WO2017084234A1 - 预防或治疗脂肪肝的药物组合物 - Google Patents

预防或治疗脂肪肝的药物组合物 Download PDF

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Publication number
WO2017084234A1
WO2017084234A1 PCT/CN2016/078039 CN2016078039W WO2017084234A1 WO 2017084234 A1 WO2017084234 A1 WO 2017084234A1 CN 2016078039 W CN2016078039 W CN 2016078039W WO 2017084234 A1 WO2017084234 A1 WO 2017084234A1
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Prior art keywords
liver
mannitol
combination
acid
sucralose
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Ceased
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PCT/CN2016/078039
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English (en)
French (fr)
Chinese (zh)
Inventor
胡幼圃
何欣恬
吴永恩
唐熙卉
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Sinew Pharma Inc
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Sinew Pharma Inc
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Priority to HK18103734.5A priority Critical patent/HK1244213A1/zh
Priority to JP2018526123A priority patent/JP2018534323A/ja
Priority to EP16865417.6A priority patent/EP3391881A4/en
Priority to US15/564,507 priority patent/US10925854B2/en
Priority to CN201680021216.3A priority patent/CN107613968A/zh
Priority to CN202310336366.5A priority patent/CN116440143A/zh
Priority to HUE21173210A priority patent/HUE072982T2/hu
Priority to ES21173210T priority patent/ES3044383T3/es
Priority to AU2016327930A priority patent/AU2016327930B2/en
Priority to TW105131118A priority patent/TWI781912B/zh
Priority to JP2018535221A priority patent/JP2018537517A/ja
Priority to EP16848179.4A priority patent/EP3353144A4/en
Priority to CA2999368A priority patent/CA2999368A1/en
Priority to CN202510506442.1A priority patent/CN120349362A/zh
Priority to KR1020187011548A priority patent/KR102891137B1/ko
Priority to EP25188784.0A priority patent/EP4609911A3/en
Priority to BR112018005905-6A priority patent/BR112018005905B1/pt
Priority to PCT/CN2016/100187 priority patent/WO2017050298A1/en
Priority to CA3232521A priority patent/CA3232521A1/en
Priority to SG10202002573RA priority patent/SG10202002573RA/en
Priority to CN201680020530.XA priority patent/CN107614475A/zh
Priority to EA201890810A priority patent/EA201890810A1/ru
Priority to CN202510528240.7A priority patent/CN120398980A/zh
Priority to EP21173210.2A priority patent/EP3991724B1/en
Priority to MX2018003700A priority patent/MX395231B/es
Priority to US15/564,526 priority patent/US10456371B2/en
Priority to HK18103735.4A priority patent/HK1244266A1/zh
Priority to KR1020247008968A priority patent/KR20240042148A/ko
Priority to HRP20250899TT priority patent/HRP20250899T1/hr
Priority to MYPI2018701141A priority patent/MY190647A/en
Publication of WO2017084234A1 publication Critical patent/WO2017084234A1/zh
Priority to PH12018500659A priority patent/PH12018500659A1/en
Priority to MX2022007816A priority patent/MX2022007816A/es
Priority to ZA2018/02373A priority patent/ZA201802373B/en
Anticipated expiration legal-status Critical
Priority to US16/573,506 priority patent/US11285123B2/en
Priority to AU2021205040A priority patent/AU2021205040B2/en
Priority to JP2021176691A priority patent/JP7261850B2/ja
Priority to US17/686,013 priority patent/US12083088B2/en
Priority to AU2024200963A priority patent/AU2024200963B2/en
Priority to US18/742,433 priority patent/US20240335404A1/en
Ceased legal-status Critical Current

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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
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23B—PRESERVATION OF FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES; CHEMICAL RIPENING OF FRUIT OR VEGETABLES
    • A23B2/00—Preservation of foods or foodstuffs, in general
    • A23B2/70—Preservation of foods or foodstuffs, in general by treatment with chemicals
    • A23B2/725—Preservation of foods or foodstuffs, in general by treatment with chemicals in the form of liquids or solids
    • A23B2/729—Organic compounds; Microorganisms; Enzymes
    • A23B2/733—Compounds of undetermined constitution obtained from animals or plants
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • 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
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • 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
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/752—Citrus, e.g. lime, orange or lemon
    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the present invention relates to a composition and method for preventing or treating fatty liver, protecting liver function, or ameliorating liver disease caused by fatty liver or other related disorders.
