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WO2023063663A1 - Composition pour la prévention ou le traitement de la fibrose hépatique, comprenant de l'acide bêta-guanidinopropionique - Google Patents

Composition pour la prévention ou le traitement de la fibrose hépatique, comprenant de l'acide bêta-guanidinopropionique Download PDF

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Publication number
WO2023063663A1
WO2023063663A1 PCT/KR2022/015198 KR2022015198W WO2023063663A1 WO 2023063663 A1 WO2023063663 A1 WO 2023063663A1 KR 2022015198 W KR2022015198 W KR 2022015198W WO 2023063663 A1 WO2023063663 A1 WO 2023063663A1
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Prior art keywords
beta
preventing
liver fibrosis
guanidinopropionic acid
present
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Ceased
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PCT/KR2022/015198
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English (en)
Korean (ko)
Inventor
이현승
송민호
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Huenchem Co Ltd
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Huenchem 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • 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
    • 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
    • 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

  • the present invention relates to a composition containing beta-guanidinopropionic acid ( ⁇ -GPA) as an active ingredient, which is excellent in preventing or treating liver fibrosis.
  • ⁇ -GPA beta-guanidinopropionic acid
  • Fibrosis is a state in which normal control is impossible during the wound healing process after tissue is damaged by various stresses (infection, chemical stimulation, radiation, etc.) in the human body, and is particularly common in chronic diseases.
  • the mechanism is very complex and has not been fully elucidated to date.
  • hepatic stellate cells When the liver is stimulated by various harmful environmental factors such as alcohol and viruses, hepatic stellate cells are activated by various cytokines including TGF- ⁇ (transforming growth factor beta) secreted from Kupffer cells.
  • TGF- ⁇ transforming growth factor beta
  • the secreted TGF- ⁇ promotes collagen synthesis, accumulates extracellular matrix, causes hepatic fibrosis by continuously accumulated collagen, and affects not only hepatic stellate cells themselves but also surrounding hepatocytes, resulting in EMT (epithelial to mesenchymal known to cause a transition. Since liver cirrhosis is eventually induced through the continuous process of hepatic fibrosis, understanding and studying the process of hepatic fibrosis is the most basic step in solving all diseases that can cause liver cirrhosis.
  • TGF- ⁇ transforming growth factor beta
  • liver fibrosis is known to be reversible, composed of thin fibrils, and without nodule formation, unlike liver cirrhosis. If the fibrosis process continues repeatedly, crosslinking between ECM (extra cellular matrix) increases, leading to irreversible liver cirrhosis with nodules.
  • ECM extra cellular matrix
  • Liver fibrosis progresses further and cirrhosis occurs.
  • liver cell necrosis occurs for some reason, liver cell regeneration and fibrous tissue increase, and when this process continues repeatedly for a long time, liver cirrhosis occurs.
  • Liver cirrhosis formed by liver nodules or nodules regenerated by persistent or repetitive diffuse liver parenchymal damage, fibrous tissue growth, and regeneration of hepatocytes is a chronic disease pathologically accompanied by necrosis, inflammation, and fibrosis.
  • it progresses to diseases such as liver cirrhosis complications and liver cancer, leading to death.
  • diseases such as liver cirrhosis complications and liver cancer, leading to death.
  • research is being actively conducted to develop methods for rapidly diagnosing and treating liver fibrosis.
  • penicillamine 16,16-dimethyl prostiglidin E2, biphenyl dimethyldicarboxylic acid, colchicine, glucocorticoid, malotilate, gamma-interferon, pentoxifylline ( pentoxifylline), pyridine-2,4-dicarboxylic-diethylamide, pyridine-2,4-dicarboxylic-di(2-methoxyethyl)amide, etc. have been developed, but their action is weak when applied clinically. or severe side effects, currently there is no treatment for liver fibrosis that is used clinically.
  • ⁇ -Guanidinopropionic acid also referred to as guanidinopropionic acid, beta-guanidinopropionic acid, or N-(aminoiminomethyl)-beta-alanine
  • ⁇ -GPA acidic guanidine derivatives, such as ⁇ -GPA, can alleviate hyperglycemia in animal models of non-insulin-dependent diabetes. Therefore, it is sometimes used as a dietary supplement in diabetic patients to control blood sugar levels.
  • ⁇ -GPA is a white crystalline powder that is highly soluble (>50 mg/mL) in water.
  • Korean Patent Registration No. 190257 discloses a pharmaceutical composition for the treatment of metabolic diseases containing 3-guanidinopropionic acid
  • Korean Patent Publication No. 2018-0059446 discloses ⁇ -guanidinopropionic acid with improved characteristics.
  • Pharmaceutically acceptable salts of and uses thereof are disclosed.
  • the present invention was derived from the above needs, and the present inventors completed the present invention by confirming the effect of improving or treating liver fibrosis of a composition containing beta-guanidinopropioic acid as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating liver fibrosis comprising beta-guanidinopropionic acid ( ⁇ -GPA) as an active ingredient.
  • ⁇ -GPA beta-guanidinopropionic acid
  • the beta-guanidinopropionic acid reduces the expression of hydroxyproline and alpha-smooth muscle actin proteins in liver tissue, and the beta-guanidinopropionic acid is an interleukin 17 and interferon gamma, and the beta-guanidinopropionic acid reduces the distribution of CD11b+Ly6C+ monocytes.
