WO2023022522A1 - Préparation complexe pour la prévention ou le traitement de la stéatohépatite, de la stéatose hépatique ou de la fibrose - Google Patents

Préparation complexe pour la prévention ou le traitement de la stéatohépatite, de la stéatose hépatique ou de la fibrose Download PDF

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WO2023022522A1
WO2023022522A1 PCT/KR2022/012301 KR2022012301W WO2023022522A1 WO 2023022522 A1 WO2023022522 A1 WO 2023022522A1 KR 2022012301 W KR2022012301 W KR 2022012301W WO 2023022522 A1 WO2023022522 A1 WO 2023022522A1
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fibrosis
steatohepatitis
steatosis
control group
compound
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PCT/KR2022/012301
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Korean (ko)
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김재선
유형철
임지웅
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제이투에이치바이오텍 주식회사
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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
    • A61K31/395—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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 disclosure relates to a pharmaceutical preparation or kit effective for the treatment or prevention of steatohepatitis, steatosis and/or fibrosis, and to a combination preparation or kit comprising two active ingredients and having improved pharmacological effects. That is, the present disclosure relates to combination therapy.
  • nonalcoholic steatohepatitis shows pathological findings such as ballooning degeneration, cell death, and inflammatory infiltration, and in some cases may show signs of fibrosis such as collagen accumulation. It is well known that non-alcoholic steatohepatitis shows a more rapid histological progression and can progress to cirrhosis, whereas simple steatosis shows a slow histological progression. (Metabolism Clinical and Experimental 65 (2016) 1038-1048).
  • Steatosis is a general term for a disease caused by an abnormality in lipid metabolism, which is distinct from steatohepatitis. Mainly, lipids accumulate in the brain, liver, and spleen, causing dementia, movement disorders, and convulsions.
  • Fibrosis can affect various organs such as the heart, liver, lungs, skeletal muscle, kidneys, blood vessels and heart.
  • fibrosis can be classified into skeletal muscle tissue (dystrophic muscle disease), heart and vascular tissue (myocardial infarction), liver tissue (non-alcoholic fatty liver disease/cirrhosis), lung tissue (idiopathic pulmonary fibrosis), and kidney tissue (chronic kidney disease). /renal fibrosis).
  • renal fibrosis can occur due to a variety of mechanisms including excess matrix synthesis, contraction, and the like.
  • Soma Meran et al. describe a mechanism involving fibroblasts and myofibroblasts in renal fibrosis ("Fibroblasts and myofibroblasts in renal fibrosis" Int J Exp Pathol. 2011 Jun; 92(3): 158-167.).
  • Liver fibrosis refers to excessive accumulation of extracellular matrix proteins, including collagen, that occurs in most chronic liver diseases.
  • Representative cells involved in liver fibrosis include hepatic stellate cells (HSC), Kupffer cells, and endothelial cells.
  • HSC hepatic stellate cells
  • Kupffer cells Kupffer cells
  • endothelial cells hepatic stellate cells
  • Hepatic stellate cells are the main producer of extracellular matrix, and when activated, they change to a myofibroblast-like phenotype, increase cell proliferation, and increase the production of various extracellular matrix including collagen type I and III. , an increase in cell contractility, and the like.
  • Tissue fibrosis defined as excessive accumulation of extracellular matrix (ECM)
  • ECM extracellular matrix
  • the problem to be solved by the present disclosure is to provide a pharmaceutical preparation or kit with a higher treatment, improvement or prevention effect of steatohepatitis, steatosis and/or fibrosis using two or more active ingredients.
  • the problem to be solved by the present disclosure is to provide a combination preparation or kit for treating, improving or preventing steatohepatitis, steatosis and/or fibrosis.
