0.1% by weight of the carrier.
- the pharmaceutical composition according to the invention may include a pharmaceutically effective amount of the compound alone or may further include one or more pharmaceutically acceptable carriers.
- the pharmaceutical composition of the present invention may be administered to a patient as a single dose, or may be administered by a fractionated treatment protocol in which multiple doses are administered over a long period of time.
- the pharmacologically effective amount refers to an amount that exhibits a higher response than that of the negative control group, and preferably refers to an amount sufficient to treat or prevent fibrotic disease.
- An effective amount of the composition according to the present invention may be 0.001 to 1000 mg/kg b.w./day, preferably 1 to 2000 mg/kg b.w./day, but is not limited thereto.
- the pharmaceutically effective amount may be appropriately changed depending on various factors such as the disease and its severity, the patient's age, weight, health condition, sex, administration route and treatment period.
- composition of the present invention can be administered to mammals including humans by any method.
- it can be administered orally or parenterally.
- Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal administration can be used.
- composition of the present invention may be formulated into a formulation for oral administration or parenteral administration according to the administration route as described above.
- composition of the present invention may be formulated into powders, granules, tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions, etc. using a method known in the art.
- preparations for oral use may be obtained by combining the active ingredient with a solid excipient, which is then milled and, after adding suitable auxiliaries, processed into a mixture of granules to obtain tablets or dragees.
- excipients examples include sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol, starches including corn starch, wheat starch, rice starch and potato starch, cellulose, Celluloses including methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethyl-cellulose, and the like, fillers such as gelatin, polyvinylpyrrolidone, and the like may be included. In addition, cross-linked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may be added as a disintegrant, if desired.
- sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol
- starches including corn starch, wheat starch, rice starch and potato starch
- cellulose Celluloses including
- the pharmaceutical composition of the present invention may further include an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifier, and a preservative.
- preparations for parenteral administration they may be formulated in the form of injections, creams, lotions, external ointments, oils, moisturizers, gels, aerosols, and nasal inhalants by methods known in the art. These formulations are described in prescriptions generally known to all pharmaceutical chemists.
- the total effective amount of the composition of the present invention can be administered to the patient in a single dose or by a fractionated treatment protocol in which multiple doses are administered over a long period of time.
- the pharmaceutical composition of the present invention may vary the content of the active ingredient according to the severity of the disease.
- the preferred total dose of the pharmaceutical composition of the present invention may be about 0.01 to 10,000 mg, most preferably 0.1 to 500 mg per patient body weight per day.
- the dosage of the pharmaceutical composition is determined by considering various factors such as the formulation method, administration route, and number of treatments as well as the patient's age, weight, health condition, sex, severity of disease, diet and excretion rate, etc. Therefore, considering this point, those skilled in the art will be able to determine an appropriate effective dosage of the composition of the present invention.
- the pharmaceutical composition according to the present invention is not particularly limited in its formulation, administration route and administration method as long as it exhibits the effects of the present invention.
- the composition containing the MTP inhibitor according to the present invention suppresses the fibrotic reaction by reducing the accumulation of collagen by inflammatory stimulation in each tissue or cell, and such an effect may be combined with parthenolide or digoxin.
- a synergistic effect can occur when
- the present invention provides a use of a microsomal triglyceride transfer protein (MTP) inhibitor for preparing a composition for treating fibrotic disease.
- MTP microsomal triglyceride transfer protein
- the present invention comprises administering an effective amount of a composition comprising a microsomal triglyceride transfer protein (MTP) inhibitor as an active ingredient to a subject in need thereof.
- MTP microsomal triglyceride transfer protein
- the 'effective amount' of the present invention refers to an amount that exhibits an effect of improving, treating, detecting, diagnosing, or suppressing or reducing the disease when administered to a subject
- the 'subject' refers to an animal, preferably a mammal , In particular, it may be an animal, including a human, and may be a cell, tissue, or organ derived from an animal.
- the subject may be a patient in need of the effect.
- the 'treatment' of the present invention comprehensively refers to improving a fibrotic disease or symptoms caused by the disease, which may include curing, substantially preventing, or improving the condition of the disease, Alleviating, curing or preventing one or most of the symptoms resulting from, but is not limited to.
- the term “comprising” is used in the same meaning as “including” or “characterized by”, and in the composition or method according to the present invention, specifically mentioned It does not exclude additional components or method steps not specified. Also, the term “consisting of” means excluding additional elements, steps or components not separately described. The term “essentially consisting of” means that in the scope of a composition or method, in addition to the described materials or steps, materials or steps that do not substantially affect the basic characteristics thereof may be included.
- composition of the present invention containing an MTP inhibitor has a very excellent effect of preventing or treating fibrosis by inhibiting collagen accumulation in cells and tissues caused by inflammatory stimuli, and this effect has a synergistic effect when used in combination with parthenolide or digoxin. Therefore, it can be very useful for preventing or developing a treatment for fibrotic diseases.
- 1 is a result of evaluating collagen production inhibitory ability by Sircol assay after a single treatment of lomitapide, parthenolide, digoxin, and a control drug (Nint) on fibrosis-induced Primary Human Pulmonary Fibroblasts, respectively.
- Figure 2 is a result (Kit) of evaluating the anti-fibrotic efficacy of lomitapide in a pulmonary fibrosis animal model (BLM IPF mouse model) by hydroxyproline assay.
- Figure 3 is the result (LC-MS) of evaluating the anti-fibrotic efficacy of lomitapide in a pulmonary fibrosis animal model (BLM IPF mouse model) by hydroxyproline assay (T1: lomitapide 10mg/kg, T2: lomitapide 50mg /kg).
- Figure 4 is a result of evaluating the anti-fibrosis efficacy according to lomitapide, digoxin, or a combination treatment thereof by expression changes of fibrosis-related genes.
- 5 is a result of evaluating the anti-fibrotic efficacy of lomitapide, digoxin or a combination thereof through changes in collagen secretion in cells.
- Figure 6 is a result of evaluating the anti-fibrotic efficacy according to lomitapide, parthenolide or a combination thereof by the expression change of the fibrosis-related gene COL1A1.
- Nintedanib (Nint) 1uM, a marketed IPF drug, was used. Nintedanib was treated at a high concentration of 1uM with reference to the paper, and lomitapide, parthenolide and digoxin were also treated at a concentration of 1uM.
- Example 2 In vivo fibrosis inhibitory activity evaluation
- Pulmonary fibrosis inducer Prepared by dissolving Bleomycin sulfate (BLM) in crinkle irrigation agent (sterilized physiological saline) as an excipient
- composition of test substance and positive control vehicle 5% DMSO + 5% Cremophor EL + 90% Saline
- test substance preparation on the day of administration
- Lung fibrosis inducer and excipient BLM was administered single intra-airway to all animals on Day 1. Before intratracheal instillation, anesthesia was performed for about 1 to 5 minutes using isoflurane inhalation.
- Test substance and excipient The test substance and test substance excipient were prepared on the day of administration and repeatedly orally administered on Days 1 to 21.
- Positive control substance (pirfenidone): The positive control substance was orally administered repeatedly on Days 1-21.
- BioVision's Hydroxyproline assay kit was used and the procedure was performed with reference to the attached protocol.
- the lung tissue was homogenized, normalized with the amount of tertiary distilled water, and then hydrolyzed at 120 degrees for 24 hours after adding HCl. It was analyzed by LC-MS.
- Cells were seeded in 6 wells at a density of 1 x 10 6 , and cell fibrosis was induced by treatment with recombinant TGF- ⁇ at a concentration of 20 ng/mL for 20 hr. Each drug was pre-treated 4 hours before TGF- ⁇ stimulation, and harvested and analyzed 24 hours after drug treatment.
- Cells were seeded in 6 wells at a density of 2 x 10 6 , and cell fibrosis was induced by treatment with recombinant TGF- ⁇ at a concentration of 20 ng/mL for 44 hr. Each drug was pre-treated 4 hours before TGF- ⁇ stimulation, and harvested and analyzed 48 hours after drug treatment. The included protocol was tested using the Sircol Collagen Assay kit, and Nintedanib 1uM, a marketed IPF drug, was used as a control drug.
- the amount of collagen secretion was reduced even in the lomitapide and digoxin alone-treated group, and in the combination-treated group, a significantly improved decrease in collagen secretion was confirmed compared to the respective drug-only treated group. That is, it was determined that each of these drugs exhibited a synergistic effect by the combined treatment.
- Lomitapide was treated at 1 ⁇ 2 Cmax and Cmax concentrations, respectively, and co-administered with Cmax concentration of parthenolide.
- the lomitapide and parthenolide combined treatment group showed a value of less than 1 in the drug combination index calculated using the bliss independence model, resulting in a synergistic effect compared to each single treatment group It was confirmed that there is
- composition of the present invention containing an MTP inhibitor has a very excellent effect of preventing or treating fibrosis by inhibiting collagen accumulation in cells and tissues caused by inflammatory stimuli, and this effect has a synergistic effect when used in combination with parthenolide or digoxin. Since it can appear, it can be very useful for preventing or developing a treatment for fibrotic disease, so industrial applicability is very high.
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Abstract
The present invention relates to a use of microsomal triglyceride transfer protein (MTP) inhibitor in the treatment of fibrosis disease and, more specifically, to a novel use of an MTP inhibitor which exhibits an inhibitory effect on the accumulation of fibrosis-related collagen, in the prevention or treatment of fibrosis disease.
Description
본 출원은 2021년 11월 30일에 출원된 대한민국 특허출원 제10-2021-0168416호를 우선권으로 주장하고, 상기 명세서 전체는 본 출원의 참고문헌이다.This application claims priority to Republic of Korea Patent Application No. 10-2021-0168416 filed on November 30, 2021, and the entire specification is a reference in this application.
본 발명은 마이크로조말 트리글리세라이드 전달 단백질 억제제(microsomal triglyceride transfer protein (MTP) inhibitor)의 섬유화 질환 치료 용도에 관한 것으로, 보다 상세하게는 섬유화 관련 콜라겐 축적의 억제 효과를 나타내는 MTP 억제제의 신규한 용도로서 섬유화 질환 예방 또는 치료 용도에 관한 것이다. The present invention relates to the use of a microsomal triglyceride transfer protein (MTP) inhibitor for the treatment of fibrotic diseases, and more particularly, as a novel use of an MTP inhibitor exhibiting an inhibitory effect on collagen accumulation associated with fibrosis, fibrosis It relates to disease prevention or treatment use.
섬유증(fibrosis)은 섬유아세포에 의한 세포 외 기질의 비정상적 생성, 축적 및 침착이 일어나는 질환으로, 기관 또는 조직의 섬유화에 의해 발병한다. 섬유증은 장기 손상을 유발하는 매우 치명적인 질환이다. 일례로 IPF (idiopathic pulmonary fibrosis)는 섬유아세포 축적 및 근섬유아세포 분화와 관련된 재발성 폐포 상피세포 손상의 결과로 나타나며, 폐 실질 (lung parenchyma) 조직의 비가역적 파괴와 함께 세포 외 기질 (extracellular matrix; ECM)의 과량 축적을 야기하는 만성, 진행성, 그리고 치사성 질환이다. 그러나 현재까지 섬유증에 대한 효과적인 치료법이 없는 실정이므로 (Fibrogenesis Tissue Repair, 2012, 5(1): 11; N Engl J Med, 2001, 345(7): 517), 섬유증을 효과적으로 예방 또는 치료할 수 있는 치료제 개발이 지속적으로 요구되고 있다.Fibrosis is a disease in which extracellular matrix is abnormally produced, accumulated, and deposited by fibroblasts, and is caused by fibrosis of organs or tissues. Fibrosis is a very fatal disease that causes organ damage. For example, idiopathic pulmonary fibrosis (IPF) occurs as a result of recurrent alveolar epithelial cell damage associated with fibroblast accumulation and myofibroblast differentiation, resulting in irreversible destruction of lung parenchyma tissue and extracellular matrix (ECM). ) is a chronic, progressive, and lethal disease that causes excessive accumulation of However, since there is no effective treatment for fibrosis to date (Fibrogenesis Tissue Repair, 2012, 5(1): 11; N Engl J Med, 2001, 345(7): 517), therapeutic agents that can effectively prevent or treat fibrosis Development is constantly required.
섬유증은 다양한 기초 질환의 결과로서 발생된다. 만성 염증 또는 조직 손상/재형성은 전형적인 섬유증 유발 사례이다. 구체적인 질환 예로는 특발성 폐 섬유증(IPF), 알콜성 및 비알콜성 간 경화증과 연관된 간 섬유증, 신장 섬유증, 심장 섬유증 및 비정상적 상처 치유로부터 발생한 켈로이드 형성을 들 수 있다 [Wynn, T. A. (2004) Nature Reviews Immunology. 4: 583-594; Friedman, S.L. (2013) Science Translation Medicine. 5(167):1-17]. 추가로, 섬유증은 류마티스 관절염, 크론병, 전신 홍반 루푸스 및 경피증을 비롯한 만성 자가면역 질환과 관련된 핵심 병리학적 특징이다. 심각한 미충족 의료 요구를 나타내는 질환으로는 특발성 폐 섬유증(IPF), 경피증 및 비알콜성 지방간염(NASH) 관련 간 섬유증을 들 수 있다. NASH 관련 간 섬유증의 증가된 발병률은 2형 당뇨병 및 비만의 것과 직접적으로 유사한 것으로 예상된다.Fibrosis develops as a result of various underlying diseases. Chronic inflammation or tissue damage/remodeling is a typical fibrosis-induced event. Specific disease examples include idiopathic pulmonary fibrosis (IPF), liver fibrosis associated with alcoholic and non-alcoholic liver cirrhosis, renal fibrosis, cardiac fibrosis, and keloid formation resulting from abnormal wound healing [Wynn, T. A. (2004) Nature Reviews. Immunology. 4: 583-594; Friedman, S.L. (2013) Science Translation Medicine. 5(167):1-17]. Additionally, fibrosis is a key pathological feature associated with chronic autoimmune diseases including rheumatoid arthritis, Crohn's disease, systemic lupus erythematosus and scleroderma. Diseases that present a significant unmet medical need include idiopathic pulmonary fibrosis (IPF), scleroderma and nonalcoholic steatohepatitis (NASH) associated liver fibrosis. The increased incidence of NASH-related liver fibrosis is expected to directly parallel that of type 2 diabetes and obesity.