  • the liver is part of the animal's digestive system and is the main organ for the production and secretion of many digestive juices.
  • the liver also has functions of absorption, metabolism, removal of toxic substances and immune protection.
  • the liver is an important organ of fat metabolism and plays an extremely important role in the process of digestion, absorption, decomposition, synthesis and transportation of fatty foods.
  • the liver is free fatty acid (FFA) in the blood, which will eventually synthesize triglyceride (TG) in the liver and store it, or very low density lipoprotein (VLDL). In the form of TG transports the liver out of the bloodstream. Therefore, once the liver is damaged, it will cause abnormal metabolism and accumulation of lipids (especially TG) in the liver cells.
  • FFA free fatty acid
  • TG triglyceride
  • VLDL very low density lipoprotein
  • fatty liver disease means that the weight of fat in the liver exceeds 5% of the weight of the liver, or more than 10% of the liver tissue sections.
  • Hepatocytes have a phenomenon of fat vacuolization 2 .
  • Fatty liver can be distinguished according to the cause of alcoholic fatty liver (AFLD), non-alcohol fatty liver disease (NAFLD) or other factors, such as drugs, fatty liver disease, pathology Appearance includes characterization of fatty metamorphosis or steatosis, steatohepatitis, and the like.
  • AFLD alcoholic fatty liver
  • NAFLD non-alcohol fatty liver disease
  • Appearance includes characterization of fatty metamorphosis or steatosis, steatohepatitis, and the like.
  • Mild fatty liver refers to less than 33% of hepatocytes with steatosis, moderate to 33-66%, and severe 66% to 3,9,21 .
  • fatty liver was considered to be a more benign and reversible disease, so it was less valued.
  • studies have found that it will cause liver fibrosis and cirrhosis, even liver cancer, and with the increase of obese population. There is an increasing trend.
  • NAFLD Non-alcoholic steatohepatitis
  • the prevalence rate is about 12.37%, which is not far from Japan's 9-13%, among which non-obese people
  • the prevalence rate is about 10%
  • the prevalence rate of morbidly obese people (BMI greater than 30) is as high as 80% 15,23 .
  • Fatty liver appeared after the first strike, and appeared after the second strike.
  • Fatty hepatitis (steatohepatitis).
  • the first strike was caused by excessive accumulation of fat in the liver, due to obesity, hyperlipidemia, etc.
  • the second strike was caused by oxidative stress and reactive oxygen species in the mitochondria.
  • ROS causes lipid peroxidation on the liver cell membrane, releasing primary inflammatory cytokines and free radicals, and activating stellate cells to produce fibrosis, leading to necrosis of hepatocytes 4,5,19 .
  • the pathogenesis of NASH is mainly related to triglyceride lipid peroxidation, oxidative stress, ROS reaction, increased peroxidation of lipids in hepatocytes, or enhancement of cytokines and liver enzymes, resulting in a series of autoimmune Reciprocal reactions 12 .
  • fatty liver is mostly the long-term intake of excessive animal fat, protein, carbohydrates, excess calories in the body converted into fat accumulation, leading to obesity and fatty liver.
  • GOT/GPT in the blood of patients with fatty liver The values may be normal. To correctly diagnose fatty liver, it is necessary to pass the abdominal ultrasound examination. The current accuracy rate is over 97%.
  • FLD has no specific therapeutic effect for specific curative effect.
  • the treatment policy is mainly to improve the potential risk factors or to use drugs to control the progress of chronic diseases. It is recommended to treat the symptoms according to the formation of fatty liver, such as: fatty liver caused by overweight, Moderate weight loss; alcoholic fatty liver, need to rely on alcohol and a balanced diet to improve; long-term exposure to liver damage to chemicals or drugs, fatty liver, you must immediately stop using these drugs; fatty liver caused by disease, Such as hepatitis C, high blood fat, etc., must start at the source, treat C liver, control blood lipids; if the body factors cause triglyceride too high, you can not improve fatty liver by weight loss.