  • Another problem to be solved by the present disclosure is the treatment, amelioration or prevention of steatohepatitis, steatosis and/or fibrosis, comprising simultaneously or sequentially administering therapeutically effective amounts of two or more active ingredients to a subject in need of treatment. is to provide a way
  • the present disclosure provides (i) a pyrimidine-4-carboxamide compound represented by Formula 1 and (ii) fenofibric acid represented by Formula 2 below, a prodrug thereof, or a prodrug thereof, as active ingredients. It provides a pharmaceutical preparation or kit for the treatment or prevention of steatohepatitis, steatosis and/or fibrosis, characterized in that it contains a pharmaceutically acceptable salt.
  • the compound of Formula 1 is a compound developed for prevention and treatment of non-alcoholic steatohepatitis, etc. (Refer to Korean Patent Registration No. 10-2177304).
  • Fenofibric acid, its prodrug (eg, isopropyl ester prodrug Fenofibrate) or its pharmaceutically acceptable salt (eg, choline salt) is a PPAR-alpha activator, and is known as a therapeutic agent for hyperlipidemia and/or dyslipidemia that reduces TG and LDL levels and increases HDL levels by inhibiting the function of apolipoprotein CIII and increasing the function of apolipoprotein AI.
  • the present inventors found that when (i) the compound of formula 1 and (ii) fenofibric acid, its prodrug, or its pharmaceutically acceptable salt (hereinafter referred to as 'fenofibrate-based drug') are used in combination, steatohepatitis , the present invention was completed by confirming that the effect significantly increased in the treatment, prevention or improvement of steatosis and / or fibrosis.
  • the present disclosure also provides a therapeutically or prophylactically effective amount of the compound of Formula 1 and a therapeutically or prophylactically effective amount of a fenofibrate-based drug for the treatment, improvement or prevention of steatohepatitis, steatosis and/or fibrosis.
  • a method for treating, improving or preventing steatohepatitis, steatosis and/or fibrosis characterized by simultaneous, sequential or sequential administration to a subject.
  • the subject includes mammals, and is preferably a human. That is, the present disclosure provides a medical use for the treatment, improvement, or prevention of steatohepatitis, steatosis, and/or fibrosis of the combined preparation or combination therapy according to the present disclosure.
  • the medicinal use for which the combined formulation or combination therapy according to the present disclosure is intended to treat, ameliorate or prevent steatohepatitis is non-alcoholic steatohepatitis. More preferably, the steatohepatitis is non-alcoholic steatohepatitis with liver fibrosis.
  • the medicinal use for which a combined formulation or combination therapy according to the present disclosure is intended to treat, ameliorate or prevent fibrosis is cardiac, liver, pulmonary, skeletal muscle, kidney, vascular, or cardiac fibrosis. More preferably, the fibrosis is liver or pulmonary fibrosis.
  • treatment includes eradication, elimination, or control of steatohepatitis, steatosis, and/or fibrosis, and minimizing or delaying the spread of steatohepatitis, steatosis, and/or fibrosis.
  • prevention includes prevention of recurrence, expansion, or development of steatohepatitis, steatosis, and/or fibrosis in a patient.
  • the compound of Formula 1 may be prepared by the method disclosed in International Patent Application Publication No. WO2011-139107.
  • fenofibrate-based drug is meant to include fenofibric acid, a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • a compound is isolated in the body to produce fenofibric acid, such compound is also included in the fenofibrate-type drugs.
  • prodrugs include biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides. (ureides), and compounds that are biohydrolyzed to yield compounds of the present invention, including biohydrolyzable moieties such as biohydrolyzable phosphate analogues, but are not limited to these specific embodiments.
  • the prodrug of fenofibric acid is a lower alkyl ester of 1 to 4 carbon atoms of a carboxylic acid.
  • Carboxylic esters are commonly formed by esterifying a portion of a carboxylic acid present in a molecule. More preferably, the prodrug of fenofibric acid is febofibrate, an isopropyl ester prodrug.
  • Pharmaceutically acceptable salts of fenofibric acid include those prepared with relatively non-toxic bases.
  • Base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts.
  • the pharmaceutically acceptable salt of fenofibric acid is a choline salt, an ethanolamine salt, a diethanolamine salt, a piperazine salt, a calcium salt, or a tromethamine salt. More preferably, the pharmaceutically acceptable salt of fenofibric acid is a choline salt.