한편, 간섬유증(liver cirrhosis 또는 hepatic fibrosis)이나 간경화증(또는 간경병증, liver cirrhosis)은 간조직이 손상과 재생을 반복하여 간염이 발생하고, 간염에서 간섬유증으로 다시 간섬유증에서 간경화증으로 진행되면서 발생되는 질환에 속한다. 간섬유증은 간세포의 지속적인 파괴와 반복적인 간손상에 따라 나타나는 섬유화 현상 (liver fibrogenesis)으로, ECM(extracellular matrix, 세포 외 기질)의 생성은 증가되지만 이에 대한 분해는 상대적으로 줄어드는 현상이 발생하고 심해지면 간경화증, 간부전이나 간암으로 진행된다. 간섬유증은 일단 섬유화가 진행되면 정상간으로 복원되기가 어려우며, 간경화증이나 간암으로 진행되어 이에 대한 사망률이 계속적으로 증가되는 추세이다. 간경화증은 만성적인 염증으로 인해 정상적인 간 조직이 재생결절(regenerative nodules; 작은 덩어리가 만들어지는 현상) 등의 섬유화 조직으로 바뀌어 간의 기능이 저하되는 것을 의미한다. 지금까지 이들 질환에 대한 구체적인 치료는 존재하지 않고 있다.On the other hand, hepatic fibrosis (liver cirrhosis or hepatic fibrosis) or liver cirrhosis (or liver cirrhosis, liver cirrhosis) occurs when liver tissue repeats damage and regeneration, resulting in hepatitis, and progresses from hepatitis to liver fibrosis and from liver fibrosis to cirrhosis. belonging to a disease Liver fibrosis is a fibrosis phenomenon (liver fibrogenesis) that occurs due to the continuous destruction of liver cells and repetitive liver damage. The production of ECM (extracellular matrix) is increased, but the degradation of it is relatively reduced. It progresses to cirrhosis, liver failure or liver cancer. Liver fibrosis is difficult to restore to a normal liver once fibrosis progresses, and it progresses to liver cirrhosis or liver cancer, resulting in a continuously increasing mortality rate. Liver cirrhosis refers to deterioration of liver function by changing normal liver tissue into fibrotic tissue such as regenerative nodules (a phenomenon in which small lumps are formed) due to chronic inflammation. So far, there is no specific treatment for these diseases.
이에, 본 발명자는 섬유화 질환을 효과적이고 안전하게 치료할 수 있는 치료제를 개발하기 위하여 예의 연구를 거듭한 결과, MTP 억제제가 섬유화 관련 콜라겐 축적을 억제하는 효과를 나타낸다는 것과, 이와 같은 효과는 다른 약물과의 병용을 통해 더욱 향상된다는 것을 발견하고 본 발명을 완성하게 되었다. Accordingly, the present inventors have conducted extensive research to develop a therapeutic agent that can effectively and safely treat fibrotic diseases. It was found that it was further improved through combined use, and the present invention was completed.
따라서, 본 발명의 목적은 마이크로조말 트리글리세라이드 전달 단백질 억제제(microsomal triglyceride transfer protein (MTP) inhibitor)를 유효성분으로 포함하는 섬유화 질환 예방 또는 치료용 약학적 조성물을 제공하는 것이다. Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating fibrotic disease, comprising a microsomal triglyceride transfer protein (MTP) inhibitor as an active ingredient.
또한, 본 발명의 목적은 마이크로조말 트리글리세라이드 전달 단백질 억제제(microsomal triglyceride transfer protein (MTP) inhibitor)로 이루어지는 섬유화 질환 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating fibrotic disease comprising a microsomal triglyceride transfer protein (MTP) inhibitor.
또한, 본 발명의 목적은 마이크로조말 트리글리세라이드 전달 단백질 억제제(microsomal triglyceride transfer protein (MTP) inhibitor)를로 필수적으로 이루어지는 섬유화 질환 예방 또는 치료용 약학적 조성물을 제공하는 것이다.In addition, an object of the present invention is to provide a pharmaceutical composition for preventing or treating fibrotic disease consisting essentially of a microsomal triglyceride transfer protein (MTP) inhibitor.
따라서, 본 발명의 목적은 섬유화 질환 치료용 조성물을 제조하기 위한 마이크로조말 트리글리세라이드 전달 단백질 억제제(microsomal triglyceride transfer protein (MTP) inhibitor)의 용도를 제공하는 것이다.Accordingly, an object of the present invention is to provide a use of a microsomal triglyceride transfer protein (MTP) inhibitor for preparing a composition for treating fibrotic disease.
따라서, 본 발명의 목적은 마이크로조말 트리글리세라이드 전달 단백질 억제제(microsomal triglyceride transfer protein (MTP) inhibitor)를 유효성분으로 포함하는 조성물의 유효량을 이를 필요로 하는 개체에 투여하는 것을 포함하는 섬유화 질환 치료 방법을 제공하는 것이다.Accordingly, an object of the present invention is to provide a method for treating fibrotic disease comprising administering an effective amount of a composition comprising a microsomal triglyceride transfer protein (MTP) inhibitor as an active ingredient to a subject in need thereof. is to provide
전술한 본 발명의 목적을 달성하기 위하여, 본 발명은 마이크로조말 트리글리세라이드 전달 단백질 억제제(microsomal triglyceride transfer protein (MTP) inhibitor)를 유효성분으로 포함하는 섬유화 질환 예방 또는 치료용 약학적 조성물을 제공한다. In order to achieve the above object of the present invention, the present invention provides a pharmaceutical composition for preventing or treating fibrotic disease comprising a microsomal triglyceride transfer protein (MTP) inhibitor as an active ingredient.
또한, 본 발명은 마이크로조말 트리글리세라이드 전달 단백질 억제제(microsomal triglyceride transfer protein (MTP) inhibitor)로 이루어진 섬유화 질환 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating fibrotic disease comprising a microsomal triglyceride transfer protein (MTP) inhibitor.
또한, 본 발명은 마이크로조말 트리글리세라이드 전달 단백질 억제제(microsomal triglyceride transfer protein (MTP) inhibitor)로 필수적으로 이루어진 섬유화 질환 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating fibrotic disease, essentially consisting of a microsomal triglyceride transfer protein (MTP) inhibitor.
본 발명의 목적을 달성하기 위하여, 본 발명은 섬유화 질환 치료용 조성물을 제조하기 위한 마이크로조말 트리글리세라이드 전달 단백질 억제제(microsomal triglyceride transfer protein (MTP) inhibitor)의 용도를 제공한다.In order to achieve the object of the present invention, the present invention provides a use of a microsomal triglyceride transfer protein (MTP) inhibitor for preparing a composition for treating fibrotic disease.
본 발명의 목적을 달성하기 위하여, 본 발명은 마이크로조말 트리글리세라이드 전달 단백질 억제제(microsomal triglyceride transfer protein (MTP) inhibitor)를 유효성분으로 포함하는 조성물의 유효량을 이를 필요로 하는 개체에 투여하는 것을 포함하는 섬유화 질환 치료 방법을 제공한다.In order to achieve the object of the present invention, the present invention comprises administering an effective amount of a composition comprising a microsomal triglyceride transfer protein (MTP) inhibitor as an active ingredient to a subject in need thereof. A method for treating fibrotic disease is provided.
본 발명에서 사용되는 용어, "치료" 또는 "치료하는 것" 이란, 환자에게 치료제 즉, 본 발명의 화합물(단독으로 또는 다른 약학적 제제와 결합하여)의 적용 또는 투여 또는 HBV 감염, HBV 감염의 증상 또는 HBV 감염으로 발전할 가능성이 있는 환자(예를 들면, 진단 또는 탈체 적용)로부터 치료, 치유, 완화, 경감, 변경, 해결, 개선, 향상 또는 HBV 감염, HBV 감염의 증상 또는 HBV 감염으로 발절될 가능성에 영향을 미치기 위한 목적을 가지고 분리된 조직 또는 세포주에 치료제의 적용 또는 투여로서 정의된다. 이러한 치료는 특히 게놈 약학의 분야로부터 얻어진 지식에 기초하여 맞춰지고 변경될 수 있다.As used herein, the term "treatment" or "treating" refers to the application or administration of a therapeutic agent, that is, a compound of the present invention (alone or in combination with other pharmaceutical agents) to a patient or HBV infection, HBV infection Treatment, cure, alleviation, alleviation, alteration, resolution, amelioration, improvement or outbreak of HBV infection, symptoms of HBV infection, or HBV infection from patients at risk of developing symptoms or HBV infection (e.g., diagnosis or ex vivo application) It is defined as the application or administration of a therapeutic agent to an isolated tissue or cell line for the purpose of influencing the likelihood of becoming infected. Such treatment can be tailored and modified based on knowledge obtained, inter alia, from the field of genomic pharmacology.
본 발명에서 사용되는 용어, "예방하다" 또는 "예방" 이란, 만약 아무것도 일어나지 않았다면, 장애 또는 질병 진전이 없는 것 또는 이미 장애 또는 질병 진전이 있었다면 더 이상의 장애 또는 질병의 진전이 없는 것을 의미한다. 또한, 고려되는 것은 장애 또는 질병에 관련된 증상의 일부 또는 전부를 예방하는 하나의 능력이다.As used herein, the term "prevent" or "prevention" means that, if nothing has happened, there is no development of the disorder or disease, or if there has already been the development of the disorder or disease, there is no further development of the disorder or disease. Also contemplated is one's ability to prevent some or all of the symptoms associated with a disorder or disease.
본 발명에서 사용되는 용어, "환자", "개체" 또는 "대상" 이란, 인간 또는 인간을 제외한 포유동물을 나타낸다. 예를 들면, 인간을 제외한 포유동물은 양 과, 소 과, 돼지 과, 개 과, 고양이 과 및 쥐 과의 포유동물와 같은 가축 및 애완동물을 포함한다. 바람직하게는 환자, 대상 또는 개체는 인간이다.As used herein, the term "patient", "individual" or "subject" refers to a human or a non-human mammal. For example, non-human mammals include livestock and pets such as ovine, bovine, porcine, canine, feline and murine mammals. Preferably the patient, subject or individual is a human.
본 발명에서 사용되는 용어, "유효량", "약학적 유효량" 및 "치료학적 유효량"이란, 원하는 생물학적 결과를 제공하는 제제의 무독성의 충분한 양을 나타낸다. 상기 결과는 신호, 증상 또는 질병의 원인의 감소 및/또는 약화이거나, 생물학적 시스템의 임의의 다른 원하는 변화일 수 있다. 임의의 개체의 경우에 적절한 치료 양은 통상의 실험을 사용하여 해당 기술분야에서 통상의 기술자에 의하여 결정될 수 있다.As used herein, the terms "effective amount", "pharmaceutically effective amount" and "therapeutically effective amount" refer to a non-toxic sufficient amount of an agent to provide a desired biological result. The result may be a reduction and/or attenuation of a signal, symptom or cause of a disease, or any other desired change in a biological system. An appropriate therapeutic amount for any individual can be determined by one skilled in the art using routine experimentation.
본 발명에서 사용되는 용어, "약학적으로 허용가능한" 이란, 화합물의 생물학적 활성 또는 특성을 저해하지 않고, 상대적으로 무독성인, 즉, 물질이 원하지 않는 생물학적 효과 또는 그것이 함유하고 있는 조성물의 임의의 구성성분과 해로운 방법으로 상호작용 없이 개체에게 투여될 수 있는 담체 또는 희석액과 같은 물질을 나타낸다.As used herein, the term "pharmaceutically acceptable" means that it does not interfere with the biological activity or properties of a compound and is relatively non-toxic, that is, a substance has an undesirable biological effect or any component of a composition it contains. Refers to a substance, such as a carrier or diluent, that can be administered to an individual without interacting in a detrimental way with the component.