  • lipid-lowering drugs have a "lip-repellent" effect, which can "catch" the lipids in the blood to the liver, and the liver has already accumulated fat, so it is difficult to treat a large amount of influx of fat, and fat will be Accumulation in the liver makes the fatty liver more serious. It can be seen that hypolipidemic drugs are not suitable for the treatment of FLD.
  • the present invention provides that one or more excipients (including flavonoid compounds, etc.) have the effect of preventing or treating fatty liver, protecting liver function, or improving liver disease caused by fatty liver or other related diseases, and the compound is selected from the following Group of components: sodium lauryl sulfate, menthol, sucralose, mannitol, sorbitol, saccharin, glycerin, benzene Sodium benzoate, oxide red, pregelatinized starch, sodium cyclamate, sorbic acid, lemon oil, lemon Citric acid, and butylated hydroxyanisole, poncirin, isovitexin, eriodictyol, Ergosterol, ⁇ -myrcene, hyperoside, catechin ((+)-catechin), galangin, morin, ginseng Flavonoids (sciadopitysin), didymin, cotton cellulose (gossypin), luteolin-7-Glucoside, dihydroquercetin
  • the invention provides the use of the compounds for the preparation of a composition for preventing or treating fatty liver, protecting liver function, or ameliorating hepatic lesions or other related conditions caused by fatty liver.
  • the present invention also proposes a method of preventing or treating fatty liver, protecting liver function, or improving liver disease caused by fatty liver or other related conditions by administering the compound.
  • the compound is selected from the group consisting of sodium lauryl sulfate, menthol, sucralose, mannitol, sorbitol. (sorbitol), saccharin, glycerin, sodium benzoate, oxide red, pregelatinized starch, sodium cyclamate, Sorbic acid, lemon oil, citric acid, and butylated hydroxyanisole, and any combination thereof.
  • the compound is selected from the group consisting of poncirin, isovitexin, eriodictyol, ergosterol, and myrcene.
  • poncirin isovitexin
  • eriodictyol ergosterol
  • myrcene hyperoside
  • catechin ((+)-catechin)
  • galangin morin
  • sciadopitysin scented grass
  • cotton cellulose cellulose
  • luteolin-7-Glucoside (+)-taxifolin, trans-cinnamic acid, fragrant Diosmin, linarin, xylitol, luteolin, swertiamarin, and any combination thereof.
  • the compound is selected from the group consisting of: eriodictyol, mannitol, menthol, sucralose, saccharin, And any combination thereof.
  • the compound is selected from the group consisting of: (1) a combination of saccharin and mannitol, (2) a combination of menthol and mannitol, and (3) sucralose and mannitol. Combination, (4) a combination of eriodictyol and mannitol, (5) a combination of eriodictyol and sucralose, (6) menthol, mannitol, eriodictyol, or (7) sucralose, mannitol , a combination of ervain.
  • one or more of the compounds described herein are used in combination with one or more selected from the group consisting of puerarin, phloridzin, and sinensetin.
  • the compounds of the invention reduce the liver fat content of an individual.
  • the compounds of the invention reduce the fat content of hepatocytes in an individual.
  • the compounds of the invention may reduce liver damage in an individual, for example, liver tissue damage or liver function damage.
  • the compounds of the invention increase the liver antioxidant activity of an individual.
  • the compounds of the invention may be used to ameliorate related conditions caused by accumulation of hepatic fat for a variety of reasons including, but not limited to, fatty liver, acute and chronic alcoholic fatty liver, acute and chronic nonalcoholic fatty liver disease. , acute and chronic alcoholic hepatitis, acute and chronic nonalcoholic steatohepatitis, non-alcoholic cirrhosis, alcoholic cirrhosis (ICD-9-CM diagnostic code 571.8, 571.0, 571.1, 571.2, 571.3, 571.4, 571.5, 571.9 ).