  • compound of Formula 1 or "fenofibrate-based drug” includes not only each compound, but also clathrates, hydrates, solvates, or polymorphs (polymorphs) thereof. it means to
  • polymorph refers to a solid crystal form of a compound of the present invention or a complex thereof. Different polymorphs of the same compound exhibit different physical, chemical and/or spectral properties. Differences in terms of physical properties include, but are not limited to, stability (e.g. heat or light stability), compressibility and density (important for formulation and product manufacturing), and dissolution rate (which may affect bioavailability). It doesn't. Differences in stability may be due to chemical reactivity changes (e.g. differential oxidation such as faster discoloration when composed of one polymorph than when composed of another polymorph) or mechanical properties (e.g.
  • kinetically Tablet fragments stored as the preferred polymorph may be thermodynamically converted to a more stable polymorph) or both (tablets of one polymorph are more susceptible to degradation at high humidity).
  • Other physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form solvates, or may be more difficult to filter or wash, than another polymorph, eg, due to its shape or particle size distribution.
  • solvent compound refers to a compound of the present invention comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents are volatile, non-toxic, and can be administered in very small amounts to humans.
  • hydrate refers to a compound of the present invention that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • clathrate refers to a compound of the present invention in the form of a crystal lattice containing spaces (eg, channels) in which guest molecules (eg, solvent or water) are confined.
  • Each of the compounds of the present invention can be administered by any suitable route in the form of a pharmaceutical composition suitable for such route, and in an effective dosage for the intended treatment.
  • An effective dosage is generally about 0.01 to about 50 mg/kg of body weight/day each, preferably about 0.05 to about 20 mg/kg/day each, in single or divided administration. Dosage levels below the lower end of this range may be suitable depending on the age, species, and disease or condition being treated. In other cases, still larger doses can be used without detrimental side effects. Larger doses may be divided into several smaller doses for administration throughout the day. Methods for determining the appropriate dosage are well known in the art.
  • “approximately” or “about” means having a range of variation of ⁇ 20%, preferably ⁇ 10% based on the numerical value.
  • the compound of Formula 1, which is the first active ingredient, and the fenofibrate-based drug, which is the second active ingredient, of the present invention may be administered simultaneously (in the same formulation or in separate formulations) or sequentially.
  • either of the two active ingredients can be given in multiple doses, or both can be given in multiple doses. If not simultaneous, the timing between multiple doses may vary arbitrarily from greater than 0 weeks to less than 20 weeks.
  • combination methods, compositions and formulations are not limited to the use of only two agents, and multiple therapeutic combinations are also envisioned.
  • a dosage regimen for treating, preventing, or ameliorating a condition may be arbitrarily changed depending on various factors. These factors include the individual's age, weight, sex, diet, and medical condition, as well as the disorder the individual suffers from.
  • the pharmaceutical agents that make up the combination therapy disclosed herein are optionally combined formulations or primarily separate formulations for simultaneous administration.
  • the pharmaceutical agents constituting the combination treatment may also be administered sequentially with either agent being administered by a regimen requiring two-step administration.
  • a two-step dosing regimen may require sequential administration of the active agents or spaced-apart administration of separate active agents.
  • the time period between multiple administration steps ranges from a few minutes to a few minutes depending on the characteristics of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the pharmaceutical agent. up to several hours Circadian variation in target molecule concentration is used to determine the optimal dosing interval.
  • the two active ingredients according to the present disclosure may be included in one formulation, or the two active ingredients may be included in separate formulations and taken together. That is, one aspect of the present disclosure provides a pharmaceutical formulation comprising the compound of Formula 1, a fenofibrate-based drug, and a pharmaceutically acceptable carrier or additive. Another aspect of the present disclosure includes a first pharmaceutical formulation comprising a compound of Formula 1 and a pharmaceutically acceptable carrier or additive, and a second pharmaceutical formulation comprising a fenofibrate-based drug, and a pharmaceutically acceptable carrier or additive
  • a kit that
  • pharmaceutically acceptable means suitable for use as a pharmaceutical preparation, generally considered safe for such use, and officially approved for such use by a national regulatory agency or approved by the Korean Pharmacopoeia or the United States Means in the pharmacopeia list.