본 발명에서 사용되는 용어, "약학적으로 허용가능한 염"이란, 약학적으로 허용가능한 무기산, 유기산, 용매 화합물, 수화물 또는 그것의 포접 화합물을 포함하는 무독성의 산으로부터 제조된 투여되는 화합물의 염을 나타낸다. 이러한 무기산의 예로는 염산, 브롬산, 요오드산, 질산, 황산, 인산, 아세트산, 헥사플루오로인산, 시트르산, 글루콘산, 벤조산, 프로피온산, 부티르산, 설포살리실산, 말레산, 라우르산, 말산, 푸마르산, 석신산, 타르타르산, 암소닉(amsonic) 산, 팜산, p-톨루엔설폰산 및 메실릭 산이 있다. 적절한 유기산은 예를 들어, 지방족, 방향족, 카복실 및 설폰 부류의 유기산으로부터 선택될 수 있으며, 그 예로, 포름산, 아세트산, 프로피온산, 석신산, 캄포설폰산, 시트르산, 푸마르산, 글루콘산, 이세티온산, 락트산, 말산, 점액산, 타르타르산, 파라-톨루엔설폰산, 글리콜산, 글루쿠론산, 말레산, 푸로산, 글루탐산, 벤조산, 아트라닐산, 살리실산, 페닐아세트산, 만델산, 엠포닉산(팜산), 메탄설폰산, 에탄설폰산, 판토텐산, 벤젠설폰산(베실레이트), 스테아르산, 설파닐산, 알긴산, 갈락투론산 등이 있다. 게다가, 약학적으로 허용가능한 염은 비제한적인 예로서, 알칼리토금속 염(예를 들면, 칼슘 또는 마그네슘), 알칼리금속 염(예를 들면, 나트륨-의존성(sodium-dependent) 또는 칼륨) 및 암모늄 염을 포함한다.As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound to be administered prepared from non-toxic acids including pharmaceutically acceptable inorganic acids, organic acids, solvates, hydrates or clathrates thereof. indicate Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, iodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, hexafluorophosphoric acid, citric acid, gluconic acid, benzoic acid, propionic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid. , succinic acid, tartaric acid, amsonic acid, palmic acid, p-toluenesulfonic acid and mesylic acid. Suitable organic acids may be selected, for example, from the aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, such as formic acid, acetic acid, propionic acid, succinic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, isethionic acid, Lactic acid, malic acid, mucous acid, tartaric acid, para-toluenesulfonic acid, glycolic acid, glucuronic acid, maleic acid, furoic acid, glutamic acid, benzoic acid, atranilic acid, salicylic acid, phenylacetic acid, mandelic acid, emphonic acid (pam acid), Examples include methanesulfonic acid, ethanesulfonic acid, pantothenic acid, benzenesulfonic acid (besylate), stearic acid, sulfanilic acid, alginic acid, and galacturonic acid. Moreover, pharmaceutically acceptable salts include, but are not limited to, alkaline earth metal salts (eg calcium or magnesium), alkali metal salts (eg sodium-dependent or potassium) and ammonium salts. includes
본 발명에서 사용되는 용어, "약학적으로 허용가능한 담체"는 본 발명내에서 유용한 화합물을 환자 내에서 또는 환자에게 그의 의도된 기능을 수행할 수 있도록 운반 또는 수송과 관련된 액체 또는 고체 필러, 안정제, 분산제, 현탁제, 희석액, 첨가제, 농조화제, 용매 또는 캡슐화 물질과 같은 약학적으로 허용가능한 물질, 조성물 또는 담체를의미한다. 전형적으로, 이러한 구성물은 하나의 기관 또는 신체의 일부로부터 신체의 다른 기관 또는 부분으로 운반되거나 수송된다. 각각의 담체는 본 발명 내에서 유용한 화합물을 포함하는 화학식의 다른 성분과 병용가능한 것 및 환자에게 손상을 주지 않는 관점에서 "허용가능" 해야 한다. 약학적으로 허용가능한 담체로서 작용할 수 있는 물질의 일부 예는 다음을 포함한다: 약학적 제형에 이용되는 락토오스, 글루코스 및 수크로오스와 같은 당류; 옥수수 전분 및 감자 전분과 같은 전분류; 셀룰로오스 및 소듐 카복시메틸 셀룰로오스, 에틸셀룰로오스 및 셀룰로오스 아세테이트와 같은 그의 유도체; 트래거캔스(tragacanth) 분말; 맥아; 젤라틴; 탈크; 코코아 버터 및 좌약 왁스와 같은 첨가제; 땅콩오일, 면실유, 홍화유, 참기름, 올리브 오일, 옥수수 오일 및 콩기름과 같은 오일; 플로필렌글리콜과 같은 글리콜; 글리세린, 솔비톨, 만니톨 및 폴리에틸렌글리콜과 같은 폴리올; 에틸올리에이트 및 에틸라우레이트와 같은 에스테르류; 한천; 마그네슘 하이드록사이드 및 알루미늄 하이드록사이드와 같은 완충제; 계면 활성제; 알긴산; 발열성 물질 제거수; 등장액; 링거 용액(Ringer's solution); 에틸알코올; 인산염 버퍼 용액; 및 다른 무독성의 병용가능한 물질. 또한, 본 발명에서 사용되는, "약학적으로 허용가능한 담체"는 본 발명내에서 유용한 화합물의 활성과 병용가능하고, 환자에게 생리학상으로 허용가능한 일부 또는 전부 코팅제, 항바이러스제 및 항균제 및 흡수 지연제 등을 포함한다. 또한, 보충의 활성 화합물은 상기 조성물내에 혼입될 수 있다. 추가로 "약학적으로 허용가능한 담체"는 본 발명 내에서 유용한 화합물의 약학적으로 허용가능한 염을 더 포함할 수 있다. 본 발명의 실시에서 사용된 약학적 조성물에 포함될 수 있는 다른 추가적인 성분은 해당 기술분야에 알려져 있다.As used herein, the term "pharmaceutically acceptable carrier" refers to a liquid or solid filler, stabilizer, A pharmaceutically acceptable substance, composition or carrier such as a dispersing agent, suspending agent, diluent, additive, thickening agent, solvent or encapsulating material. Typically, these components are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formula, including compounds useful within the present invention, and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose used in pharmaceutical formulations; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc; additives such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; Surfactants; alginic acid; pyrogen-free water; isotonic solution; Ringer's solution; ethyl alcohol; phosphate buffer solution; and other non-toxic compatible substances. In addition, as used in the present invention, "pharmaceutically acceptable carrier" is compatible with the activity of compounds useful within the present invention, and is physiologically acceptable to patients in part or in whole coating agent, antiviral and antibacterial agent, and absorption delaying agent. Include etc. Supplementary active compounds may also be incorporated into the compositions. Further "pharmaceutically acceptable carriers" may further include pharmaceutically acceptable salts of compounds useful within the present invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of this invention are known in the art.
본 발명에서 사용되는 용어, "조성물" 또는 "약학적 조성물"은 본 발명 내에서 유용한 적어도 하나의 화합물과 약학적으로 허용가능한 담체의 혼합물을 나타낸다. 약학적 조성물은 환자 또는 대상에게 상기 화합물의 투여를 용이하게 한다. 이에 제한되지 않지만 정맥주사, 경구, 에어로졸, 비경구, 안구, 폐 및 국소의 투여를 포함하는 화합물을 투여하는 다양한 기술들이 해당 기술분야에 존재한다.As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful within the present invention with a pharmaceutically acceptable carrier. A pharmaceutical composition facilitates administration of the compound to a patient or subject. A variety of techniques exist in the art for administering compounds including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary and topical administration.
본 발명에서 사용되는 용어, "병용 요법" 또는 "조합하여"라는 용어는 본 명세서에 기재된 병태 또는 장애(즉, 대사성 질환 및 섬유화 질환)를 치료하기 위해 2가지 이상의 치료제를 투여하는 것을 지칭한다. 이러한 투여는 이들 치료제를 실질적으로 동시적인 방식으로, 예컨대 고정된 비율의 활성 성분을 갖는 단일 캡슐로 공동 투여하는 것을 포함한다. 대안적으로, 이러한 투여는 각각의 활성 성분에 대해 다중 또는 개별 용기(예를 들어, 캡슐, 분말, 및 액체)로 공동 투여하는 것을 포함한다. 분말 및/또는 액체는 투여 전에 원하는 용량으로 재구성되거나 희석될 수 있다. 또한, 이러한 투여는 거의 동시에 또는 서로 다른 시간에 각 유형의 치료제를 순차적으로 사용하는 것도 포함한다. 어느 경우든, 치료 요법은 본원에 기재된 병태 또는 장애의 치료에 있어서 약물 병용의 이로운 효과를 제공할 것이다.As used herein, the terms "combination therapy" or "in combination" refer to the administration of two or more therapeutic agents to treat the conditions or disorders described herein (ie, metabolic diseases and fibrotic diseases). Such administration includes co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed proportion of the active ingredients. Alternatively, such administration includes co-administration in multiple or separate containers (eg, capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to the desired dosage prior to administration. In addition, such administration includes sequential use of each type of therapeutic agent at about the same time or at different times. In either case, the treatment regimen will provide beneficial effects of the drug combination in the treatment of the conditions or disorders described herein.
병용 요법은 "시너지 효과"를 제공할 수 있고 "시너지적"임을 입증할 수 있다. 즉, 활성 성분들이 함께 사용될 때 달성되는 효과가 화합물을 개별적으로 사용함으로써 발생하는 효과의 합보다 크다. 시너지 효과는 활성 성분이 (1) 공동 제형화되어 조합된 단위 투여 제형으로 동시에 투여되거나 전달될 때; (2) 개별 제형으로서 교대로 또는 병행하여 전달될 때; 또는 (3) 일부 다른 계획에 의해 전달될 때, 얻어질 수 있다. 교대 요법으로 전달되는 경우, 시너지 효과는 화합물이 순차적으로, 예를 들어 개별 주사기로 서로 달리 주사하여 투여되거나 전달될 때 얻을 수 있다. 일반적으로, 교대 요법 동안에는, 각각의 활성 성분의 유효 투여량이 순차적으로, 즉 연속하여 투여되는 반면, 병용 요법에서는 2가지 이상의 활성 성분의 유효 투여량이 함께 투여된다. 본원에서 사용되는 시너지 효과는 2가지 치료제가 단독으로 투여되는 각 약물의 효과의 단순 합보다 더 큰 효과를 생성하는 작용을 의미한다. 시너지 효과는 예를 들어 Sigmoid-Emax 방정식, Loewe 가산성 방정식, 및 중위수 효과 방정식과 같은 적합한 방법을 사용하여 계산될 수 있다. 상기 언급된 각각의 방정식은 약물 병용의 효과를 평가하는 데 도움이 되는 해당 그래프를 생성하기 위해 실험 데이터에 적용될 수 있다. 상기 언급된 방정식과 관련된 해당 그래프는 각각 농도-효과 곡선, 이소볼로그램 곡선, 및 병용지수 곡선이다.Combination therapy can provide a "synergistic effect" and can prove to be "synergistic." That is, the effect achieved when the active ingredients are used together is greater than the sum of the effects produced by using the compounds individually. A synergistic effect occurs when the active ingredients are (1) co-formulated and administered or delivered simultaneously in a combined unit dosage form; (2) when delivered alternately or in parallel as separate dosage forms; or (3) when delivered by some other initiative. When delivered in alternating therapy, a synergistic effect can be obtained when the compounds are administered or delivered sequentially, eg by different injections in separate syringes. Generally, during alternation therapy, effective doses of each active ingredient are administered sequentially, i.e. consecutively, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. Synergistic effect as used herein refers to the action of two therapeutic agents to produce an effect greater than the simple sum of the effects of each drug administered alone. The synergistic effect can be calculated using suitable methods such as, for example, the Sigmoid-Emax equation, the Loewe additive equation, and the median effect equation. Each of the equations mentioned above can be applied to experimental data to generate corresponding graphs that help evaluate the effects of drug combinations. Corresponding graphs related to the above-mentioned equations are concentration-effect curves, isobologram curves, and combination index curves, respectively.
이하, 본 발명에 대해 상세히 설명한다. Hereinafter, the present invention will be described in detail.
본 발명은 마이크로조말 트리글리세라이드 전달 단백질 억제제(microsomal triglyceride transfer protein (MTP) inhibitor)를 유효성분으로 포함하는 섬유화 질환 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating fibrotic disease comprising a microsomal triglyceride transfer protein (MTP) inhibitor as an active ingredient.
MTP는 인간에서 MTTP 유전자에 의해 암호화되는 단백질로서, 이형이량체 마이크로솜 트리아글리세라이드 전달 단백질을 완성하며, 이는 지단백질 조립에서 중심 역할을 한다. MTP는 간에서 초저밀도 지단백질(LDL)을, 장에서는 킬로마이크론 조립 및 분비에 필요한 지질 전달 단백질이다. 본 발명에서 상기 MTP 억제제는 MTP 단백질을 암호화하는 유전자의 발현 또는 단백질의 활성을 억제하는 것을 모두 포함할 수 있다. 예를 들면, MTP 단백질을 암호화하는 MTTP mRNA에 대한 안티센스 뉴클레오티드, 앱타머, 작은 간섭 RNA (siRNA), 짧은 헤어핀 RNA (shRNA), 마이크로 RNA (miRNA) 또는 RNA 간섭 (RNAi) 등, 그리고 MTP 단백질의 발현 및/또는 활성을 억제할 수 있는 천연물, 유기화합물, 저분화화합물, 항체, 단백질 등이 포함될 수 있으나 이에 제한되는 것은 아니다. MTP is the protein encoded by the MTTP gene in humans, which completes the heterodimeric microsomal triaglyceride transporter protein, which plays a central role in lipoprotein assembly. MTP is a lipid transport protein required for the assembly and secretion of very-low-density lipoproteins (LDL) in the liver and chylomicrons in the intestine. In the present invention, the MTP inhibitor may include those that inhibit the expression of a gene encoding an MTP protein or the activity of a protein. For example, antisense nucleotides, aptamers, small interfering RNA (siRNA), short hairpin RNA (shRNA), micro RNA (miRNA) or RNA interference (RNAi) against MTTP mRNA encoding the MTP protein, and the like, and It may include, but is not limited to, natural products, organic compounds, poorly differentiated compounds, antibodies, proteins, etc. capable of inhibiting expression and/or activity.