  • the individual suitable for the compound of the invention is a patient with fatty liver disease or an obese person.
  • the compounds of the invention may be formulated into pharmaceuticals, food supplements or health foods.
  • the present invention provides a composition comprising any two or more compounds selected from the above.
  • composition of the present invention comprises any two or more compounds selected from the group consisting of: eriodictyol, mannitol, menthol, Sucralose and saccharin.
  • compositions of the present invention comprise a combination selected from the group consisting of: (1) a combination of saccharin and mannitol, (2) a combination of menthol and mannitol, and (3) three. a combination of sucralose and mannitol, (4) a combination of eriodictyol and mannitol, (5) a combination of eriodicty and sucralose, (6) menthol, mannitol, eriodictol, or (7) A combination of sucralose, mannitol, and eriodictyol.
  • Figure 1 shows liver tissue sections after 4 weeks of treatment with different test substances in mice after induction of fatty liver production by mice.
  • the present invention discloses that one or more of the compounds described above have the effect of reducing liver fat content and ameliorating related conditions. Accordingly, the present invention provides the use of a compound according to the composition for the preparation of a composition for preventing or treating fatty liver, protecting liver function, or ameliorating liver disease caused by fatty liver or other related disorders.
  • the invention also provides a method for preventing or treating fatty liver, protecting liver function, or improving liver disease caused by fatty liver Or a method of other related disorders which comprises administering to a subject in need thereof an effective amount of the compound.
  • the invention also provides compositions for preventing or treating fatty liver, protecting liver function, or ameliorating hepatic lesions or other related conditions caused by fatty liver.
  • liver fat content refers to the amount of fat accumulated in the liver in an individual, including lipids in a broad sense, such as triglyceride (TG) and cholesterol.
  • reducing liver fat content generally refers to a reduction in abnormal liver fat content in an individual, that is, a reduction in abnormal liver fat content, and more specifically, a reduction to a normal level. For example, under normal circumstances, fat accounts for about 3% of the liver's weight. When the weight of fat in the liver exceeds 5% of the weight of the liver, it is abnormal accumulation of fat. (The above-mentioned liver fat content is a relative value and is an example, may be due to individual ethnic groups and Other factors have changed).
  • reducing liver fat content may mean lowering the abnormal liver fat content in an individual, for example, from 5% or more of the liver weight to 3% of the liver weight.
  • Standard methods of analysis can be used to assess liver fat content, including but not limited to, ultrasound analysis, magnetic resonance imaging MRI, magnetic resonance spectrum MRS, computed tomography CT, and liver pathology.
  • liver function refers to one or more of the many physiological functions performed by the liver and can be analyzed by a number of routine tests, for example, alanine aminotransferase (ALT) analysis or aspartic Aspartate transaminase (AST) analysis.
  • ALT alanine aminotransferase
  • AST aspartic Aspartate transaminase
  • the compounds can be used to protect liver function, including improving liver function or avoiding damage to liver function.
  • liver lesions may refer to liver cells that are injured or destroyed by certain factors and may cause liver function to be affected. According to the invention, the compounds can be used to improve liver lesions caused by fatty liver. More specifically, “hepatic injury” as used herein refers to a condition in which the liver is damaged in tissue or biochemical function compared to normal liver. In the specific aspect, “hepatic injury” as used herein refers to liver damage caused by alcohol or non-alcoholic factors such as a high-fat diet or obesity. In a specific aspect, “liver injury” may damage the liver tissue, and may be selected from one or more of the following characteristics: steatosis, lobular inflammation, hepatocyte ballooning.
  • liver injury may be an impaired biochemical function of the liver, which may be determined by serum alanine aminotransferase (ALT) or aspartate transaminase (AST) activity. Judging, the higher the activity, the more severe the damage to the biochemical function of the liver.
  • ALT serum alanine aminotransferase
  • AST aspartate transaminase
  • liver antioxidant activity refers to the activity or ability of the liver to combat oxidative stress.