  • the present invention provides a food composition for preventing or improving liver fibrosis comprising beta-guanidinopropionic acid ( ⁇ -GPA) as an active ingredient.
  • ⁇ -GPA beta-guanidinopropionic acid
  • the present invention provides a method for preventing or treating liver fibrosis in a non-human subject comprising administering beta-guanidinopropionic acid ( ⁇ -GPA).
  • ⁇ -GPA beta-guanidinopropionic acid
  • composition containing beta-guanidinopropionic acid ( ⁇ -GPA) of the present invention is effective in expressing hydroxyproline and alpha-smooth muscle actin proteins in liver tissue, interleukin 17 and interferon Since it has an effect on reducing the expression of gamma and the distribution of CD11b+Ly6C+ monocytes, it can be usefully used for preventing or treating liver fibrosis.
  • FIG. 1 shows the structure of ⁇ -guanidinopropioic acid according to an embodiment of the present invention.
  • FIG. 2 shows an experimental protocol for a high-fat, high-fructose diet-based steatohepatitis/hepatic fibrosis animal model according to an embodiment of the present invention.
  • FIG. 3 shows a graph of weight change by ⁇ -guanidinopropioic acid in an animal model of steatohepatitis/hepatic fibrosis according to an embodiment of the present invention.
  • FIG. 4 shows changes in food intake by ⁇ -guanidinopropioic acid in an animal model of steatohepatitis/hepatic fibrosis according to an embodiment of the present invention.
  • FIG. 5 shows the results of measuring liver tissue hydroxyproline by ⁇ -guanidinopropioic acid in an animal model of steatohepatitis/hepatic fibrosis according to an embodiment of the present invention.
  • FIG. 6 shows the results of measuring alpha-smooth muscle actin protein expression in liver tissue by ⁇ -guanidinopropioic acid in an animal model of steatohepatitis/hepatic fibrosis according to an embodiment of the present invention.
  • FIG. 7 shows the distribution of memory/naive CD4+, CD8+ T cells in liver tissue by ⁇ -guanidinopropioic acid in an animal model of steatohepatitis/hepatic fibrosis according to an embodiment of the present invention. will be.
  • IL-17 liver tissue interleukin 17
  • IFN- ⁇ interferon gamma
  • FIG. 9 shows the distribution of monocytes in the liver by ⁇ -guanidinopropioic acid in an animal model of steatohepatitis/hepatic fibrosis according to an embodiment of the present invention.
  • prevention means suppressing or delaying the occurrence of a disease from its cause.
  • treatment means to stop the progression of damage by suppressing the progression and/or deterioration of symptoms even if not completely cured, or to improve some or all of the symptoms and lead them in the direction of healing.
  • the term “improvement” refers to all activities that improve or beneficially change symptoms.
  • the present invention provides a pharmaceutical composition for preventing or treating liver fibrosis comprising beta-guanidinopropionic acid ( ⁇ -GPA) as an active ingredient.
  • ⁇ -GPA beta-guanidinopropionic acid
  • the beta-guanidinopropionic acid reduces the expression of hydroxyproline and alpha-smooth muscle actin proteins in liver tissue, and the beta-guanidinopropionic acid is an interleukin 17 and interferon gamma, and the beta-guanidinopropionic acid reduces the distribution of CD11b+Ly6C+ monocytes.
  • the composition may include additional ingredients useful for preventing or treating liver fibrosis, and the additional ingredients include all ingredients known to be effective in liver fibrosis, including compounds and natural products.
  • additional ingredients include all ingredients known to be effective in liver fibrosis, including compounds and natural products.
  • composition of the present invention may be prepared in any form of composition by further including appropriate carriers, excipients and diluents commonly used in the preparation of compositions, preferably in the form of pharmaceutical compositions, health functional food compositions or cosmetic compositions. It may be, but is not limited thereto.
  • the pharmaceutical composition of the present invention may be formulated in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterile injection solutions according to conventional methods, and powders , tablets, capsules, injections and solutions are more preferred.
  • oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterile injection solutions according to conventional methods, and powders , tablets, capsules, injections and solutions are more preferred.
  • Such formulation may be performed by a method commonly performed in the pharmaceutical field, and may be preferably formulated according to each disease or component using a method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA.
  • Carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like.
  • diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient such as starch, calcium carbonate, sucrose or lactose ( lactose) and gelatin.
  • excipients such as starch, calcium carbonate, sucrose or lactose ( lactose) and gelatin.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid formulations for oral administration include suspensions, internal solutions, emulsions, syrups, etc., and various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included in addition to water and liquid paraffin, which are commonly used simple diluents. there is.
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories.
  • Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous agents and suspending agents.
  • As the base of the suppository witepsol, macrogol, tween, cacao butter, laurin paper, glycerogeratin and the like may be used.