본 발명의 일실시예에 따르면, 상기 MTP 억제제는 인간 폐 섬유아세포에서 염증성 인자에 의한 콜라겐 축적을 억제하는 활성이 매우 뛰어나 신체 내 각 조직의 섬유화 질환 예방 또는 치료 효과를 나타낼 수 있는 것으로 확인되었다. According to one embodiment of the present invention, it was confirmed that the MTP inhibitor has a very excellent activity of inhibiting collagen accumulation by inflammatory factors in human lung fibroblasts, and can exhibit an effect of preventing or treating fibrotic disease in each tissue in the body.
본 발명에서 상기 섬유화 질환은 섬유증(fibrosis)으로도 불리며, 세포외 기질(ECM)의 과잉 축적으로 관련 조직의 딱딱해짐 및/또는 반흔으로 이어짐을 특징으로 하는 만성적 및 진행성 질환이다. 이것은 복잡한 세포, 세포외 기질, 사이토카인 및 성장 인자의 상호 작용을 통해 발달한다. 다른 세포 유형은 거주 간엽세포(섬유아 세포 및 근육섬유 아세포) 및 상피와 내피 세포 유래의 ECM 생산 세포(상피- 및 내피-간엽 전환으로 불리는 과정을 통해), 국부 또는 골수 유래 줄기세포(섬유세포) 등을 포함한다. 섬유아세포는 정상적인 상처 치유에 관여하는 주요 세포 유형으로서, 및 섬유 형성에서 중요한 이펙터 세포로서 오랫동안 간주되어 왔다. 그들은 콜라겐 및 다른 ECM 성분에 매우 합성적이며, 또한 α-평활근 액틴(α-SMA)의 드 노보 발현을 특징으로 한다(Scotton C.J. and Chambers R.C., 2007에서 검토). 섬유증의 동물모델에서 섬유성 병변의 근육섬유 아세포의 존재는 활성 섬유증의 발병과 상관하며, 인간의 질병의 섬유성 병소에 대한 지속성 및 국부화는 질환의 진행과 관련되어 있다(Kuhn C. and McDonald J.A., 1991, 및 Zhang et al., 1994). 근육섬유 아세포는 또한 강화된 이주 표현형을 나타내며(Suganuma etal. 1995) 다수의 전섬유화 매개체를 방출할 수 있다.In the present invention, the fibrotic disease is also called fibrosis, and is a chronic and progressive disease characterized by excessive accumulation of extracellular matrix (ECM) leading to hardening and/or scarring of related tissues. It develops through complex interactions of cells, extracellular matrix, cytokines, and growth factors. Other cell types include resident mesenchymal cells (fibroblasts and myofibroblasts) and ECM-producing cells derived from epithelial and endothelial cells (through a process called epithelial- and endothelial-mesenchymal transition), and local or bone marrow-derived stem cells (fibroblasts). ), etc. Fibroblasts have long been considered as the major cell type involved in normal wound healing and as important effector cells in fibrogenesis. They are highly synthetic to collagen and other ECM components, and are also characterized by de novo expression of α-smooth muscle actin (α-SMA) (reviewed in Scotton C.J. and Chambers R.C., 2007). The presence of myofibroblasts in fibrotic lesions in animal models of fibrosis correlates with the onset of active fibrosis, and the persistence and localization of fibrotic lesions in humans is associated with disease progression (Kuhn C. and McDonald J.A., 1991, and Zhang et al., 1994). Myofibroblasts also display an enhanced migration phenotype (Suganuma et al. 1995) and are capable of releasing multiple mediators of profibrosis.
본 발명에서 상기 섬유화 질환은 그 종류가 특별히 제한되지 않으며, 만성 염증 또는 조직 손상/재형성 등에 의해 발생하고, 세포외 기질(ECM)의 과잉 축적으로 관련 조직의 딱딱해짐 및/또는 반흔으로 이어지는 진행성 질환이라면 모두 포함될 수 있다. 상기 섬유화 질환의 비제한적인 예시로 폐 섬유증, 간 섬유증, 피부 섬유증, 신장 섬유증, 췌장 섬유증, 전신성 경화증 및 심장 섬유증이 포함될 수 있다. In the present invention, the type of fibrotic disease is not particularly limited, and is caused by chronic inflammation or tissue damage/remodeling, etc., and is a progressive disease that leads to hardening and/or scarring of related tissues due to excessive accumulation of extracellular matrix (ECM). Any disease can be included. Non-limiting examples of the fibrotic disease may include pulmonary fibrosis, liver fibrosis, skin fibrosis, renal fibrosis, pancreatic fibrosis, systemic sclerosis and cardiac fibrosis.
상기 폐 섬유증(lung fibrosis)은 폐 조직의 반흔을 포함하는 심각한 의학적 증상이다. 이러한 증상은 폐의 폐포와 간질 조직에 염증이 생겨 스스로를 복구하기 위한 시도로 조직에 반흔으로 발전할 때 발생한다. 폐 섬유증은 섬유성 조직(섬유 상흔)과 정상 폐 실질의 점진적 교환을 포함한다. The lung fibrosis is a serious medical condition involving scarring of lung tissue. These symptoms occur when the alveoli and interstitial tissue of the lungs become inflamed and develop scars in the tissue in an attempt to repair itself. Pulmonary fibrosis involves progressive exchange of fibrotic tissue (fibrous scar) with normal lung parenchyma.
폐 섬유증은 만성 염증성 과정(유육종증, 베게너 육아종 질환), 감염, 환경 작용제(석면, 실리카, 특정 가스에 노출), 이온화 방사선에 노출(예를 들면 가슴의 종양을 치료하기 위한 방사선 요법), 만성 증상(루푸스), 및 특정 약물(예를 들면 아미오다론, 블레오마이신, 핑기앙마이신(pingyangmycin), 부설판, 메토트렉세이트, 및 니트로푸란토인)을 포함하는 많은 조건이 원인이 될 수 있다.Pulmonary fibrosis is characterized by chronic inflammatory processes (sarcomatosis, Wegener's granulomatous disease), infections, environmental agents (exposure to asbestos, silica, certain gases), exposure to ionizing radiation (e.g. radiation therapy to treat tumors in the chest), and chronic conditions. (lupus), and certain medications (eg amiodarone, bleomycin, pingyangmycin, busulfan, methotrexate, and nitrofurantoin).
과민성 폐렴으로 알려진 상태에서, 폐의 섬유화는 흡입된 유기 먼지 또는 산업 화학 물질에 대한 높은 면역 반응 후에 발전할 수 있다. 이러한 증상은 대부분 세균, 곰팡이, 동물 산물로 오염된 먼지의 흡입으로부터 초래된다.In a condition known as hypersensitivity pneumonitis, fibrosis of the lungs may develop after a high immune response to inhaled organic dust or industrial chemicals. These symptoms mostly result from inhalation of dust contaminated with bacteria, fungi, or animal products.
상기 간 섬유증 또는 간성 섬유증은 대부분의 만성 간 질환에서 일어나는 세포외 기질 단백질(콜라겐을 포함)의 과도한 축적 및 이후의 반흔 형성과정이다. 경시적으로 진행된 간 섬유증은 간경변을 초래한다. 간경변은 만성 간 질환의 마지막 단계이며, 일반적으로 불량한 장기 예후와 비가역적이다. 진행된 단계에서 유일한 선택사항은 간 이식이다. 간암의 위험은 간경변이 현저히 증가하며 간경변은 전암상태(간세포 암)로 볼 수 있다. 실제로, 간경변 및 간암은 전세계 사망의 10 가지 원인 중 하나이다. 따라서, 간 섬유증 및 이후의 간경변증의 효과적인 치료에 대한 필요성이 존재한다. 불행하게도, 이용가능한 치료 선택사항이 거의 없으며, 대부분의 치료는 간경변의 원인 및/또는 증상을 해결하는 것으로 구성된다. The liver fibrosis or hepatic fibrosis is a process of excessive accumulation of extracellular matrix proteins (including collagen) and subsequent scar formation that occurs in most chronic liver diseases. Liver fibrosis that progresses over time results in cirrhosis. Cirrhosis is the final stage of chronic liver disease and is generally irreversible with poor long-term prognosis. At an advanced stage, the only option is a liver transplant. The risk of liver cancer is significantly increased with cirrhosis, and cirrhosis can be seen as a precancerous condition (hepatocellular carcinoma). In fact, cirrhosis and liver cancer are among the top 10 causes of death worldwide. Thus, there is a need for effective treatment of liver fibrosis and subsequent cirrhosis. Unfortunately, there are few treatment options available, and most treatment consists of addressing the causes and/or symptoms of cirrhosis.
제한된 수의 임상 시험은 간에서 섬유증의 억제 또는 지연을 특이적으로 대응하는 후보 약물로 진행중이다. 그러나 이들 시험은 NASH(비알코올성 지방간염)등의 특정 간질환을 표적으로 한다. A limited number of clinical trials are ongoing with candidate drugs that specifically address the inhibition or retardation of fibrosis in the liver. However, these trials target specific liver diseases, such as non-alcoholic steatohepatitis (NASH).
상기 피부 섬유증 또는 표피 섬유증은 피부의 과도한 상흔이며, 병리학적 상처 치유 반응의 결과이다. 광범위한 섬유성 피부 질환이 있다: 강피증, 신성섬유화성 피부증, 혼합성 결합조직 질환, 경화성 점액수종, 경화성 수종, 및 호산구성 근막염. 화학 물질이나 물리적 작용제(기계적 외상, 화상상처)에 대한 노출은 또한 섬유성 피부 질환의 잠재적인 원인이다. 피부 섬유증은 면역, 자가 면역 및 염증 기전에 의해 주도될 수 있다. 섬유 아세포의 콜라겐 생성 및 분해의 균형은 피부 섬유증의 병태 생리 과정에서 중요한 역할을 한다. 형질전환 성장 인자-β(TGB-β) 및 인터루킨-4(IL-4)와 같은 특정의 시토카인은 상처 치유 및 섬유화를 촉진하는 반면, 인터페론-γ(IFN-γ) 및 종양 괴사 인자-α(TNF-α)등의 다른 것은 항섬유증이다. 정상 피부의 섬유아세포는 정지되어 있다. 이들은 결합조직 단백질의 양을 제어하고 낮은 증식활성을 갖는다. 피부 손상 후, 이러한 세포들은 활성화되고, 즉 이들은 α-평활근 액틴(α-SMA)을 발현하고 다량의 결합조직 단백질을 합성한다. 활성화된 세포들은 흔히 근육섬유 아세포라고 불리운다.The skin fibrosis or epidermal fibrosis is excessive scarring of the skin and results from a pathological wound healing response. There are a wide range of fibrotic skin diseases: scleroderma, nephrogenic dermatosis, mixed connective tissue disease, sclerosing myxedema, sclerotic hydrocele, and eosinophilic fasciitis. Exposure to chemical or physical agents (mechanical trauma, burns) is also a potential cause of fibrotic skin disease. Skin fibrosis can be driven by immune, autoimmune and inflammatory mechanisms. The balance of collagen production and degradation in fibroblasts plays an important role in the pathophysiological process of skin fibrosis. Certain cytokines such as transforming growth factor-β (TGB-β) and interleukin-4 (IL-4) promote wound healing and fibrosis, while interferon-γ (IFN-γ) and tumor necrosis factor-α ( Others, such as TNF-α), are anti-fibrotic. Fibroblasts in normal skin are quiescent. They control the amount of connective tissue proteins and have low proliferative activity. After skin injury, these cells are activated, ie they express α-smooth muscle actin (α-SMA) and synthesize large amounts of connective tissue proteins. Activated cells are often called myofibroblasts.
피부 경화증은 피부 섬유증을 말한다; 공막 = 하드 및 진피 피부. 그러나, 피부 섬유증은 특히 전신 피부 경화증의 일부인 경우 건강 결과에 중요한 영향을 미칠 수 있다. 후자는 자가 면역 병인의 결합조직 질환을 의미한다. 제한된 피부 경피증은 얼굴과 발의 피부로 제한되는 반면, 확산 피부 경피증은 더 많은 피부를 커버하며 내장기관으로 진행할 수 있다.scleroderma refers to skin fibrosis; Sclera = hard and dermal skin. However, dermal fibrosis can have a significant impact on health outcomes, particularly when it is part of systemic scleroderma. The latter refers to connective tissue diseases of autoimmune etiology. Restricted cutaneous scleroderma is limited to the skin of the face and feet, whereas diffuse cutaneous scleroderma covers more skin and may progress to the visceral organs.
상기 신장섬유증은 세포의 과도한 증식, 조직과 반흔의 경화를 의미한다. 신장 섬유증은 신부전 및 도관 설치, 예를 들면 복막 및 혈관 접근 섬유증에 따른 투석으로부터 야기될 수 있다. 신장 섬유증은 또한 사구체 질환(예를 들면 사구체 경화증, 사구체 신염), 만성 신부전, 급성 신부전, 말기 신장질환 및 신장 장애와 같은 신장병증으로부터 발생할 수 있다. 병인론과 상관없이, 모든 만성 신장질환 환자들은 경시적으로 신장 기능의 점진적 쇠퇴를 나타낸다. 섬유증, 소위 반흔은 병태생리학의 주요 원인이다. 섬유증은 세포외 기질(주로 콜라겐으로 구성됨)의 과도한 축적을 수반하며, 통상적으로 정상 조직이 반흔조직으로 대체되는 경우 기능 상실을 초래한다. 이 과정은 주로 비가역적이며, 필수적으로 말기 신부전, 즉 평생 투석 또는 신장 이식을 필요로 하는 증상을 유도한다. The renal fibrosis means excessive proliferation of cells, hardening of tissues and scars. Renal fibrosis can result from renal failure and catheterization, eg dialysis following peritoneal and vascular access fibrosis. Renal fibrosis can also result from nephropathy such as glomerular disease (eg glomerulosclerosis, glomerulonephritis), chronic renal failure, acute renal failure, end-stage renal disease and renal failure. Regardless of etiology, all patients with chronic kidney disease exhibit a gradual decline in renal function over time. Fibrosis, so-called scarring, is a major cause of the pathophysiology. Fibrosis involves excessive accumulation of extracellular matrix (composed primarily of collagen), usually resulting in loss of function when normal tissue is replaced by scar tissue. This process is often irreversible and essentially leads to end-stage renal failure, a condition requiring lifelong dialysis or kidney transplantation.