  • the compound according to the present invention may increase the liver antioxidant activity of an individual, including, but not limited to, reducing the oxidative stress or increasing the enzyme activity or content of a member of the antioxidant system, and the member of the antioxidant system may be glutathione Glutathione peroxidase (GPx), glutathione (GSH), glutathione reductase (GRd), and/or superoxide dismutase (SOD).
  • GPx glutathione Glutathione peroxidase
  • GSH glutathione
  • GRd glutathione reductase
  • SOD superoxide dismutase
  • the compounds include conventional excipients and bioflavonoids, which are useful for lowering liver fat content and ameliorating related conditions.
  • the "related conditions” described herein include conditions caused by abnormal accumulation of liver fat, including but not limited to, fatty liver, acute and chronic alcoholic fatty liver, acute and chronic nonalcoholic fatty liver, acute and chronic alcoholic hepatitis.
  • prevention refers to a preventive or preventive measure for a disease, a symptom or condition of a disease, including but not limited to, the application or administration of one or more active agents to a possible unrecognized condition.
  • treatment refers to a treatment for a disease, a symptom or condition of a disease, including, but not limited to, the administration or administration of one or more active agents to have the disease, the symptoms or condition of the disease, or An individual whose disease has deteriorated, the purpose of which is to treat, cure, alleviate, alleviate, alter, remedy, improve, improve, or affect the disease, the symptoms or conditions of the disease, the disability caused by the disease, or the deterioration of the disease.
  • the terms "individual” or “individual” include human or non-human animals, in particular, mammals, such as companion animals (such as dogs, cats, etc.), farm animals (such as cattle, sheep, pigs). , horses, etc.), or experimental animals (such as rats, mice, guinea pigs, etc.).
  • mammals such as companion animals (such as dogs, cats, etc.), farm animals (such as cattle, sheep, pigs). , horses, etc.), or experimental animals (such as rats, mice, guinea pigs, etc.).
  • the term "effective amount” refers to the amount of active ingredient that produces a desired biological or medical effect on an individual being treated, for example, reducing the liver fat content of an individual or ameliorating a related condition.
  • a therapeutically effective amount of the active ingredient according to the invention may be formulated into a pharmaceutical composition in a suitable form with apharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention is preferably a package
  • the active ingredient is present in an amount of from about 0.1% by weight to about 100% by weight, based on the total weight of the composition.
  • the term "pharmaceutically acceptable” means that the carrier is compatible with the active ingredient of the composition (without affecting the action of the active ingredient), and is preferably stable to the active ingredient and is safe for the individual to be treated .
  • the carrier can be a diluent, carrier, excipient, or vehicle of the active ingredient.
  • suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, poly Vinyl pyrrolidone, cellulose, sterile water, syrup, and methylcellulose.
  • the composition may additionally comprise a lubricant such as talc, magnesium stearate, and mineral oil; a wetting agent; an emulsifier and a suspending agent; a preservative such as methyl and propyl hydroxybenzoate; a sweetener; Agent.
  • a lubricant such as talc, magnesium stearate, and mineral oil
  • a wetting agent such as talc, magnesium stearate, and mineral oil
  • an emulsifier and a suspending agent such as methyl and propyl hydroxybenzoate
  • a preservative such as methyl and propyl hydroxybenzoate
  • the composition may be in any form, for example, as a tablet, a pill, a powder, a lozenge, a sachet, a cachet, an elixir, a suspension, an emulsion, a solution, a syrup, a soft and hard gelatin capsule. , suppositories, sterile injections, and packaging powders.
  • compositions of the invention may be delivered via any physiologically acceptable route, for example, orally, parenterally (e.g., intramuscular, intravenous, subcutaneous, and intraperitoneal), transdermal, suppository, and intranasal methods.
  • parenterally e.g., intramuscular, intravenous, subcutaneous, and intraperitoneal
  • transdermal e.g., transdermal
  • suppository e.g., transdermal
  • intranasal methods e.g., transdermal, suppository, and intranasal methods.
  • a sterile aqueous solution which may contain other substances such as salts or glucose sufficient to render the solution isotonic with blood.