  • the compound of Formula 1 and/or the fenofibrate-based drug described herein can be administered as follows.
  • the compound(s) of the present invention can be administered orally, which is a concept that includes swallowing. Oral administration allows the compound(s) of the present invention to enter the gastrointestinal tract or be directly absorbed from the mouth into the bloodstream, eg, by buccal or sublingual administration.
  • compositions suitable for oral administration may be in solid, liquid, gel, or powder form, and may have formulations such as tablets, lozenges, capsules, granules, powders, and the like. .
  • compositions for oral administration may optionally be enteric coated and exhibit delayed or sustained release through the enteric coating. That is, the composition for oral administration according to the present invention may be a formulation having an immediate or modified release pattern.
  • Liquid formulations may include solutions, syrups and suspensions, and such liquid compositions may be contained in soft or hard capsules.
  • Such formulations may include a pharmaceutically acceptable carrier such as water, ethanol, polyethylene glycol, cellulose, or oil.
  • the formulation may also contain one or more emulsifying and/or suspending agents.
  • the amount of active ingredient drug may be present from about 0.05% to about 95% by weight, more typically from about 2% to about 50% by weight of the total weight of the tablet.
  • Tablets may also contain a disintegrant comprising from about 0.5% to about 35% by weight, more usually from about 2% to about 25% by weight of the dosage form.
  • disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.
  • Suitable glidants included for making into tablets may be present in amounts from about 0.1% to about 5% by weight, and include talc, silicon dioxide, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, and the like. It can be used as a lubricant, but the present invention is not limited to these types of additives.
  • Gelatin polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. may be used as a binder for preparing tablets.
  • Mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc. may be used as suitable diluents for preparing tablets, but the present invention is not limited to these types of additives. .
  • the solubilizing agent that may optionally be included in the tablet may be used in an amount of about 0.1% to about 3% by weight based on the total weight of the tablet, for example, polysorbate, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, Diethylene glycol monoethyl ether, dimethylisosorbide, polyoxyethylene glycolated natural or hydrogenated castor oil, HCOR TM (Nikkol), oleyl ester, Gelucire TM , caprylic/caprylic mono/ Diglyceride, sorbitan fatty acid ester, Solutol HS TM and the like may be used in the pharmaceutical composition according to the present invention, but the present invention is not limited to specific types of these solubilizers.
  • the compound(s) of the present invention can be administered directly into the blood stream, muscle, or intestine.
  • Suitable methods for parenteral administration include intravenous, intramuscular, subcutaneous intraarterial, intraperitoneal, intrathecal, intracranial injection, and the like.
  • Suitable devices for parenteral administration include injectors (including needle and needleless syringes) and infusion methods.
  • compositions for parenteral administration may be formulations with an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.
  • parenteral formulations are liquid compositions, and these liquid compositions are aqueous solutions containing the active ingredient, salt, buffer, tonicity agent and the like according to the present invention.
  • Parenteral formulations may also be prepared in dried form (eg lyophilized) or as sterile non-aqueous solutions. These formulations may be used with a suitable vehicle such as sterile water. Solubility-enhancing agents may also be used in the preparation of parenteral solutions.
  • the compound(s) of the present invention may be administered topically to the skin or transdermally.
  • Formulations for this topical administration include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, and the like.
  • Pharmaceutically acceptable carriers for topical formulations may include water, alcohol, mineral oil, glycerin, polyethylene glycol, and the like. Topical administration can also be performed by electroporation, iontophoresis, phonophoresis, and the like.
  • compositions for topical administration may be formulations with an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.
  • the present invention can exhibit better therapeutic or preventive effects on steatohepatitis, steatosis and/or fibrosis by administering the two active ingredients together.
