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WO2022114459A1 - Composition pharmaceutique destinée à prévenir ou à traiter une fibrose d'organe, comprenant du fumarate de monométhyle en tant que principe actif - Google Patents

Composition pharmaceutique destinée à prévenir ou à traiter une fibrose d'organe, comprenant du fumarate de monométhyle en tant que principe actif Download PDF

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Publication number
WO2022114459A1
WO2022114459A1 PCT/KR2021/011365 KR2021011365W WO2022114459A1 WO 2022114459 A1 WO2022114459 A1 WO 2022114459A1 KR 2021011365 W KR2021011365 W KR 2021011365W WO 2022114459 A1 WO2022114459 A1 WO 2022114459A1
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WO
WIPO (PCT)
Prior art keywords
fibrosis
pharmaceutical composition
monomethyl fumarate
disease
cells
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Ceased
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PCT/KR2021/011365
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English (en)
Korean (ko)
Inventor
오창주
김명화
표정인
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Curacle Co Ltd
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Curacle Co Ltd
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Publication of WO2022114459A1 publication Critical patent/WO2022114459A1/fr
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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/30—Other Organic compounds

Definitions

  • It relates to a pharmaceutical composition for preventing or treating organ fibrosis comprising monomethyl fumarate as an active ingredient.
  • Fibrosis is a disease characterized by excessive deposition of connective tissue proteins involving abnormal extracellular matrix metabolism in organs such as skin, lung, heart, liver, and kidney. Fibrosis can lead to a decrease in healthy cells in any organ or tissue and an increase in the mass of fibrotic connective tissue, which in turn can damage the normal structure of the organ or tissue. Such damage can impair the physiological and biochemical functions of the affected organ or tissue, and can result in complete failure of the organ. Pathology, diagnostic methods, prevention and treatment methods for organ and tissue fibrosis have been extensively studied. However, there are still many challenges, particularly in the field of development of effective therapeutic agents.
  • TGF- ⁇ transforming growth factor-beta
  • ECM quiescent extracellular matrix
  • TGF- ⁇ transforming growth factor-beta
  • One object of the present invention is to provide a pharmaceutical composition comprising monomethyl fumarate (MMF) effective for the prevention or treatment of organ fibrosis.
  • MMF monomethyl fumarate
  • Another object of the present invention is to provide a health functional food composition comprising monomethyl fumarate, which is effective in preventing or improving organ fibrosis.
  • the present invention provides a pharmaceutical composition for preventing or treating organ fibrosis comprising monomethyl fumarate (MMF) as an active ingredient.
  • MMF monomethyl fumarate
  • the present invention provides a health functional food composition for preventing or improving organ fibrosis comprising monomethyl fumarate as an active ingredient.
  • the present invention provides a method for treating organ fibrosis, comprising administering monomethyl fumarate to a subject or subject in need thereof.
  • the invention also provides monomethylfumarate for use in the treatment of organ fibrosis.
  • the invention also provides the use of said monomethyl fumarate for use in the manufacture of a medicament for the treatment of organ fibrosis.
  • the pharmaceutical composition for the prevention or treatment of organ fibrosis comprising monomethyl fumarate of the present invention as an active ingredient has an effect of excellently inhibiting the expression of collagen I and extracellular matrix components in cells, thus preventing or treating organ fibrosis. effective in treatment.
  • Example 1 is a view showing a Western blot result confirming the effect of reducing the collagen I expression of Example 1 in SV40 MES 13 cells, which are mouse kidney-derived mesangial cells.
  • FIG. 2 is a graph showing the results of analyzing the collagen I expression of Example 1 in SV40 MES 13 cells, which are mouse kidney-derived mesangial cells.