  • the aqueous solution is suitably buffered (preferably having a pH of 3 to 9) depending on the requirements.
  • suitable parenteral compositions under sterile conditions by standard standard standard pharmacological techniques.
  • the human liver cancer cell line Hep G2 was used to analyze the activity of various compounds of the present invention to reduce fat content.
  • DMEM Dulbecco's Modified Eagle's Medium
  • the DMEM culture medium of No. A-F was stored at 2-8 ° C, and it was used after being warmed in a 37 ° C water bath before the experiment.
  • 0.4% trypan blue will infiltrate into dead cells and color, while living cells will not penetrate because of the integrity of the cell membrane. Take 100 ⁇ l of cell suspension and mix it with 100 ⁇ l of 0.4% trypan blue. uniform. A small amount of mixed solution (about 20 ⁇ l) was added from the groove above the blood cell counting disk chamber, and the cover plate was covered under a light microscope to observe that the living cells were not stained, and the dead cells were blue.
  • HepG2 cell line 15 ⁇ 10 6 HepG2 cell line was cultured in DMEM medium of No. B, cultured in a 37 ° C, 5% CO 2 incubator for 24 hours, and then serially numbered DMEM medium (serum-free medium)) After 24 hours of culture, the DMEM medium (oleic acid ester/albumin complex) of No. D was finally replaced and cultured for 48 hours to induce HepG2 cell line into fatty liver cells.
  • the HepG2 cell line was divided into 6 groups, including: (1) blank group: no treatment; (2) DMSO group: blank group cells were added with dimethyl sulfoxide (DMSO); (3) control group: Oleic acid induced the formation of fatty liver cells; (4) Carrier group: Fatty liver cells induced by oleic acid were added to DMSO; (5) Positive control group: Fatty liver cells were added with silymarin; and (6) Test group: Fatty liver cells were added A variety of compounds of the invention.
  • DMSO group blank group cells were added with dimethyl sulfoxide (DMSO)
  • control group Oleic acid induced the formation of fatty liver cells
  • Carrier group Fatty liver cells induced by oleic acid were added to DMSO
  • Positive control group Fatty liver cells were added with silymarin
  • Test group Fatty liver cells were added A variety of compounds of the invention.
  • the cells were washed twice with phosphate buffered saline (PBS), and then added with 0.5 mL of trypsin/ethylenediaminetetraacetic acid (trypsin/EDTA) for 3 minutes, and then 2 mL of PBS was added.
  • PBS phosphate buffered saline
  • trypsin/EDTA trypsin/ethylenediaminetetraacetic acid
  • 2 mL of PBS was added.
  • the cells were scraped off, transferred to a centrifuge tube, and the cells were disrupted by ultrasonic waves. 20 ⁇ L of the cell extract was taken to measure the protein content in the cells.
  • the TG assay was carried out using a commercially available combination reagent (Randox). The ratio obtained by dividing the TG content obtained above by the protein content represents the relative content of TG in the cells.
  • mice B6 mice recommended by the Department of Health's "Determination of Liver Health Benefits of Healthy Foods" were selected. The number of test animals in each group was only 4, and only 12 of each group were confirmed. Male mice were housed in the normal light and dark cycle (lighting period from 7:00 am to 7:00 pm, the rest is dark period), temperature 23 ⁇ 2 ° C, relative humidity 55 ⁇ 15% in the animal room, weight 18-23g It was purchased by Lesco (Taipei) into the National Defense Animal Center, and the Department of Animal Experiments was conducted in accordance with the National Health Center Experimental Guide. First, feed 3-5g/day with normal feed every day, and keep 1-2 weeks to observe the health status. The water is supplied indefinitely, and the body weight is recorded once a week.
  • test animals were randomly divided into a blank control group (Blank), a high-fat control group (HFD), a positive control group (PS), and a test group.
  • the blank control group was given normal feed; the high-fat control group was given high-fat diet; the positive control group was given high-fat diet and tube fed silymarin (5 mg/kg/day); and the experimental group was given high-fat feed and tube feeding.