상기 심장 섬유증은, 심장 질환의 특징으로, 심장 돌연사, 심실 부정맥, 좌심실(LV) 기능장애, 및 심장 장애에 기여하는 것으로 생각된다. 심장 섬유증은 심근세포 사멸 후에 발생하는 섬유화 콜라겐의 불균형적인 축적, 염증, 증가된 작업 부하, 비대 및 다수의 호르몬, 시토카인 및 성장 인자에 의한 자극을 특징으로 한다.The cardiac fibrosis, a hallmark of heart disease, is thought to contribute to sudden cardiac death, ventricular arrhythmias, left ventricular (LV) dysfunction, and cardiac disorders. Cardiac fibrosis is characterized by disproportionate accumulation of fibrotic collagen, inflammation, increased workload, hypertrophy, and stimulation by a number of hormones, cytokines, and growth factors that occur after cardiomyocyte death.
심장 섬유증은 또한 심장 섬유아세포의 불균형적 증식으로 인하여 심장 판막의 이상 농축을 의미할 수 있지만, 더욱 일반적으로는 심장 근육의 섬유아세포의 증식을 의미한다. 섬유 세포는 일반적으로 콜라겐을 분비하고, 심장에 대한 구조적 지지를 제공하는 작용을 한다. 지나치게 활성화되면, 이 과정은 판막의 농축과 섬유증의 원인이 되며, 이때 백색 조직은 주로 삼첨판을 구축할 뿐만 아니라, 폐 동맥판에서도 발생한다. 농축 및 유연성 상실은 결국 판막 부전과 우측 심장 마비가 발생할 수 있다.Cardiac fibrosis can also refer to abnormal thickening of heart valves due to disproportionate proliferation of cardiac fibroblasts, but more generally refers to proliferation of fibroblasts in the heart muscle. Fibrous cells normally secrete collagen and function to provide structural support for the heart. When overly activated, this process causes thickening and fibrosis of the valves, at which time white tissue not only builds the tricuspid valve, but also occurs in the pulmonary valve. Concentration and loss of flexibility can eventually lead to valve failure and right-sided heart failure.
상기 췌장섬유증을 유발하는 만성 췌장염(CP)은 비가역적인 형태학적 변화 및 샘의 점진적 섬유화 대체를 특징으로 하는 췌장의 진행성 염증성 질환이다. 실질성 섬유증에서 외분비 및 내분비 기능의 손실이 생긴다. CP의 주요 증상은 복통과 소화불량이다. 극도로, 췌장은 낭종 또는 석회화 또는 종양과 함께 또는 이들 없이 확대 또는 위축될 수 있다. 관은 확장되거나 불규칙적이거나 수축될 수 있다. 주요한 병적 특징은 소엽 조직의 불규칙적이고 불균일한 손실, 만성 염증, 동맥 관 변화 및 섬유증을 포함한다. 유전자 돌연변이(이들로 제한되지 않지만, 낭포성 섬유증, 양이온 트립시노겐 유전자, 특발성 급성 및 만성 췌장염의 CFTR 유전자 돌연변이, 췌장 분비성 트립신 억제제 유전자, 키모트립시노겐 C 유전자, 칼슘 감지 수용체 유전자, α-1 안티트립신 결핍을 포함함), 대사(알코올, 담배 흡연, 고칼슘 혈증, 고지혈증, 만성 신부전), 환경 요인(미량 영양소 결핍(아연, 구리 및 셀레늄 등의 영양인자; 또한 조사후 노출), 폐쇄성(종양), 허혈성(혈관 질환)) 및 자가 면역 질환과 관련되어 있거나 1차 경화성 담관 불꽃, 쇼그렌 증후군, 1차 담즙성 장애 및 1형 당뇨병과 관련된 복합적인 병원성 기전의 최종 증상이다. Chronic pancreatitis (CP), which causes pancreatic fibrosis, is a progressive inflammatory disease of the pancreas characterized by irreversible morphological changes and progressive fibrotic replacement of the gland. In parenchymal fibrosis, loss of exocrine and endocrine function occurs. The main symptoms of CP are abdominal pain and indigestion. Extremely, the pancreas may be enlarged or atrophied with or without cysts or calcifications or tumors. The tube may be dilated, irregular or constricted. The major pathological features include irregular and non-uniform loss of lobular tissue, chronic inflammation, ductal changes and fibrosis. Gene mutations (including but not limited to cystic fibrosis, cationic trypsinogen gene, CFTR gene mutation in idiopathic acute and chronic pancreatitis, pancreatic secretory trypsin inhibitor gene, chymotrypsinogen C gene, calcium sensing receptor gene, α- 1 including antitrypsin deficiency), metabolic (alcohol, tobacco smoking, hypercalcemia, hyperlipidemia, chronic renal failure), environmental factors (micronutrient deficiencies (nutritional factors such as zinc, copper and selenium; also post-irradiation exposure), obstructive ( tumor), ischemic (vascular disease)) and autoimmune diseases, or is the final manifestation of a complex pathogenic mechanism associated with primary sclerosing bile duct flames, Sjogren's syndrome, primary biliary disorders and type 1 diabetes mellitus.
이와 같은 다양한 섬유증에 있어서, 본 발명에 다른 비-뉴클레오시드 역전사효소 억제제를 포함하는 조성물은 각 조직 또는 세포에서 procollagen alpha 1의 양을 감소시켜 섬유화 반응을 억제하며, 이와 같은 효과는 Bcl-2 (B-cell lymphoma 2) 억제제, DPP-4 (Dipeptidyl peptidase-4) 억제제 및 니클로사미드(Niclosamide)로 이루어진 군에서 선택된 1종 이상의 약물과 병용되었을 때 시너지 효과가 나타날 수 있다. In such various fibrosis, the composition containing the non-nucleoside reverse transcriptase inhibitor according to the present invention suppresses the fibrotic reaction by reducing the amount of procollagen alpha 1 in each tissue or cell, and this effect is (B-cell lymphoma 2) inhibitors, DPP-4 (Dipeptidyl peptidase-4) inhibitors, and niclosamide (Niclosamide) when used in combination with one or more drugs can show synergistic effects.
본 발명의 일 양태에서, 상기 조성물에는 파테놀라이드(Parthenolide), 디곡신(Dogoxin) 및 이들의 약학적으로 허용가능한 염으로 이루어진 군에서 선택된 하나 이상이 추가로 포함될 수 있다. 즉, MTP 억제제와 파테놀라이드 또는 디곡신은 병용 요법으로서, 또는 병용 제제로서 섬유화 질환 치료에 시너지 효과를 나타낼 수 있다.In one aspect of the present invention, the composition may further include at least one selected from the group consisting of parthenolide, digoxin, and pharmaceutically acceptable salts thereof. That is, an MTP inhibitor and parthenolide or digoxin can show a synergistic effect in the treatment of fibrotic disease as a combination therapy or as a combination agent.
본 발명의 바람직한 일 양태에서, MTP 억제제로서 로미타파이드; 및 파테놀라이드 또는 디곡신을 포함하는 병용 요법 또는 병용 제제는 섬유화 질환 치료에 시너지 효과를 나타낼 수 있다. In a preferred aspect of the present invention, lomitapide as an MTP inhibitor; and parthenolide or digoxin, the combination therapy or combination preparation may show a synergistic effect in the treatment of fibrotic disease.
이 경우, 상기 병용 제제에 포함된 각 구성성분은 별개로, 동시에 또는 순차적으로 사용되기 위해 제제화될 수 있다. 즉, 순차적으로 투여하는 경우, 병용 제제는 2회 이상 투여로 투여할 수 있다. 병용 투여에는 별개의 제형 또는 단일 제약 제형을 사용하여 동시-투여하는 것과, 어느 한 순서로 순차적으로 투여하는 것이 포함될 수 있다. In this case, each component included in the combination preparation may be formulated for use separately, simultaneously or sequentially. That is, in the case of sequential administration, the combination preparation may be administered in two or more administrations. Concomitant administration can include co-administration using separate formulations or a single pharmaceutical formulation, as well as sequential administration in either order.
본 발명에서 상기 MTP 억제제 및 파테놀라이드가 병용 요법 또는 병용 제제로서 사용되는 경우, 이들 병용 약물은 1:0.01 내지 1000의 몰비로, 바람직하게는 1:1 내지 500의 몰비로, 더 바람직하게는 1:50 내지 500의 몰비로, 보다 더 바람직하게는 1:100 내지 500의 몰비로, 가장 바람직하게는 1:150 내지 350의 몰비로 병용 투여될 수 있다. In the present invention, when the MTP inhibitor and parthenolide are used as a combination therapy or combination drug, these combination drugs are used in a molar ratio of 1:0.01 to 1000, preferably in a molar ratio of 1:1 to 500, more preferably It may be administered in combination at a molar ratio of 1:50 to 500, more preferably at a molar ratio of 1:100 to 500, and most preferably at a molar ratio of 1:150 to 350.
본 발명에서 상기 MTP 억제제 및 디곡신이 병용 요법 또는 병용 제제로서 사용되는 경우, 이들 병용 약물은 1:0.1 내지 100의 몰비로, 바람직하게는 1:0.1 내지 50의 몰비로, 보다 더 바람직하게는 1:0.5 내지 20의 몰비로, 가장 바람직하게는 1:1 내지 10의 몰비로 병용 투여될 수 있다. In the present invention, when the MTP inhibitor and digoxin are used as a combination therapy or combination drug, these combination drugs are used in a molar ratio of 1:0.1 to 100, preferably in a molar ratio of 1:0.1 to 50, and more preferably 1 : It may be co-administered at a molar ratio of 0.5 to 20, most preferably at a molar ratio of 1:1 to 10.
본 발명은 또한 로미타파이드 또는 이의 약학적으로 허용가능한 염; 및 파테놀라이드(Parthenolide), 디곡신(Dogoxin) 및 이들의 약학적으로 허용가능한 염으로 이루어진 군에서 선택된 하나 이상을 유효성분으로 포함하는 섬유화 질환 예방 또는 치료용 약학적 조성물을 제공한다. The present invention also relates to lomitapide or a pharmaceutically acceptable salt thereof; And parthenolide (Parthenolide), digoxin (Dogoxin) and provides a pharmaceutical composition for preventing or treating fibrotic disease comprising at least one selected from the group consisting of pharmaceutically acceptable salts thereof as an active ingredient.
본 발명에 따른 약학적 조성물은 MTP 억제제를 단독으로 함유하거나 약학적으로 허용되는 담체와 함께 적합한 형태로 제형화 될 수 있으며, 부형제 또는 희석제를 추가로 함유할 수 있다. 상기에서 '약학적으로 허용되는'이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증 등과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 비독성의 조성물을 말한다.The pharmaceutical composition according to the present invention may contain the MTP inhibitor alone or may be formulated in a suitable form together with a pharmaceutically acceptable carrier, and may further contain an excipient or diluent. In the above, 'pharmaceutically acceptable' refers to a non-toxic composition that is physiologically acceptable and does not cause allergic reactions such as gastrointestinal disorders, dizziness, etc., or similar reactions when administered to humans.
약학적으로 허용되는 담체로는 예컨대, 경구 투여용 담체 또는 비경구 투여용 담체를 추가로 포함할 수 있다.A pharmaceutically acceptable carrier may further include, for example, a carrier for oral administration or a carrier for parenteral administration.
경구 투여용 담체는 락토스, 전분, 셀룰로스 유도체, 마그네슘 스테아레이트, 스테아르산 등을 포함할 수 있다.Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like.
아울러, 경구투여용으로 사용되는 다양한 약물전달물질을 포함할 수 있다. 또한, 비경구 투여용 담체는 물, 적합한 오일, 식염수, 수성 글루코오스 및 글리콜 등을 포함할 수 있으며, 안정화제 및 보존제를 추가로 포함할 수 있다. 적합한 안정화제로는 아황산수소나트륨, 아황산나트륨 또는 아스코르브산과 같은 항산화제가 있다. 적합한 보존제로는 벤즈알코늄 클로라이드, 메틸-또는 프로필-파라벤 및 클로로부탄올이 있다.In addition, various drug delivery materials used for oral administration may be included. In addition, the carrier for parenteral administration may include water, suitable oil, saline, aqueous glucose and glycol, and the like, and may further include a stabilizer and a preservative. Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.
본 발명의 약학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현택제 등을 추가로 포함할 수 있다. 그 밖의 약학적으로 허용되는 담체 및 제제는 당업계에 공지되어 있는 것을 참고로 할 수 있다.The pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifier, a suspending agent, and the like in addition to the above components. Reference may be made to other pharmaceutically acceptable carriers and agents known in the art.