  • FIG. 3 is a view showing the Western blot results confirming the effect of reducing the expression of ⁇ -SMA, PAI-1, collagen I of Example 1 in NRK-49F cells, which are rat-derived renal fibroblast cells.
  • NRK-49F cells which are rat-derived renal fibroblast cells.
  • NRK-49F cells which are rat-derived renal fibroblast cells.
  • Example 6 is a graph showing the results of analyzing the collagen I expression of Example 1 in NRK-49F cells, which are rat-derived renal fibroblast cells.
  • the present invention provides a pharmaceutical composition for preventing or treating organ fibrosis comprising monomethyl fumarate (MMF) as an active ingredient.
  • MMF monomethyl fumarate
  • Monomethyl fumarate can be purchased by a general method or obtained by synthesizing it by a conventionally known method.
  • the monomethyl fumarate has an effect of reducing collagen I expression in cells.
  • the present invention showed that collagen I expression was significantly increased by monomethyl fumarate in SV40 MES 13 cells, which are mouse kidney-derived mesangial cells, and NRK-49F cells, which are rat-derived renal fibroblast cells, through experiments. It was confirmed that it was inhibited and decreased to the control level.
  • the monomethyl fumarate has an effect of reducing the expression of ⁇ -SMA (alpha-smooth muscle actin) or PAI-1 (plasminogen activator inhibitor 1) in cells.
  • ⁇ -SMA alpha-smooth muscle actin
  • PAI-1 plasmaogen activator inhibitor 1
  • the expression of extracellular matrix components, ⁇ -SMA and PAI-1 was significantly inhibited by monomethyl fumarate in NRK-49F cells, which are rat-derived renal fibroblast cells, through an experiment. ) was confirmed to decrease to the level.
  • the pharmaceutical composition comprising monomethyl fumarate according to the present invention as an active ingredient is effective for preventing or treating organ fibrosis.
  • the organ fibrosis is at least one selected from the group consisting of renal fibrosis, cardiac fibrosis, pancreatic fibrosis, pulmonary fibrosis, vascular fibrosis, skin fibrosis, bone marrow fibrosis, liver fibrosis, scleroderma, cystic fibrosis, pancreatic fibrosis and intestinal fibrosis;
  • the renal fibrosis is at least one selected from the group consisting of renal failure, diabetic nephropathy, glomerulosclerosis, renal tubular fibrosis, glomerulonephritis, chronic renal failure, acute renal injury, chronic kidney disease, end-stage renal disease, and albuminuria
  • the liver fibrosis is cirrhosis, hepatic nephrotic syndrome, hepatic purpura, metabolic liver disease, chronic liver disease, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomia
  • the pharmaceutical composition comprising monomethyl fumarate according to the present invention as an active ingredient is a neurodegenerative disease, psoriasis, polyarthritis, juvenile diabetes, Hashimoto's disease, Grave's disease, systemic lupus erythematosus, Sjogren's syndrome, It may also be effective in the prevention or treatment of pernicious anemia, chronic active hepatitis, lupus-like hepatitis, rheumatoid arthritis or optic neuritis.
  • the monomethyl fumarate effective for the prevention or treatment of organ fibrosis according to the present invention may be used in the form of a pharmaceutically acceptable formulation.
  • the monomethyl fumarate may be administered in various oral and parenteral formulations during clinical administration.
  • formulation it is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in one or more compounds, for example, starch, calcium carbonate, sucrose or lactose ( lactose), gelatin, etc.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid formulations for oral administration include suspensions, solutions, emulsions, syrup medium-chain triglycerides, castor oil, hydrogenated castor oil, polyoxy 35 hydrogenated castor oil, polyoxy 40 hydrogenated castor oil, monodiglyceride, etc.
  • various excipients for example, wetting agents, sweetening agents, fragrances, preservatives, and the like may be included.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, and emulsions.
  • Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • the pharmaceutical composition containing monomethyl fumarate as an active ingredient may be administered parenterally, and parenteral administration is performed by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