  • the combination of active ingredients according to the present invention has synergistically significantly increased therapeutic effects in the treatment or prevention of steatohepatitis, steatosis and/or fibrosis.
  • G2 Vehicle control (AMLN diet control)
  • G3 Positive control (Obeticholic acid) 30 mg/kg/day
  • G4 Fenofibrate 40 mg/kg/day + Formula 1 Compound 10 mg/kg/day
  • G5 Formula 1 compound 3 mg/kg/day
  • G6 Formula 1 compound 10 mg/kg/day
  • G7 20 mg/kg/day of a compound of Formula 1.
  • Figure 1 shows the change in body weight of each group during the 12-week test substance administration period in the non-alcoholic steatohepatitis disease model. ####: There is a significant difference at p ⁇ 0.0001 level compared to G1. ****/***/**/*: There is a significant difference at the p ⁇ 0.0001/p ⁇ 0.001/p ⁇ 0.01/p ⁇ 0.05 level, respectively, compared to G2.
  • Figure 2 shows the ratio of liver weight to body weight in each group. ####: There is a significant difference at p ⁇ 0.0001 level compared to G1. **/*: There is a significant difference at the p ⁇ 0.01/p ⁇ 0.05 level, respectively, compared to G2.
  • NAS NAFLD activity score
  • Example 1 Disease induction and administration in non-alcoholic steatohepatitis treatment model
  • a non-alcoholic steatohepatitis animal model AMLN (Amylin Liver NASH) model
  • test substance was repeatedly administered for 12 weeks to a non-alcoholic steatohepatitis C57BL/6N mouse model induced over 30 weeks by AMLN diet.
  • Test substances were administered once daily for 12 weeks.
  • fenofibrate a lipid-lowering agent that reduces blood cholesterol and triglycerides.
  • obeticholic acid which is currently undergoing phase 3 clinical trials, was used as an indication for non-alcoholic steatohepatitis.
  • test substance compound of Formula 1
  • concomitant substance Frazier, fetal sulfate
  • positive control substance Optase
  • Appropriate amounts of the test substance (compound of Formula 1), concomitant substance (Fenofibrate), and positive control substance (Obeticholic acid) were weighed and diluted in a 0.5 weight % methylcellulose aqueous solution to which 1 weight % Tween 80 was added and administered. During oral administration, the body weight of the animal was measured to determine the administered dose of the test substance.
  • the dose and frequency of substance administration for each group were as follows.
  • G3 AMLN diet fed group, obeticholic acid 30 mg/kg/day
  • G4 AMLN diet fed group, fenofibrate 40 mg/kg/day + Formula 1 compound 10 mg/kg/day
  • G5 AMLN diet fed group, Formula 1 compound 3 mg/kg/day
  • G6 AMLN diet fed group, Formula 1 compound 10 mg/kg/day
  • G7 AMLN diet fed group, Formula 1 compound 20 mg/kg/day
  • Example 2 Observation and test items in non-alcoholic steatohepatitis treatment model
  • test substance On the day of autopsy, after fasting for 4 hours, the test substance was administered and blood was collected 1 hour later. The separated serum was examined for the following items using an Erba EM360 clinical chemistry analyzer.
  • Test items TG (Triglyceride), TC (Total cholesterol), Glucose, ALT (Alanine transaminase), AST (Aspartate transaminase), HDL (Higy-density lipoprotein), LDL (Low-density lipoprotein)
  • pimonidazole was diluted in saline at a concentration of 30 mg/ml and administered intravenously at a dose of 60 mg/kg. Animals were euthanized 90 minutes after dosing. At each necropsy point, the animals were inhaled anesthetized with ether. When anesthesia was confirmed, blood was collected using a syringe from the posterior vena cava by laparotomy. Thereafter, the abdominal aorta and posterior vena cava were severed and sacrificed by exsanguination. Blood was injected into a vacutainer tube containing a clot activator and left at room temperature for about 15 minutes to coagulate. Thereafter, serum was separated by centrifugation at 3,000 rpm for 10 minutes. Serum was stored in a deep freezer set at -70 ° C or lower until analysis, and used for blood biochemical tests.