본 발명에서 상기 조성물은 사용목적 내지 양상에 따라 함량은 크게 제한되지 않으며, 예를 들면 조성물 총 중량을 기준으로 0.01~99 중량%, 바람직하게는 0.5~50 중량%, 더 바람직하게는 1~30 중량%일 수 있다. 또한, 본 발명에 따른 약학적 조성물은 유효성분 외에 약학적으로 허용가능한 담체, 부형제 또는 희석제와 같은 첨가제를 더 포함할 수 있다. 본 발명의 약학적 조성물은 마이크로조말 트리글리세라이드 전달 단백질 억제제를 포함하는 조성물을 0.1 내지 99.9 중량%로 포함하고, 담체를 99.9% 내지 0.1 중량%로 포함할 수 있다.In the present invention, the content of the composition is not significantly limited depending on the purpose or aspect of use, for example, 0.01 to 99% by weight, preferably 0.5 to 50% by weight, more preferably 1 to 30% by weight based on the total weight of the composition. weight percent. In addition, the pharmaceutical composition according to the present invention may further include additives such as pharmaceutically acceptable carriers, excipients or diluents in addition to active ingredients. The pharmaceutical composition of the present invention may include 0.1 to 99.9% by weight of the composition containing the microsomal triglyceride transfer protein inhibitor and 99.9% to 0.1% by weight of the carrier.
발명에 따른 약학적 조성물은 약학적으로 유효한 양의 상기 화합물을 단독으로 포함하거나 하나 이상의 약학적으로 허용되는 담체를 추가로 포함할 수 있다. 본 발명의 약학적 조성물은 단일 투여량(single dose)으로 환자에게 투여될 수 있으며, 다중 투여량(multiple dose)이 장기간 투여되는 분할 치료방법(fractionated treatment protocol)에 의해 투여될 수 있다. 상기에서 약학적으로 유효한 양이란 음성 대조군에 비해 그 이상의 반응을 나타내는 양을 말하며 바람직하게는 섬유화 질환을 치료 또는 예방하기에 충분한 양을 말한다. 본 발명에 따른 조성물의 유효한 양으로는 0.001 내지 1000 mg/kg b.w./day일 수 있고, 바람직하게 1 내지 2000mg/kg b.w./day일 수 있으나 이에 한정되는 것은 아니다. 그러나 상기 약학적으로 유효한 양은 상기 질환 및 이의 중증정도, 환자의 연령, 체중, 건강상태, 성별, 투여 경로 및 치료기간 등과 같은 여러 인자에 따라 적절히 변화될 수 있다.The pharmaceutical composition according to the invention may include a pharmaceutically effective amount of the compound alone or may further include one or more pharmaceutically acceptable carriers. The pharmaceutical composition of the present invention may be administered to a patient as a single dose, or may be administered by a fractionated treatment protocol in which multiple doses are administered over a long period of time. In the above, the pharmacologically effective amount refers to an amount that exhibits a higher response than that of the negative control group, and preferably refers to an amount sufficient to treat or prevent fibrotic disease. An effective amount of the composition according to the present invention may be 0.001 to 1000 mg/kg b.w./day, preferably 1 to 2000 mg/kg b.w./day, but is not limited thereto. However, the pharmaceutically effective amount may be appropriately changed depending on various factors such as the disease and its severity, the patient's age, weight, health condition, sex, administration route and treatment period.
본 발명의 조성물은 인간을 비롯한 포유동물에 어떠한 방법으로도 투여할 수 있다. 예를 들면, 경구 또는 비경구적으로 투여할 수 있다. 비경구적인 투여방법으로는 이에 한정되지는 않으나, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장내 투여일 수 있다.The composition of the present invention can be administered to mammals including humans by any method. For example, it can be administered orally or parenterally. Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal administration can be
본 발명의 약학적 조성물은 상술한 바와 같은 투여 경로에 따라 경구 투여용 또는 비경구 투여용 제제로 제형화할 수 있다.The pharmaceutical composition of the present invention may be formulated into a formulation for oral administration or parenteral administration according to the administration route as described above.
경구 투여용 제제의 경우에 본 발명의 조성물은 분말, 과립, 정제, 환제, 당의정제, 캡슐제, 액제, 겔제, 시럽제, 슬러리제, 현탁액 등으로 당업계에 공지된 방법을 이용하여 제형화될 수 있다. 예를 들어, 경구용 제제는 활성성분을 고체 부형제와 배합한 다음 이를 분쇄하고 적합한 보조제를 첨가한 후 과립 혼합물로 가공함으로써 정제 또는 당의정제를 수득할 수 있다. 적합한 부형제의 예로는 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨 및 말티톨 등을 포함하는 당류와 옥수수 전분, 밀 전분, 쌀 전분 및 감자 전분 등을 포함하는 전분류, 셀룰로즈, 메틸 셀룰로즈, 나트륨 카르복시메틸셀룰로오즈 및 하이드록시프로필메틸-셀룰로즈 등을 포함하는 셀룰로즈류, 젤라틴, 폴리비닐피롤리돈 등과 같은 충전제가 포함될 수 있다. 또한, 경우에 따라 가교결합 폴리비닐피롤리돈, 한천, 알긴산 또는 나트륨 알기네이트 등을 붕해제로 첨가할 수 있다.In the case of preparations for oral administration, the composition of the present invention may be formulated into powders, granules, tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions, etc. using a method known in the art. can For example, preparations for oral use may be obtained by combining the active ingredient with a solid excipient, which is then milled and, after adding suitable auxiliaries, processed into a mixture of granules to obtain tablets or dragees. Examples of suitable excipients include sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol, starches including corn starch, wheat starch, rice starch and potato starch, cellulose, Celluloses including methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethyl-cellulose, and the like, fillers such as gelatin, polyvinylpyrrolidone, and the like may be included. In addition, cross-linked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may be added as a disintegrant, if desired.
나아가, 본 발명의 약학적 조성물은 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다.Furthermore, the pharmaceutical composition of the present invention may further include an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifier, and a preservative.
비경구 투여용 제제의 경우에는 주사제, 크림제, 로션제, 외용연고제, 오일제, 보습제, 겔제, 에어로졸 및 비강 흡입제의 형태로 당업계에 공지된 방법으로 제형화할 수 있다. 이들 제형은 모든 제약 화학에 일반적으로 공지된 처방서에 기재되어 있다.In the case of preparations for parenteral administration, they may be formulated in the form of injections, creams, lotions, external ointments, oils, moisturizers, gels, aerosols, and nasal inhalants by methods known in the art. These formulations are described in prescriptions generally known to all pharmaceutical chemists.
본 발명의 조성물의 총 유효량은 단일 투여량(single dose)으로 환자에게 투여될 수 있으며, 다중 투여량(multiple dose)으로 장기간 투여되는 분할 치료 방법(fractionated treatment protocol)에 의해 투여될 수 있다. 본 발명의 약학적 조성물은 질환의 정도에 따라 유효성분의 함량을 달리할 수 있다. 바람직하게 본 발명의 약학적 조성물의 바람직한 전체 용량은 1일당 환자 체중 1 당 약 0.01 내지 10,000mg, 가장 바람직하게는 0.1 내지 500mg일 수 있다. 그러나 상기 약학적 조성물의 용량은 제제화 방법, 투여 경로 및 치료 횟수뿐만 아니라 환자의 연령, 체중, 건강 상태, 성별, 질환의 중증도, 식이 및 배설율 등 다양한 요인들을 고려하여 환자에 대한 유효 투여량이 결정되는 것이므로, 이러한 점을 고려할 때 당 분야의 통상적인 지식을 가진 자라면 본 발명의 조성물의 적절한 유효 투여량을 결정할 수 있을 것이다. 본 발명에 따른 약학적 조성물은 본 발명의 효과를 보이는 한 그 제형, 투여 경로 및 투여 방법에 특별히 제한되지 아니한다.The total effective amount of the composition of the present invention can be administered to the patient in a single dose or by a fractionated treatment protocol in which multiple doses are administered over a long period of time. The pharmaceutical composition of the present invention may vary the content of the active ingredient according to the severity of the disease. Preferably, the preferred total dose of the pharmaceutical composition of the present invention may be about 0.01 to 10,000 mg, most preferably 0.1 to 500 mg per patient body weight per day. However, the dosage of the pharmaceutical composition is determined by considering various factors such as the formulation method, administration route, and number of treatments as well as the patient's age, weight, health condition, sex, severity of disease, diet and excretion rate, etc. Therefore, considering this point, those skilled in the art will be able to determine an appropriate effective dosage of the composition of the present invention. The pharmaceutical composition according to the present invention is not particularly limited in its formulation, administration route and administration method as long as it exhibits the effects of the present invention.
이와 같은 다양한 섬유증에 있어서, 본 발명에 따른 MTP 억제제를 포함하는 조성물은 각 조직 또는 세포에서 염증성 자극에 의한 콜라겐 축적을 감소시켜 섬유화 반응을 억제하며, 이와 같은 효과는 파테놀라이드 또는 디곡신과 병용되었을 때 시너지 효과가 나타날 수 있다. In such various fibrosis, the composition containing the MTP inhibitor according to the present invention suppresses the fibrotic reaction by reducing the accumulation of collagen by inflammatory stimulation in each tissue or cell, and such an effect may be combined with parthenolide or digoxin. A synergistic effect can occur when
본 발명의 목적을 달성하기 위하여, 본 발명은 섬유화 질환 치료용 조성물을 제조하기 위한 마이크로조말 트리글리세라이드 전달 단백질 억제제(microsomal triglyceride transfer protein (MTP) inhibitor)의 용도를 제공한다.In order to achieve the object of the present invention, the present invention provides a use of a microsomal triglyceride transfer protein (MTP) inhibitor for preparing a composition for treating fibrotic disease.
본 발명의 목적을 달성하기 위하여, 본 발명은 마이크로조말 트리글리세라이드 전달 단백질 억제제(microsomal triglyceride transfer protein (MTP) inhibitor)를 유효성분으로 포함하는 조성물의 유효량을 이를 필요로 하는 개체에 투여하는 것을 포함하는 섬유화 질환 치료 방법을 제공한다.In order to achieve the object of the present invention, the present invention comprises administering an effective amount of a composition comprising a microsomal triglyceride transfer protein (MTP) inhibitor as an active ingredient to a subject in need thereof. A method for treating fibrotic disease is provided.
본 발명의 상기 '유효량'이란 개체에게 투여하였을 때, 섬유화 질환의 개선, 치료, 검출, 진단 또는 상기 질환의 억제 또는 감소 효과를 나타내는 양을 말하며, 상기 '개체'란 동물, 바람직하게는 포유동물, 특히 인간을 포함하는 동물일 수 있으며, 동물에서 유래한 세포, 조직, 기관 등일 수도 있다. 상기 개체는 상기 효과가 필요한 환자(patient) 일 수 있다.The 'effective amount' of the present invention refers to an amount that exhibits an effect of improving, treating, detecting, diagnosing, or suppressing or reducing the disease when administered to a subject, and the 'subject' refers to an animal, preferably a mammal , In particular, it may be an animal, including a human, and may be a cell, tissue, or organ derived from an animal. The subject may be a patient in need of the effect.
본 발명의 상기 '치료'는 섬유화 질환 또는 상기 질환으로 인한 증상을 개선시키는 것을 포괄적으로 지칭하고, 이는 상기 질환을 치유하거나, 실질적으로 예방하거나, 또는 상태를 개선시키는 것을 포함할 수 있으며, 상기 질환으로부터 비롯된 한 가지 증상 또는 대부분의 증상을 완화시키거나, 치유하거나 예방하는 것을 포함하나, 이에 제한되는 것은 아니다.The 'treatment' of the present invention comprehensively refers to improving a fibrotic disease or symptoms caused by the disease, which may include curing, substantially preventing, or improving the condition of the disease, Alleviating, curing or preventing one or most of the symptoms resulting from, but is not limited to.
본 명세서에서 용어 "을 포함하는(comprising)"이란 "함유하는(including)" 또는 "특징으로 하는(characterized by)"과 동일한 의미로 사용되며, 본 발명에 따른 조성물 또는 방법에 있어서, 구체적으로 언급되지 않은 추가적인 구성 성분 또는 방법의 단계 등을 배제하지 않는다. 또한 용어 "로 이루어지는(consisting of)"이란 별도로 기재되지 않은 추가적인 요소, 단계 또는 성분 등을 제외하는 것을 의미한다. 용어 "필수적으로 이루어지는(essentially consisting of)"이란 조성물 또는 방법의 범위에 있어서, 기재된 물질 또는 단계와 더불어 이의 기본적인 특성에 실질적으로 영향을 미치지 않는 물질 또는 단계 등을 포함할 수 있는 것을 의미한다.In this specification, the term "comprising" is used in the same meaning as "including" or "characterized by", and in the composition or method according to the present invention, specifically mentioned It does not exclude additional components or method steps not specified. Also, the term "consisting of" means excluding additional elements, steps or components not separately described. The term "essentially consisting of" means that in the scope of a composition or method, in addition to the described materials or steps, materials or steps that do not substantially affect the basic characteristics thereof may be included.
MTP 억제제를 포함하는 본 발명의 조성물은 염증성 자극에 의한 세포 및 조직에서의 콜라겐 축적을 억제하여 섬유화를 예방 또는 치료하는 효과가 매우 탁월하며, 이러한 효과는 파테놀라이드 또는 디곡신과 병용함으로써 시너지 효과가 나타날 수 있어 섬유화 질환 예방 또는 치료제 개발에 매우 유용하게 활용될 수 있다. The composition of the present invention containing an MTP inhibitor has a very excellent effect of preventing or treating fibrosis by inhibiting collagen accumulation in cells and tissues caused by inflammatory stimuli, and this effect has a synergistic effect when used in combination with parthenolide or digoxin. Therefore, it can be very useful for preventing or developing a treatment for fibrotic diseases.