  • the monomethyl fumarate in order to formulate a formulation for parenteral administration, may be mixed with water together with a stabilizer or buffer to prepare a solution or suspension, which may be prepared in an ampoule or vial unit dosage form.
  • the composition may be sterilized and/or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts and/or buffers for regulating osmotic pressure, and other therapeutically useful substances, and mixing, granulation, in the usual manner It can be formulated according to the method of formulation or coating.
  • Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc. , dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine and the like, and optionally starch, agar, alginic acid or sodium salt thereof, etc. It may contain releasing or boiling mixtures and/or absorbents, colorants, flavoring agents, and sweetening agents.
  • binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine and
  • the present invention provides a health functional food composition for preventing or improving organ fibrosis comprising monomethyl fumarate (MMF) as an active ingredient.
  • MMF monomethyl fumarate
  • the monomethyl fumarate according to the present invention may be added to food as it is or used together with other food or food ingredients, and may be appropriately used according to a conventional method.
  • the mixing amount of the active ingredient may be suitably determined according to the purpose of its use (for prevention or improvement).
  • the amount of the compound in the health food may be added in an amount of 0.1 to 90 parts by weight based on the total weight of the food.
  • the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
  • the health functional beverage composition of the present invention is not particularly limited in other ingredients other than containing the compound as an essential ingredient in the indicated ratio, and may contain various flavoring agents or natural carbohydrates as additional ingredients like a conventional beverage.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents taumatin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
  • the proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.
  • monomethyl fumarate according to the present invention contains various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and fillers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
  • Proteins were separated on a 10-12% SDS-polyacrylamide gel and transferred to PVDF membranes (Millipore, County Cork, Ireland).
  • Antibodies are collagen I (Abcam, Cambridge, MA, USA), ⁇ -SMA ( ⁇ -smooth muscle actin, Abcam), PAI-1 (BD science, USA), and GAPDH (Cell Signaling Technology, Beverly, MA, USA) was used.
  • Each Western blot data was expressed as a relative number using the Image J program (NIH, USA).
  • SV40 MES 13 cells which are mouse kidney-derived mesangial cells, were purchased from ATCC (Manassas, VA, USA), 5% fetal bovine serum (FBS, Hyclone, Logan, UT, USA) and antibiotics (100 units/ml penicillin, 100 units/ml penicillin, Gibco, Grand Island, NY, USA) was cultured in DMEM (high glucose, Gibco) medium.
  • ATCC Manassas, VA, USA
  • FBS Hyclone, Logan, UT, USA
  • antibiotics 100 units/ml penicillin, 100 units/ml penicillin, Gibco, Grand Island, NY, USA
  • DMEM high glucose, Gibco
  • Example 1 For an experiment to confirm the effect of inhibiting collagen I expression in SV40 MES 13 cells by the pharmaceutical composition comprising monomethyl fumarate according to Example 1, a low glucose treatment group (LG, 5.5 mM glucose) as an experimental group, Cells were prepared in a total of 5 groups in which Example 1 was treated with 40, 60, and 80 ⁇ M, respectively, in the high glucose treatment group (HG, 30 mM glucose) and the high glucose treatment group.
  • LG low glucose treatment group
  • HG high glucose treatment group
  • SV40 MES 13 cells were cultured in DMEM (low glucose, Gibco) supplemented with 5% FBS in 1.5 X 10 5 cells in a 60 mm culture dish. After 24 hours of cell culture, the cells were further cultured in DMEM (low glucose, Gibco) containing 0.5% FBS for 24 hours. The next day, 24.5 mM of mannitol was further added to the low-glucose-treated group (LG) to achieve osmotic balance, and 5 mM glucose was further added to the high-glucose-treated group (HG) to obtain 30 mM glucose. The medium was treated with Example 1 for each concentration.