  • the liver was removed and weighed, and a part of the left lobe of the liver was fixed in 10% neutral buffered formalin solution. The remaining left lobe of the liver was stained with Oil-Red-O. A part of the right lobe of the liver was flash-frozen using liquid nitrogen and stored in an ultra-low temperature freezer, and the rest of the right lobe of the liver was stored in RNA Later.
  • the fixed tissue was prepared as a specimen for histopathological examination through general tissue processing procedures such as trimming, dehydration, paraffin embedding, and cutting. After that, Oil-Red-O, Hematoxylin & Eosin (H&E), and Sirius red staining were performed.
  • general tissue processing procedures such as trimming, dehydration, paraffin embedding, and cutting.
  • Oil-Red-O, Hematoxylin & Eosin (H&E), and Sirius red staining were performed.
  • the gene expression of the following items was analyzed through QRT-PCR using a TaqMan probe with liver tissue stored in RNA Later.
  • Figure 1 shows the change in body weight of each group during the 12-week test substance administration period in the non-alcoholic steatohepatitis disease model.
  • the body weight level of the AMLN diet control group (G2) was significantly higher than that of the normal control group (G1) (p ⁇ 0.0001).
  • the combination administration group (G4) and Formula 1 Compound 3 mg/kg alone administration group (G5) showed significant weight loss compared to the AMLN diet control group (G2).
  • Figure 2 shows the ratio of liver weight to body weight in each group.
  • the liver weight/body weight ratio of the AMLN diet control group (G2) was significantly higher by 42% compared to that of the normal control group (G1) (p ⁇ 0.0001).
  • the groups (G5-G7) administered with 3, 10, and 20 mg/kg of the compound of Formula 1 alone a significant decrease was shown by 18, 20, and 20%, respectively, compared to the AMLN diet control group (G2) (p ⁇ 0.01).
  • the positive control group (G3) showed a significant decrease of about 18% compared to the AMLN diet control group (G2) (p ⁇ 0.05).
  • the TG, TC, ALT, AST, HDL, and LDL levels of the AMLN diet control group (G2) after administration of the test substance for 12 weeks were significantly higher than those of the normal control group (G1).
  • the levels of TG, TC, Glucose, ALT, AST, HDL and LDL in the combined administration group (G4) were significantly decreased compared to the AMLN diet control group (G2), and in the group administered alone with Formula 1 compound (G5-G7), TG, TC, ALT, AST and LDL levels were significantly decreased compared to the AMLN diet control group (G2).
  • the levels of TG, TC, ALT, AST, HDL and LDL in the positive control group (G3) were significantly decreased compared to the AMLN diet control group (G2).
  • TG Triglyceride
  • the TG level of the AMLN diet control group (G2) was significantly higher by 47% compared to the normal control group (G1) (p ⁇ 0.001). 56 (p ⁇ 0.0001), 34 (p ⁇ 0.001), 39 (p ⁇ 0.0001) and 37 (p ⁇ 0.001) %.
  • the positive control group (G3) there was a significant decrease of about 45% compared to the AMLN diet control group (G2) (p ⁇ 0.0001).
  • TC 4 is a result of measuring total cholesterol (TC).
  • the TC level of the AMLN diet control group (G2) was significantly higher by 193% compared to the normal control group (G1) (p ⁇ 0.0001).
  • the positive control group (G3) showed a significant decrease of about 57% compared to the AMLN diet control group (G2) (p ⁇ 0.0001).
  • the combination administration group (G4) showed a significant decrease of about 42% compared to the AMLN diet control group (G2) (p ⁇ 0.001).
  • ALT Alanine transaminase measurement results.
  • the ALT level of the AMLN diet control group (G2) was significantly higher by 866% compared to the normal control group (G1) (p ⁇ 0.0001).
  • the positive control group (G3) showed a significant decrease of about 47% compared to the AMLN diet control group (G2) (p ⁇ 0.01).