도 1은 로미타파이드, 파테놀라이드, 디곡신 및 대조약물(Nint)을 각각 섬유화-유도된 Primary Human Pulmonary Fibroblasts에 단회 처리한 후 콜라겐 생성 억제능을 Sircol assay로 평가한 결과이다. 1 is a result of evaluating collagen production inhibitory ability by Sircol assay after a single treatment of lomitapide, parthenolide, digoxin, and a control drug (Nint) on fibrosis-induced Primary Human Pulmonary Fibroblasts, respectively.
도 2는 폐섬유화 동물모델(BLM IPF 마우스 모델)에서 로미타파이드의 항섬유화 효능을 hydroxyproline assay로 평가한 결과(Kit)이다. Figure 2 is a result (Kit) of evaluating the anti-fibrotic efficacy of lomitapide in a pulmonary fibrosis animal model (BLM IPF mouse model) by hydroxyproline assay.
도 3은 폐섬유화 동물모델(BLM IPF 마우스 모델)에서 로미타파이드의 항섬유화 효능을 hydroxyproline assay로 평가한 결과(LC-MS)이다(T1: 로미타파이드 10mg/kg, T2: 로미타파이드 50mg/kg).Figure 3 is the result (LC-MS) of evaluating the anti-fibrotic efficacy of lomitapide in a pulmonary fibrosis animal model (BLM IPF mouse model) by hydroxyproline assay (T1: lomitapide 10mg/kg, T2: lomitapide 50mg /kg).
도 4는 로미타파이드, 디곡신 또는 이의 병용 처리에 따른 항섬유화 효능을 섬유화 관련 유전자의 발현 변화로 평가한 결과이다.Figure 4 is a result of evaluating the anti-fibrosis efficacy according to lomitapide, digoxin, or a combination treatment thereof by expression changes of fibrosis-related genes.
도 5는 로미타파이드, 디곡신 또는 이의 병용 처리에 따른 항섬유화 효능을 세포에서 콜라겐 분비량 변화를 통해 평가한 결과이다. 5 is a result of evaluating the anti-fibrotic efficacy of lomitapide, digoxin or a combination thereof through changes in collagen secretion in cells.
도 6은 로미타파이드, 파테놀라이드 또는 이의 병용 처리에 따른 항섬유화 효능을 섬유화 관련 유전자 COL1A1의 발현 변화로 평가한 결과이다.Figure 6 is a result of evaluating the anti-fibrotic efficacy according to lomitapide, parthenolide or a combination thereof by the expression change of the fibrosis-related gene COL1A1.
도 7은 로미타파이드, 파테놀라이드 또는 이의 병용 처리에 따른 항섬유화 효능을 섬유화 관련 유전자 a-SMA의 발현 변화로 평가한 결과이다.7 is a result of evaluating the anti-fibrotic efficacy according to lomitapide, parthenolide or a combination treatment thereof by the expression change of a-SMA, a fibrosis-related gene.
도 8은 로미타파이드, 파테놀라이드 또는 이의 병용 처리에 따른 항섬유화 효능을 세포에서 콜라겐 분비량 변화를 통해 평가한 결과이다.8 is a result of evaluating the anti-fibrotic efficacy of lomitapide, parthenolide, or a combination thereof through changes in collagen secretion in cells.
이하, 본 발명을 하기 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명이 이들에 의해 제한되는 것은 아니다.Hereinafter, the present invention will be described in detail by the following examples. However, the following examples are only for illustrating the present invention, and the present invention is not limited thereto.
실시예 1: 콜라겐 축적 억제능 평가 Example 1: Evaluation of collagen accumulation inhibitory ability
논문 등에 공개된 환자 유전체 데이터를 AI 기반으로 분석하여 섬유화능 억제를 보일것으로 예측한 단일제 약물로 로미타파이드(lomitapide), 파테놀라이드(parthenolide) 및 디곡신(digoxin)을 선택하고 이들의 단회 처리에 따른 콜라겐 형성 억제능을 in vitro에서 확인하였다. We selected lomitapide, parthenolide, and digoxin as single-agent drugs predicted to show fibrogenic inhibition by AI-based analysis of patient genome data published in papers, etc. The ability to inhibit collagen formation was confirmed in vitro.
Sircol Collagen Assay kit를 사용하여 제조사의 지시에 따라 실험을 수행하였다. 대조약물로는 마켓화된 IPF 약물인 Nintedanib (Nint) 1uM을 사용하였다. Nintedanib은 논문을 참고하여 1uM의 고농도로 처리하였고, 로미타파이드, 파테놀라이드 및 디곡신도 1uM의 농도로 처리하였다.Experiments were performed using the Sircol Collagen Assay kit according to the manufacturer's instructions. As a control drug, Nintedanib (Nint) 1uM, a marketed IPF drug, was used. Nintedanib was treated at a high concentration of 1uM with reference to the paper, and lomitapide, parthenolide and digoxin were also treated at a concentration of 1uM.
구체적으로, Primary Human Pulmonary Fibroblasts isolated from human lung tissue (구입처: Promo Cell)로 실험하였다. 세포를 1 x 105의 density로 6 well에 seeding하였으며, 섬유화는 recombinant TGF-β를 20ng/mL의 농도로 44hr 처리하여 유발하였다. 각 약물은 TGF-β stimulation 4시간 전에 pre-treat하였으며, 약물 처리 48시간 후에 harvest 하여 분석하였다. 이에 대한 결과를 도 1에 나타내었다. Specifically, experiments were performed with Primary Human Pulmonary Fibroblasts isolated from human lung tissue (purchased by Promo Cell). Cells were seeded in 6 wells at a density of 1 x 10 5 , and fibrosis was induced by treatment with the recombinant TGF-β at a concentration of 20 ng/mL for 44 hr. Each drug was pre-treated 4 hours before TGF-β stimulation, harvested and analyzed 48 hours after drug treatment. The results for this are shown in Figure 1.
실시예 2: In vivo 섬유화 억제능 평가Example 2: In vivo fibrosis inhibitory activity evaluation
BLM IPF 마우스모델에서 로미타파이드의 항섬유화 효능을 두 가지 용량에서 확인하였다. 구체적인 실험조건은 아래와 같다:In the BLM IPF mouse model, the anti-fibrotic efficacy of lomitapide was confirmed at two doses. The specific experimental conditions are as follows:
실험동물: 수컷 마우스(Specific Pathogen Free; SPF) C57BL/6NCrlOriExperimental animal: male mouse (Specific Pathogen Free; SPF) C57BL/6NCrlOri
폐섬유화 유도물질: Bleomycin sulfate (BLM)을 부형제인 크린클 관류제 (멸균생리식염수)에 용해하여 조제Pulmonary fibrosis inducer: Prepared by dissolving Bleomycin sulfate (BLM) in crinkle irrigation agent (sterilized physiological saline) as an excipient
시험물질 및 양성대조군 부형제 조성: 5% DMSO + 5% Cremophor EL + 90% SalineComposition of test substance and positive control vehicle: 5% DMSO + 5% Cremophor EL + 90% Saline
시험물질 조제: 투여 당일 조제Preparation of test substance: preparation on the day of administration
BLM 및 약물 투여BLM and drug administration
투여방법Administration method
폐 섬유화 유도물질 및 부형제: Day1에 모든 동물에 대하여 BLM을 단회 기도내 투여하였다. 기도내 점적 투여 전 isoflurane 흡입을 이용하여 약 1 - 5분간 마취를 실시했다. Lung fibrosis inducer and excipient: BLM was administered single intra-airway to all animals on Day 1. Before intratracheal instillation, anesthesia was performed for about 1 to 5 minutes using isoflurane inhalation.
시험물질 및 부형제: 시험물질과 시험물질 부형제는 투여 당일 조제하여 Day 1~21에 반복 경구투여했다.Test substance and excipient: The test substance and test substance excipient were prepared on the day of administration and repeatedly orally administered on Days 1 to 21.
양성대조물질 (pirfenidone): 양성대조물질은 Day 1~21에 반복 경구투여했다.Positive control substance (pirfenidone): The positive control substance was orally administered repeatedly on Days 1-21.
BioVision 사의 Hydroxyproline assay kit를 사용하여 첨부된 protocol을 참고하여 진행하였다.BioVision's Hydroxyproline assay kit was used and the procedure was performed with reference to the attached protocol.
구체적으로, 폐조직 10 mg당 50 ul의 물로 homogenize 하였으며 동량의 HCl 첨가 후, 120도 온도로 5시간 동안 hydrolyze 조건으로 변형하였고 의외에는 모두 kit protocol과 동일하게 수행하였다. OD값은 BioTek SYNERGY Mx 기기를 사용하여 측정하였다. Specifically, it was homogenized with 50 ul of water per 10 mg of lung tissue, and after adding the same amount of HCl, it was modified to hydrolyze conditions at 120 ° C for 5 hours, and unexpectedly, all the kit protocols were performed. OD values were measured using a BioTek SYNERGY Mx instrument.
이에 대한 결과를 도 2에 나타내었다. The results for this are shown in Figure 2.
도 2에 나타낸 바와 같이, 로미타파이드 투여군에서 양성대조군보다 현저히 우수한 항섬유화 효능을 나타내는 것으로 확인되었다. As shown in Figure 2, it was confirmed that the lomitapide-administered group showed significantly better antifibrotic efficacy than the positive control group.
상기 도 2에서의 결과를 다시 한번 확인하기 위하여 hydroxyproline 농도를 LC-MS로 측정하였다. In order to confirm the results in FIG. 2 once again, the concentration of hydroxyproline was measured by LC-MS.
구체적으로, 폐조직을 homogenize 하여 3차 증류수의 양으로 normalization을 진행한 후 HCl을 첨가 후, 120도 온도로 24시간 동안 hydrolyze 하였다. 이를 LC-MS로 분석하였다. Specifically, the lung tissue was homogenized, normalized with the amount of tertiary distilled water, and then hydrolyzed at 120 degrees for 24 hours after adding HCl. It was analyzed by LC-MS.
이에 대한 결과를 도 3에 나타내었다. The results for this are shown in Figure 3.
도 3에 나타낸 바와 같이, 로미타파이드 투여군에서 양성대조군과 동등한 수준의 우수한 항섬유화 효능을 나타내는 것으로 확인되었다. As shown in Figure 3, it was confirmed that the lomitapide-administered group showed excellent antifibrotic efficacy equivalent to that of the positive control group.
실시예 3: In vitro 섬유화 억제능 (1)Example 3: In vitro fibrosis inhibitory ability (1)
상기 실시예 1에서 항섬유화 효능을 나타내는 것으로 확인된 디곡신(Digoxin)을 로미타파이드와 병용처리하였을 때, 시너지 효과가 나타나는지 확인해보고자 하였다. When digoxin (Digoxin), which was confirmed to exhibit antifibrotic efficacy in Example 1, was treated in combination with lomitapide, it was attempted to determine whether a synergistic effect appeared.
구체적으로, 로미타파이드를 19.89 nM로, 디곡신을 100 nM 농도로 각각 처리한 그룹과 로미타파이드 19.89 nM과 Digoxin 100nM을 병용 처리하여 섬유화 관련 유전자 발현 변화를 확인하였다. Primary Human Pulmonary Fibroblasts isolated from human lung tissue (구입처: Promo Cell)를 사용하였다.Specifically, the group treated with 19.89 nM of lomitapide and 100 nM of digoxin, respectively, and the combined treatment with 19.89 nM of lomitapide and 100 nM of digoxin were confirmed for fibrosis-related gene expression changes. Primary Human Pulmonary Fibroblasts isolated from human lung tissue (purchased by Promo Cell) were used.
세포는 1 x 106의 density로 6 well에 seeding하였으며, 세포 섬유화는 recombinant TGF-β를 20ng/mL의 농도로 20hr 처리하여 유발하였다. 각 약물은 TGF-β stimulation 4시간 전에 pre-treat하였으며, 약물 처리 24hr 후에 harvest 하여 분석하였다. Cells were seeded in 6 wells at a density of 1 x 10 6 , and cell fibrosis was induced by treatment with recombinant TGF-β at a concentration of 20 ng/mL for 20 hr. Each drug was pre-treated 4 hours before TGF-β stimulation, and harvested and analyzed 24 hours after drug treatment.
이에 대한 결과를 도 4에 나타내었다. The results for this are shown in FIG. 4 .
도 4에 나타낸 바와 같이, 로미타파이드와 디곡신 병용 처리군에서 각각의 단일 처리군과 비교해 현저히 향상된 항섬유화 활성을 나타내는 것으로 확인되었다.As shown in Figure 4, it was confirmed that the lomitapide and digoxin combined treatment group exhibits significantly improved antifibrotic activity compared to each single treatment group.
로미타파이드와 디곡신의 병용처리 효과를 sircol collagen assay를 통해 다시 한번 확인하여, 실제 세포에서 분비되는 soluble collagen의 양이 감소하는지를 확인해보았다. The effect of the combined treatment of lomitapide and digoxin was confirmed again through sircol collagen assay, and it was confirmed whether the amount of soluble collagen secreted from cells actually decreased.
구체적으로, 로미타파이드 또는 디곡신을 단일제로 1uM 농도로 처리한 그룹과 이들을 각각 0.5uM씩 병용 투여한 그룹의 결과를 비교하였다. Primary Human Pulmonary Fibroblasts isolated from human lung tissue (구입처: Promo Cell)를 사용하였다. Specifically, the results of the group treated with lomitapide or digoxin at a concentration of 1uM as a single agent and the group administered with 0.5uM each of them were compared. Primary Human Pulmonary Fibroblasts isolated from human lung tissue (purchased by Promo Cell) were used.