  • the cells were scraped after 48 hours, washed once with 1xPBS (Gibco), and stored in a -70°C freezer until the experiment.
  • the experimental methods 1. Western blot and 2.
  • Statistical analysis were used to analyze the results, and the results are shown in FIGS. 1 and 2 .
  • Example 1 As a result of confirming whether the expression of collagen I was reduced after treatment of Example 1 with high glucose in SV40 MES 13 cells, which are mouse kidney-derived mesenteric cells, monomethyl fumarate was effective as shown in FIGS. 1 and 2 . It was confirmed that the concentration-dependent decrease in collagen I expression of Example 1 included as a component (FIG. 2, *p ⁇ 0.01 vs LG; **p ⁇ 0.05, ***p ⁇ 0.01 vs HG).
  • NRK-49F cells a rat-derived renal fibroblast cell, were purchased from ATCC (Manassas, VA, USA), 5% fetal bovine serum (FBS, Hyclone, Logan, UT, USA) and antibiotics ( It was cultured in DMEM (high glucose, Gibco) medium supplemented with 100 units/ml penicillin, 100 units/ml penicillin, Gibco, Grand Island, NY, USA).
  • ATCC Manassas, VA, USA
  • FBS fetal bovine serum
  • FBS Hyclone, Logan, UT, USA
  • antibiotics It was cultured in DMEM (high glucose, Gibco) medium supplemented with 100 units/ml penicillin, 100 units/ml penicillin, Gibco, Grand Island, NY, USA).
  • test group was a control group, a TGF- ⁇ (5 ng/ml) treatment group, and a total of 5 samples treated with 40, 60, and 80 ⁇ M of Example 1 in TGF- ⁇ , respectively.
  • Cells were prepared in groups.
  • NRK-49F cells were cultured in DMEM (high glucose, Gibco) supplemented with 5% FBS in 4 X 10 5 cells in a 60 mm culture dish. After 24 hours of cell culture, the cells were further cultured for 16 hours in DMEM (high glucose, Gibco) containing 0.5% FBS. The next day, while replacing the medium with DMEM (high glucose, Gibco) containing 0.5% FBS, Example 1 was treated by concentration. After 1 hour, TGF- ⁇ (5 ng/ml) was treated and 48 hours later, the cells were scraped, washed once with 1xPBS (Gibco), and stored in a -70 degree freezer until the experiment.
  • DMEM high glucose, Gibco
  • TGF- ⁇ 5 ng/ml
  • the pharmaceutical composition comprising monomethyl fumarate of Example 1 according to the present invention as an active ingredient can significantly reduce the expression of collagen I and extracellular matrix components in cells, It was confirmed that the pharmaceutical composition of 1 has an excellent effect in preventing or treating organ fibrosis.
  • the monomethyl fumarate according to the present invention can be formulated in various forms depending on the purpose.
  • the following exemplifies some formulation methods containing the monomethyl fumarate as an active ingredient according to the present invention, but the present invention is not limited thereto.
  • the above ingredients are mixed and filled in an airtight bag to prepare a powder.
  • tablets are prepared by tableting according to a conventional manufacturing method of tablets.
  • the above ingredients are mixed and filled in a gelatin capsule to prepare a capsule.
  • the content of the above ingredients per 1 ampoule (2 ml) is prepared.
  • each component is added to purified water to dissolve, an appropriate amount of lemon flavor is added, the above components are mixed, purified water is added, the whole is adjusted to 100 ml by adding purified water, and then filled in a brown bottle. Sterilize to prepare a liquid.
  • composition of the present invention may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically) according to a desired method, and the dosage may vary depending on the weight, age, sex, and health status of the patient. , diet, administration time, administration method, excretion rate and the severity of the disease, etc., the range varies.
  • the daily dose of the active ingredient may be included in 50 mg to 500 mg, may be included in about 60 mg, may be included in about 90 mg, may be included in about 120 mg, may be included in about 240 mg, It may be included in about 360 mg, may be included in about 480 mg, preferably 60 mg, 90 mg, 120 mg, 240 mg, 360 mg or 480 mg may be included, and it is preferable to divide and administer once to several times a day. do.