  • AST Aspartate transaminase measurement result.
  • the AST level of the AMLN diet control group (G2) was significantly higher by 267% compared to the normal control group (G1) (p ⁇ 0.0001).
  • G4 and Formula 1 Compound 20 mg/kg alone administration group (G7) significant decreases were shown by 60 (p ⁇ 0.001) and 36 (p ⁇ 0.05) %, respectively, compared to the AMLN diet control group (G2).
  • G3 positive control group
  • HDL High-density lipoprotein
  • LDL Low-density lipoprotein
  • the LDL level of the AMLN diet control group (G2) was significantly higher by 177% compared to the normal control group (G1) (p ⁇ 0.0001). 51 (p ⁇ 0.0001), 31 (p ⁇ 0.01), and 35 (p ⁇ 0.001), respectively, compared to the AMLN diet control group (G2) in the combined administration group (G4) and Formula 1 Compound 10, 20 mg/kg alone administration group (G6-G7) ) showed a significant decrease of about %.
  • the positive control group (G3) showed a significant decrease of about 58% compared to the AMLN diet control group (G2) (p ⁇ 0.0001).
  • the Steatosis level, NAS (NAFLD activity score) level, degree of collagen deposition, and degree of fibroblast staining of the AMLN diet control group (G2) were significantly higher than those of the normal control group (G1). .
  • Steatosis level, NAS level, degree of collagen deposition, and degree of fibroblast staining were significantly decreased in the combined administration group (G4) and the compound administration group of Formula 1 alone (G5-G7) compared to the AMLN diet control group (G2).
  • Steatosis and NAS levels in the positive control group (G3) were significantly decreased compared to the AMLN diet control group (G2).
  • the steatosis score of the AMLN diet control group (G2) was significantly higher by about 400% compared to the normal control group (G1) (p ⁇ 0.0001). 57 (p ⁇ 0.0001), 20 (p ⁇ 0.05), 47 (p ⁇ 0.05), 47 (p ⁇ 0.0001) and 43 (p ⁇ 0.0001) %. In the positive control group (G3), there was a significant decrease of about 33% compared to the AMLN diet control group (G2) (p ⁇ 0.001).
  • NAS NAFLD activity score
  • the NAS level of the AMLN diet control group (G2) was significantly higher by 88% compared to the normal control group (G1) (p ⁇ 0.0001). 47 (p ⁇ 0.0001), 20 (p ⁇ 0.01), and 33 (p ⁇ 0.0001), respectively, compared to the AMLN diet control group (G2) in the combined administration group (G4) and Formula 1 Compound 10 and 20 mg/kg alone administration groups (G6-G7) ) showed a significant decrease of about %.
  • the positive control group (G3) showed a significant decrease of about 27% compared to the AMLN diet control group (G2) (p ⁇ 0.0001).
  • the degree of collagen deposition in the AMLN diet control group (G2) was significantly higher by 398% compared to the normal control group (G1) (p ⁇ 0.0001).
  • the combination administration group (G4) and Formula 1 Compound 20 mg/kg alone administration group (G7) significant reductions were shown by 71 (p ⁇ 0.0001) and 59 (p ⁇ 0.001) %, respectively, compared to the AMLN diet control group (G2).
  • FIG. 13 is a result of measuring the specific gravity of fibroblasts in liver tissue using immunohistochemical staining.
  • G2 the degree of staining of ER-TR7, a marker of fibroblasts, was significantly higher by 76% compared to that in the normal control group (G1) (p ⁇ 0.0001). 55 (p ⁇ 0.0001), 34 (p ⁇ 0.05), 33 (p ⁇ 0.05) and 43 (p ⁇ 0.01) %.
  • TIMP-1 and collagen type 1 gene expressions in the AMLN diet control group were normal after 12 weeks of test substance administration. It was significantly higher than the control group (G1).
  • the expression of TIMP-1 and collagen type 1 genes in the combination administration group (G4) was significantly decreased compared to the AMLN diet control group (G2).
