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WO2023101441A1 - Utilisation d'un inhibiteur de protéine de transfert de triglycéride microsomale dans le traitement d'une maladie fibrotique - Google Patents

Utilisation d'un inhibiteur de protéine de transfert de triglycéride microsomale dans le traitement d'une maladie fibrotique Download PDF

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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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fibrosis
inhibitor
mtp
pharmaceutical composition
acid
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Korean (ko)
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김율담
이수민
김정훈
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SK Chemicals Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4353—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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

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

La présente invention concerne une utilisation d'un inhibiteur de protéine de transfert de triglycéride microsomale (MTP) dans le traitement d'une maladie fibrotique et, plus précisément, une nouvelle utilisation d'un inhibiteur de MTP qui présente un effet inhibiteur sur l'accumulation de collagène lié à la fibrose, dans la prévention ou le traitement d'une maladie fibrotique.
PCT/KR2022/019267 2021-11-30 2022-11-30 Utilisation d'un inhibiteur de protéine de transfert de triglycéride microsomale dans le traitement d'une maladie fibrotique Ceased WO2023101441A1 (fr)

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KR20210045400A (ko) * 2017-05-16 2021-04-26 보우 리버 엘엘씨 Cyp3a4 기질 약물을 사용한 치료 방법

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KR20190061027A (ko) * 2016-09-27 2019-06-04 미쓰비시 타나베 파마 코퍼레이션 비-알코올성 지방간 질환의 치료를 위한 약학 조성물 및 방법
KR20210045400A (ko) * 2017-05-16 2021-04-26 보우 리버 엘엘씨 Cyp3a4 기질 약물을 사용한 치료 방법

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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 *

Cited By (2)

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Publication number Priority date Publication date Assignee Title
CN118766941A (zh) * 2024-08-14 2024-10-15 中国药科大学 洛美他派及其组合物在制备治疗肝纤维化的药物中的应用
CN118766941B (zh) * 2024-08-14 2025-11-14 中国药科大学 洛美他派及其组合物在制备治疗肝纤维化的药物中的应用

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