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Abstract

La présente invention concerne une composition pharmaceutique pour prévenir ou traiter une fibrose d'organe, comprenant du fumarate de monométhyle en tant que principe actif, la composition pharmaceutique comprenant du fumarate de monométhyle en tant que principe actif inhibant efficacement l'expression de collagène I et de composants de la matrice extracellulaire dans des cellules connues pour présenter une accumulation élevée de ceux-ci chez les patients atteints de fibrose d'organe pour ainsi être efficace dans la prévention ou le traitement de la fibrose d'organe.
PCT/KR2021/011365 2020-11-27 2021-08-25 Composition pharmaceutique destinée à prévenir ou à traiter une fibrose d'organe, comprenant du fumarate de monométhyle en tant que principe actif Ceased WO2022114459A1 (fr)

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KR10-2020-0161990 2020-11-27
KR1020200161990A KR20220073985A (ko) 2020-11-27 2020-11-27 모노메틸푸마레이트를 유효성분으로 포함하는 장기 섬유증의 예방 또는 치료용 약학적 조성물

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024103012A1 (fr) * 2022-11-11 2024-05-16 Imet Inc. Composés polycycliques destinés à être utilisés dans des troubles neurodégénératifs
WO2025032553A1 (fr) * 2023-08-10 2025-02-13 Cochlear Limited Méthodes de traitement de la fibrose de l'oreille interne

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US20140057917A1 (en) * 2012-08-22 2014-02-27 Xenoport, Inc. Methods of Administering Monomethyl Fumarate and Prodrugs Thereof Having Reduced Side Effects
KR101379427B1 (ko) * 2013-02-13 2014-03-28 경북대학교병원 디메틸푸마레이트를 유효성분으로 포함하는 신섬유증의 예방 또는 치료용 조성물
WO2018095056A1 (fr) * 2016-11-23 2018-05-31 中南大学湘雅医院 Applications de fumarates dans la préparation d'un médicament pour le traitement de maladies hépatiques
JP2018131429A (ja) * 2017-02-14 2018-08-23 拓己 佐藤 Ｎｒｆ２活性化剤の効果を増強する方法としての有機酸の使用

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US20140057917A1 (en) * 2012-08-22 2014-02-27 Xenoport, Inc. Methods of Administering Monomethyl Fumarate and Prodrugs Thereof Having Reduced Side Effects
KR101379427B1 (ko) * 2013-02-13 2014-03-28 경북대학교병원 디메틸푸마레이트를 유효성분으로 포함하는 신섬유증의 예방 또는 치료용 조성물
WO2018095056A1 (fr) * 2016-11-23 2018-05-31 中南大学湘雅医院 Applications de fumarates dans la préparation d'un médicament pour le traitement de maladies hépatiques
JP2018131429A (ja) * 2017-02-14 2018-08-23 拓己 佐藤 Ｎｒｆ２活性化剤の効果を増強する方法としての有機酸の使用

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Title
PASCALE CRISSEY L, MARTINEZ ALEJANDRA N, CARR CHRISTOPHER, SAWYER DAVID M, RIBEIRO-ALVES MARCELO, CHEN MIMI, O'DONNELL DEVON B, GU: "Treatment with dimethyl fumarate reduces the formation and rupture of intracranial aneurysms: Role of Nrf2 activation", JOURNAL OF CEREBRAL BLOOD FLOW & METABOLISM, vol. 40, no. 5, 1 May 2020 (2020-05-01), US , pages 1077 - 1089, XP055932346, ISSN: 0271-678X, DOI: 10.1177/0271678X19858888 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024103012A1 (fr) * 2022-11-11 2024-05-16 Imet Inc. Composés polycycliques destinés à être utilisés dans des troubles neurodégénératifs
WO2025032553A1 (fr) * 2023-08-10 2025-02-13 Cochlear Limited Méthodes de traitement de la fibrose de l'oreille interne

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