  • TIMP-1 gene expression was significantly decreased in the group administered with Compound 1 alone (G5-G7) compared to the AMLN diet control group (G2).
  • TIMP-1 gene expression in the positive control group (G3) was significantly decreased compared to AMLN diet (G2).
  • TIMP-1 is known to be involved in various fibrosis including pulmonary fibrosis (Matrix Biology, Volumes 44-46, May-July 2015, Pages 247-254; Int J Immunopathol Pharmacol Jul-Sep 2006, 19(3), 471-487).
  • TIMP-1 gene 14 is a result of analyzing the expression of the TIMP-1 gene.
  • the expression of TIMP-1 gene in the AMLN diet control group (G2) was significantly increased by 30.8 times compared to the normal control group (G1) (p ⁇ 0.0001). 4.6 (p ⁇ 0.0001), 8.1 (p ⁇ 0.001), and 7.8 (p ⁇ 0.001), respectively, compared to the normal control group (G1) in the combination administration group (G4) and Formula 1 Compound 10, 20 mg/kg alone administration group (G6-G7)
  • the fold level showed a significant decrease compared to the AMLN diet control group (G2).
  • the positive control group (G3) showed a significant decrease compared to the AMLN diet control group (G2) by 12.2 times that of the normal control group (G1) (p ⁇ 0.01).

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Abstract

La présente divulgation concerne une préparation pharmaceutique pour le traitement ou la prévention de la stéatohépatite, de la stéatose et/ou de la fibrose, contenant deux principes actifs. La présente divulgation concerne une préparation complexe. La présente divulgation concerne également une polythérapie. La présente divulgation est basée sur le fait que deux principes actifs sont utilisés en association de telle sorte que les effets du traitement ou de la prévention de la stéatohépatite, de la stéatose et/ou de la fibrose peuvent être augmentés de manière synergique.
PCT/KR2022/012301 2021-08-18 2022-08-17 Préparation complexe pour la prévention ou le traitement de la stéatohépatite, de la stéatose hépatique ou de la fibrose WO2023022522A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070197606A1 (en) * 2006-02-22 2007-08-23 Burczynski Frank J Use of ppar agonists as anti-oxidants
WO2008040548A2 (fr) * 2006-10-04 2008-04-10 Ares Trading S.A. Traitement pour l'hépatite stéatosique non alcoolique
KR20110123657A (ko) * 2010-05-07 2011-11-15 에스케이케미칼주식회사 피콜린아마이드 및 피리미딘-4-카복사미드 화합물, 이의 제조방법 및 이를 함유하는 약제학적 조성물
US20190134041A1 (en) * 2017-10-06 2019-05-09 Gilead Sciences, Inc. Combination therapy comprising an acc inhibitor
US20190247343A1 (en) * 2016-04-15 2019-08-15 Gencod Use of fenofibric acid in the treatment of hepatic diseases
KR102177304B1 (ko) * 2018-07-23 2020-11-10 제이투에이치바이오텍 (주) 비알콜성 지방간염의 예방 또는 치료용 약학 조성물

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070197606A1 (en) * 2006-02-22 2007-08-23 Burczynski Frank J Use of ppar agonists as anti-oxidants
WO2008040548A2 (fr) * 2006-10-04 2008-04-10 Ares Trading S.A. Traitement pour l'hépatite stéatosique non alcoolique
KR20110123657A (ko) * 2010-05-07 2011-11-15 에스케이케미칼주식회사 피콜린아마이드 및 피리미딘-4-카복사미드 화합물, 이의 제조방법 및 이를 함유하는 약제학적 조성물
US20190247343A1 (en) * 2016-04-15 2019-08-15 Gencod Use of fenofibric acid in the treatment of hepatic diseases
US20190134041A1 (en) * 2017-10-06 2019-05-09 Gilead Sciences, Inc. Combination therapy comprising an acc inhibitor
KR102177304B1 (ko) * 2018-07-23 2020-11-10 제이투에이치바이오텍 (주) 비알콜성 지방간염의 예방 또는 치료용 약학 조성물

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