세포는 2 x 106의 density로 6 well에 seeding하였으며, 세포 섬유화는 recombinant TGF-β를 20ng/mL의 농도로 44hr 처리하여 유발하였다. 각 약물은 TGF-β stimulation 4시간 전에 pre-treat하였으며, 약물 처리 48hr 후에 harvest 하여 분석하였다. Sircol Collagen Assay kit를 사용하여 포함되어 있는 protocol 그대로 실험하였으며, 대조약물로는 마켓화된 IPF 약물인 Nintedanib 1uM을 사용하였다. Cells were seeded in 6 wells at a density of 2 x 10 6 , and cell fibrosis was induced by treatment with recombinant TGF-β at a concentration of 20 ng/mL for 44 hr. Each drug was pre-treated 4 hours before TGF-β stimulation, and harvested and analyzed 48 hours after drug treatment. The included protocol was tested using the Sircol Collagen Assay kit, and Nintedanib 1uM, a marketed IPF drug, was used as a control drug.
이에 대한 결과를 도 5에 나타내었다.The results for this are shown in FIG. 5 .
도 5에 나타낸 바와 같이, 로미타파이드 및 디곡신 단독 처리군에서도 콜라겐 분비량이 감소하였으며, 병용 처리군에서는 각각의 약물 단독 처리군과 비교해 현저히 향상된 콜라겐 분비량 감소가 확인되었다. 즉, 이들 각각의 약물은 병용 처리에 의해 시너지 효과가 나타나는 것으로 판단되었다. As shown in FIG. 5, the amount of collagen secretion was reduced even in the lomitapide and digoxin alone-treated group, and in the combination-treated group, a significantly improved decrease in collagen secretion was confirmed compared to the respective drug-only treated group. That is, it was determined that each of these drugs exhibited a synergistic effect by the combined treatment.
실시예 4: In vitro 섬유화 억제능 (2)Example 4: In vitro fibrosis inhibitory ability (2)
Cmax 농도(19.89nM)의 로미타파이드와 Cmax 농도(3uM)의 파테놀라이드 각각 단독, 또는 병용투여 하였을 경우 농도의존적 약효를 mRNA 레벨에서 확인하였다. When lomitapide at Cmax concentration (19.89nM) and parthenolide at Cmax concentration (3uM) were administered alone or in combination, concentration-dependent efficacy was confirmed at the mRNA level.
로미타파이드는 각각 ½ Cmax, 그리고 Cmax 농도로 처리하여 Cmax 농도의 파테놀라이드와 병용투여하였다. Lomitapide was treated at ½ Cmax and Cmax concentrations, respectively, and co-administered with Cmax concentration of parthenolide.
구체적으로는, Primary Human Pulmonary Fibroblasts isolated from human lung tissue (구입처: Promo Cell)로 실험하였다. 세포는 5 x 105의 density로 12 well에 seeding하였으며, 섬유화는 recombinant TGF-β를 20ng/mL의 농도로 18hr 처리하여 유발하였다. 각 약물은 TGF-β stimulation 4시간 전에 pre-treat하였으며, 약물 처리 24hr 후에 harvest 하여 fibrosis와 관련 있는 marker gene 중 a-SMA 및 COL1A1 2가지의 발현량 변화와 콜라겐 축적량 변화(sircol collagen assay)를 분석하였다.Specifically, experiments were performed with Primary Human Pulmonary Fibroblasts isolated from human lung tissue (purchased by Promo Cell). Cells were seeded in 12 wells at a density of 5 x 10 5 , and fibrosis was induced by treatment with recombinant TGF-β at a concentration of 20 ng/mL for 18 hr. Each drug was pre-treated 4 hours before TGF-β stimulation, harvested 24 hours after drug treatment, and analyzed the change in the expression level of two marker genes related to fibrosis, a-SMA and COL1A1, and the change in collagen accumulation (sircol collagen assay) did
이에 대한 결과를 도 6 내지 8에 나타내었다. The results for this are shown in Figures 6 to 8.
도 6 내지 8에서 확인할 수 있는 바와 같이, 로미타파이드와 파테놀라이드 병용 처리군은 bliss independence model을 사용하여 계산한 drug combination index에서 1 미만의 수치를 나타내어 각각의 단독 처리군과 비교하여 시너지 효과가 있음이 확인되었다.As can be seen in FIGS. 6 to 8, the lomitapide and parthenolide combined treatment group showed a value of less than 1 in the drug combination index calculated using the bliss independence model, resulting in a synergistic effect compared to each single treatment group It was confirmed that there is
MTP 억제제를 포함하는 본 발명의 조성물은 염증성 자극에 의한 세포 및 조직에서의 콜라겐 축적을 억제하여 섬유화를 예방 또는 치료하는 효과가 매우 탁월하며, 이러한 효과는 파테놀라이드 또는 디곡신과 병용함으로써 시너지 효과가 나타날 수 있어 섬유화 질환 예방 또는 치료제 개발에 매우 유용하게 활용될 수 있어 산업상 이용가능성이 매우 높다. The composition of the present invention containing an MTP inhibitor has a very excellent effect of preventing or treating fibrosis by inhibiting collagen accumulation in cells and tissues caused by inflammatory stimuli, and this effect has a synergistic effect when used in combination with parthenolide or digoxin. Since it can appear, it can be very useful for preventing or developing a treatment for fibrotic disease, so industrial applicability is very high.
Claims (14)
- 마이크로조말 트리글리세라이드 전달 단백질 억제제(microsomal triglyceride transfer protein (MTP) inhibitor)를 유효성분으로 포함하는 섬유화 질환 예방 또는 치료용 약학적 조성물. A pharmaceutical composition for preventing or treating fibrotic disease comprising a microsomal triglyceride transfer protein (MTP) inhibitor as an active ingredient.
- 제1항에 있어서, 상기 MTP 억제제는 로미타파이드(lomitapide), 임플리타파이드(implitapide), 디얼로타파이드(dirlotapide), 미트라타파이드(mitratapide), SLx-4090, CP-346086, CP-346, CP-741952, JTT-130, R-256918 및 이들의 약학적으로 허용가능한 염으로 이루어진 군에서 선택된 것을 특징으로 하는 약학적 조성물. The method of claim 1, wherein the MTP inhibitor is lomitapide, implitapide, dilotapide, mitratapide, SLx-4090, CP-346086, CP-346 , CP-741952, JTT-130, R-256918, and a pharmaceutical composition, characterized in that selected from the group consisting of pharmaceutically acceptable salts thereof.
- 제1항에 있어서, 상기 섬유화 질환은 폐 섬유증, 간 섬유증, 피부 섬유증, 신장 섬유증, 췌장 섬유증, 전신성 경화증 및 심장 섬유증으로 이루어진 군에서 선택되는 것을 특징으로 하는 약학적 조성물. The pharmaceutical composition according to claim 1, wherein the fibrotic disease is selected from the group consisting of pulmonary fibrosis, liver fibrosis, skin fibrosis, kidney fibrosis, pancreatic fibrosis, systemic sclerosis and cardiac fibrosis.
- 제1항에 있어서, 파테놀라이드(Parthenolide), 디곡신(Dogoxin) 및 이들의 약학적으로 허용가능한 염으로 이루어진 군에서 선택된 하나 이상을 추가로 포함하는 것을 특징으로 하는 약학적 조성물. The pharmaceutical composition according to claim 1, further comprising at least one selected from the group consisting of parthenolide, digoxin, and pharmaceutically acceptable salts thereof.
- 제4항에 있어서, 상기 MTP 억제제; 및 디곡신(Dogoxin) 및 이들의 약학적으로 허용가능한 염으로 이루어진 군에서 선택된 하나 이상은 동시에, 개별적으로 또는 순차적으로 병용 투여되는 것을 특징으로 하는 약학적 조성물. The method of claim 4, wherein the MTP inhibitor; And digoxin (Dogoxin) and at least one selected from the group consisting of pharmaceutically acceptable salts thereof are simultaneously, individually or sequentially administered in combination, a pharmaceutical composition characterized in that.
- 제4항에 있어서, 상기 MTP 억제제 및 파테놀라이드는 1:0.01 내지 1000의 몰비로 병용 투여되는 것을 특징으로 하는 약학적 조성물. The pharmaceutical composition according to claim 4, wherein the MTP inhibitor and parthenolide are co-administered in a molar ratio of 1:0.01 to 1000.
- 제4항에 있어서, 상기 MTP 억제제 및 디곡신은 1:0.1 내지 100의 몰비로 병용 투여되는 것을 특징으로 하는 약학적 조성물. The pharmaceutical composition according to claim 4, wherein the MTP inhibitor and digoxin are co-administered in a molar ratio of 1:0.1 to 100.
- 로미타파이드 또는 이의 약학적으로 허용가능한 염; 및 파테놀라이드(Parthenolide), 디곡신(Dogoxin) 및 이들의 약학적으로 허용가능한 염으로 이루어진 군에서 선택된 하나 이상을 유효성분으로 포함하는 섬유화 질환 예방 또는 치료용 약학적 조성물. lomitapide or a pharmaceutically acceptable salt thereof; And Parthenolide (Parthenolide), digoxin (Dogoxin) and a pharmaceutical composition for preventing or treating fibrotic disease comprising at least one selected from the group consisting of pharmaceutically acceptable salts thereof as an active ingredient.
- 섬유화 질환 치료용 조성물을 제조하기 위한 마이크로조말 트리글리세라이드 전달 단백질 억제제(microsomal triglyceride transfer protein (MTP) inhibitor)의 용도.Use of a microsomal triglyceride transfer protein (MTP) inhibitor for preparing a composition for the treatment of fibrotic disease.
- 제9항에 있어서, 상기 MTP 억제제는 로미타파이드(lomitapide), 임플리타파이드(implitapide), 디얼로타파이드(dirlotapide), 미트라타파이드(mitratapide), SLx-4090, CP-346086, CP-346, CP-741952, JTT-130, R-256918 및 이들의 약학적으로 허용가능한 염으로 이루어진 군에서 선택된 것을 특징으로 하는 용도. 10. The method of claim 9, wherein the MTP inhibitor is lomitapide, implitapide, dilotapide, mitratapide, SLx-4090, CP-346086, CP-346 , CP-741952, JTT-130, R-256918 and pharmaceutically acceptable salts thereof.
- 제9항에 있어서, 상기 섬유화 질환은 폐 섬유증, 간 섬유증, 피부 섬유증, 신장 섬유증, 췌장 섬유증, 전신성 경화증 및 심장 섬유증으로 이루어진 군에서 선택되는 것을 특징으로 하는 용도. 10. Use according to claim 9, characterized in that the fibrotic disease is selected from the group consisting of pulmonary fibrosis, liver fibrosis, skin fibrosis, kidney fibrosis, pancreatic fibrosis, systemic sclerosis and cardiac fibrosis.
- 마이크로조말 트리글리세라이드 전달 단백질 억제제(microsomal triglyceride transfer protein (MTP) inhibitor)를 유효성분으로 포함하는 조성물의 유효량을 이를 필요로 하는 개체에 투여하는 것을 포함하는 섬유화 질환 치료 방법.A method for treating fibrotic disease comprising administering an effective amount of a composition comprising a microsomal triglyceride transfer protein (MTP) inhibitor as an active ingredient to a subject in need thereof.
- 제12항에 있어서, 상기 MTP 억제제는 로미타파이드(lomitapide), 임플리타파이드(implitapide), 디얼로타파이드(dirlotapide), 미트라타파이드(mitratapide), SLx-4090, CP-346086, CP-346, CP-741952, JTT-130, R-256918 및 이들의 약학적으로 허용가능한 염으로 이루어진 군에서 선택된 것을 특징으로 하는 방법. 13. The method of claim 12, wherein the MTP inhibitor is lomitapide, implitapide, dilotapide, mitratapide, SLx-4090, CP-346086, CP-346 , CP-741952, JTT-130, R-256918 and pharmaceutically acceptable salts thereof.
- 제12항에 있어서, 상기 섬유화 질환은 폐 섬유증, 간 섬유증, 피부 섬유증, 신장 섬유증, 췌장 섬유증, 전신성 경화증 및 심장 섬유증으로 이루어진 군에서 선택되는 것을 특징으로 하는 방법. 13. The method of claim 12, wherein the fibrotic disease is selected from the group consisting of pulmonary fibrosis, liver fibrosis, skin fibrosis, kidney fibrosis, pancreatic fibrosis, systemic sclerosis and cardiac fibrosis.
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KR20210045400A (en) * | 2017-05-16 | 2021-04-26 | 보우 리버 엘엘씨 | Treatment method using CYP3A4 substrate drugs |
Non-Patent Citations (2)
Title |
---|
ELIZABETH P. NEWBERRY; YAN XIE; SUSAN M. KENNEDY; MARK J. GRAHAM; ROSANNE M. CROOKE; HUI JIANG; ANPING CHEN; DANIEL S. ORY; NICHOL: "Prevention of hepatic fibrosis with liver microsomal triglyceride transfer protein deletion in liver fatty acid binding protein null mice", HEPATOLOGY, JOHN WILEY & SONS, INC., US, vol. 65, no. 3, 19 January 2017 (2017-01-19), US , pages 836 - 852, XP071563152, ISSN: 0270-9139, DOI: 10.1002/hep.28941 * |
SACKS FRANK M., STANESA MAXINE, HEGELE ROBERT A.: "Severe Hypertriglyceridemia With Pancreatitis : Thirteen Years’ Treatment With Lomitapide", JAMA INTERNAL MEDICINE, AMERICAN MEDICAL ASSOCIATION, US, vol. 174, no. 3, 1 March 2014 (2014-03-01), US , pages 443 - 447, XP093070670, ISSN: 2168-6106, DOI: 10.1001/jamainternmed.2013.13309 * |
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