  • the preferred dosage of the pharmaceutical composition of the present invention varies depending on the condition and body weight of the patient, the severity of the disease, the drug type, the route and duration of administration, but can be appropriately selected by those skilled in the art. However, for desirable effects, the pharmaceutical composition of the present invention may be included in an amount of 0.01 to 99.9% by weight, preferably 0.1 to 99% by weight per day.
  • the daily dosage may be about 0.1 to 1,000 mg/kg, preferably 100 to 300 mg/kg.
  • the present invention provides a food composition for preventing or improving liver fibrosis comprising beta-guanidinopropionic acid ( ⁇ -GPA) as an active ingredient.
  • ⁇ -GPA beta-guanidinopropionic acid
  • Health functional foods to which the composition can be added include, for example, various general foods, beverages, gum, tea, vitamin complexes, and the like.
  • the composition may be added to food or beverages for the purpose of preventing diseases.
  • the amount of the extract in the food or beverage may be added at 0.01 to 15% by weight of the total food weight, and the health drink composition may be added at a rate of 0.02 to 5 g, preferably 0.3 to 1 g based on 100 g there is.
  • the health functional beverage composition of the present invention is not particularly limited in other components other than containing the extract as an essential component in the indicated ratio, and may contain additional components such as various flavoring agents or natural carbohydrates like conventional beverages.
  • 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 dextrins, cyclodextrins, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • flavoring agents other than those described above include natural flavoring agents such as thaumatin and stevia extracts such as rebaudioside A and glycyrrhizin; and synthetic flavoring agents such as saccharin, aspartame, and the like can advantageously be 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.
  • the extract of the present invention is various nutrients, vitamins, minerals (electrolytes), synthetic and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective Colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, and the like may be contained.
  • the extracts of the present invention may contain fruit flesh for the production of natural fruit juice, fruit juice beverages and vegetable beverages. These components may be used independently or in combination. At this time, the proportion of the additive is not particularly important, but is generally selected in the range of 0.01 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
  • the present invention provides a method for preventing or treating liver fibrosis in a non-human subject comprising administering beta-guanidinopropionic acid ( ⁇ -GPA).
  • ⁇ -GPA beta-guanidinopropionic acid
  • a total of 12 6-week-old C57BL/6J male mice were fed either a normal diet or a high-fat, high-fructose diet (Rodent Diets With 40 kcal% Fat (Palm Oil), 20 kcal% Fructose and 2% Cholesterol; D09100310 Saeron Bio).
  • a high-fat, high-fructose diet was used to induce liver fibrosis caused by steatohepatitis.
  • mice When the mice were 21 weeks old, the normal diet group and the high-fat, high-fructose diet group were treated with beta-Guanidinopropanoic acid (cat no: BD9459; BLD pharmatech Ltd.) at a concentration of 2% by weight in drinking water, respectively, and drank twice a week. The barrel was changed so that it could be freely drunk (Fig. 2). After a total of 12 weeks of 2% beta-Guanidinopropanoic acid in drinking water, mice were necropsied and blood and liver tissue were collected.
  • beta-Guanidinopropanoic acid catalog no: BD9459; BLD pharmatech Ltd.
  • the administration period of the high-fat, high-fructose diet for the induction of hepatic fibrosis by steatohepatitis was 27 weeks, and 2% beta-Guanidinopropanoic acid was administered for a total of 12 weeks to determine the antifibrotic effect (FIG. 2).
  • the groups used in the experiment were normal diet (normal diet-DW), normal diet + drinking water containing 2 wt% beta-Guanidinopropanoic acid (normal diet- ⁇ -GPA), and high-fat, high-fructose diet (high-fat/high-fructose diet-DW).
  • normal diet-DW normal diet + drinking water containing 2 wt% beta-Guanidinopropanoic acid
  • high-fat/high-fructose diet-DW high-fat/high-fructose diet-DW
  • a high-fat high-fructose diet + beta-Guanidinopropanoic acid-containing drinking water high-fat/high-fructose diet- ⁇ -GPA was administered (Fig. 3).
  • Antibodies used for flow cytometry anti-CD3-PerCP-Cy5.5, anti-CD3-PE-Cy7, anti-CD4-AF700, anti-CD8-PE, anti-CD8-APC, anti-CD62L-APC, anti -CD44-FITC, anti-CD11b-PerCP-Cy5.5, anti-Ly6C-FITC, anti-IFN- ⁇ -APC, anti-IL-17A-APC, fixable viability dye-APC-Cy7 (all supplied by eBioscience, San Diego, CA, USA)
  • beta-Guanidinopropanoic acid did not affect mouse feed intake (FIG. 4).
  • Beta-Guanidinopropanoic acid induced a significant decrease in liver tissue hydroxyproline in the high-fat, high-fructose diet group (FIG. 5). This result suggests that beta-Guanidinopropanoic acid has the function of inhibiting liver fibrosis.
  • alpha-smooth muscle actin a protein representing the degree of hepatic fibrosis, was significantly decreased in the beta-Guanidinopropanoic acid-treated group (FIG. 6).
  • liver tissue memory CD4+ and CD8+ T cells increased, whereas non-contact CD4+ and CD8+ T cells decreased (FIG. 7).
  • beta-Guanidinopropanoic acid reduced inflammatory cytokines (interleukin 17, interferon gamma) inducing an intrahepatic inflammatory response, resulting in a reduction in fibrosis shown in FIGS. 5 and 6 .
  • Monocytes expressing CD11b+Ly6C+ tended to increase in steatohepatitis/hepatic fibrosis caused by the high-fat, high-fructose diet, and beta-Guanidinopropanoic acid reduced the distribution of CD11b+Ly6C+ monocytes (FIG. 9). This suggests that it may have contributed to reducing the inflammatory response in the liver and inhibiting fibrosis.

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Abstract

La présente invention concerne une composition comprenant un acide bêta-guanidinopropionique (β-GPA), et son utilisation pour la prévention ou le traitement de la fibrose hépatique.
PCT/KR2022/015198 2021-10-13 2022-10-07 Composition pour la prévention ou le traitement de la fibrose hépatique, comprenant de l'acide bêta-guanidinopropionique Ceased WO2023063663A1 (fr)

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KR1020210135618A KR102615692B1 (ko) 2021-10-13 2021-10-13 베타-구아니디노프로피온산을 포함하는 간섬유화 예방 또는 치료용 조성물
KR10-2021-0135618 2021-10-13

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100190257B1 (ko) * 1990-02-28 1999-06-01 로버트 에이. 아미테이지 3-구아니디노프로피온산을 포함하는, 대사질환 치료용 약학 조성물
WO2014071067A2 (fr) * 2012-10-31 2014-05-08 The Rockefeller University Traitement et diagnostic du cancer du côlon
KR20180059446A (ko) * 2015-08-25 2018-06-04 알제닉스, 인크. 개선된 특성의 β-구아니디노프로피온산의 약제학적으로 허용 가능한 염 및 이의 용도
US20210177790A1 (en) * 2019-12-11 2021-06-17 Rgenix, Inc. Methods of treating cancer

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100190257B1 (ko) * 1990-02-28 1999-06-01 로버트 에이. 아미테이지 3-구아니디노프로피온산을 포함하는, 대사질환 치료용 약학 조성물
WO2014071067A2 (fr) * 2012-10-31 2014-05-08 The Rockefeller University Traitement et diagnostic du cancer du côlon
KR20180059446A (ko) * 2015-08-25 2018-06-04 알제닉스, 인크. 개선된 특성의 β-구아니디노프로피온산의 약제학적으로 허용 가능한 염 및 이의 용도
US20210177790A1 (en) * 2019-12-11 2021-06-17 Rgenix, Inc. Methods of treating cancer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CROCKER CHELSEA L.; BAUMGARNER BRADLEY L.; KINSEY STEPHEN T.: "β-guanidinopropionic acid and metformin differentially impact autophagy, mitochondria and cellular morphology in developing C2C12 muscle cells", JOURNAL OF MUSCLE RESEARCH AND CELL MOTILITY., CHAPMAN, LONDON., GB, vol. 41, no. 2-3, 13 December 2019 (2019-12-13), GB , pages 221 - 237, XP037292347, ISSN: 0142-4319, DOI: 10.1007/s10974-019-09568-0 *

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