  • Test compound was given normal feed; the high-fat control group was given high-fat diet; the positive control group was given high-fat diet and tube fed silymarin (5 mg/kg/day); and the experimental group was given high-fat feed and tube feeding. Test compound.
  • the blank control group was given normal feed for 12 weeks, and the high-fat control group, the positive control group and the test group were fed with high-fat diet for 12 weeks. After 8 weeks of feeding, the blank control group and the high-fat control group were given deionized water once a day; the control group was given a silymarin once a day; the test group was given a test compound once a day for 4 weeks or 8 weeks. .
  • AST aspartate transaminase
  • ALT Alanine aminotransferase
  • TG total cholesterol
  • TCHO total cholesterol
  • TC low density lipoprotein cholesterol
  • HDL-C high
  • mice were taken abdominal fat and liver specimens after laparotomy. After weighing, the fat weight, liver weight and liver weight/body weight ratio were compared, and the largest right lobe liver was cut into two pieces of about 1 cm cube. It was fixed in 10% neutral formalin solution, and the paraffin-encapsulated sections were subjected to H&E staining for histopathological observation. In addition, the remaining livers were cryopreserved and the levels of triglycerides and total cholesterol in the liver were measured. In addition, the liver function of each group of animals was evaluated using the Galactose Single Point Method, which is recommended by the US Food and Drug Administration and the Taiwan Department of Health for the quantitative use of liver function in clinical use.
  • mice were sacrificed, and a piece of tissue of about 1 cm cube was cut from the largest right lobe liver and fixed in 10% neutral formalin, followed by ethanol at different concentrations (30, 50, 70, 95, 99.5%) and xylene were subjected to dehydration and transparency steps, then xylene was replaced by hot paraffin solution, and finally the tissue was embedded in a paraffin solution.
  • the completed paraffin specimens were cut into 5 ⁇ m paraffin sections by a microtome, and the sections were adhered to a clean glass slide and dried at 37 ° C for further H&E staining.
  • liver tissue sections were placed in xylene for 30 minutes for dewaxing, and then placed in 99.5, 95, 70, 50 and 30% ethanol for 30 minutes each time to rehydrate, and then immersed in distilled water for 10 minutes to be dyed.
  • the hematoxylin was first soaked for 30 seconds, and then washed with distilled water for several minutes, then stained with eosin for 2-5 minutes, and washed with distilled water for several minutes.
  • the dehydration process is carried out, and placed in 50, 70, 95 and 100% alcohol for 30 seconds, respectively, and then transparently treated with xylene twice, and finally sealed with a sealing rubber.
  • liver tissue was H&E stained to assess liver fat accumulation.
  • all histopathological sections were cut from the same position of the largest right lobe liver and then pathologically stained.
  • double-blind analysis should be performed by a human or veterinary pathologist. If the design of the experiment is not clear, all the sections should be scored (NAS score) 16 and finally statistical analysis. Methods The differences in each group were analyzed.
  • liver tissue of the sacrificial animal was taken, homogenized by a homogenizer (biomasher) for 10 minutes, and then 9 times hepatic weight (w/w) buffer (pH 7.4, 50 mmol/L Tris-HCl, 180 mmol/) was added. L KCl), then mix with a test tube shaker (Vortex).
  • the obtained liver tissue homogenate samples were analyzed for various components of the liver antioxidant system, including glutathione peroxidase (GPx), glutathione (GSH), and glutathione reduction.
  • GPx glutathione peroxidase
  • GSH glutathione
  • glutathione reduction glutathione reduction.
  • the enzyme glutthione reductase, GRd
  • SOD superoxide dismutase
  • the results of reducing the TG content of HepG2 adipocytes measured at the test concentrations of the immobilized test compounds are shown in Table 3.
  • the results showed that the test compound exhibited different effects on reducing the TG content of hepatocytes in the fatty liver cells induced by HepG2 cells compared with the control group.
  • the TG reduction rate (%) was calculated as: [1 - (test group TG content - blank group TG content) / (oleic acid induced group TG content - blank group TG content)] x 100%.
  • Table 3 Test compounds reduce TG content in fatty liver cells
  • Table 3-1 Some test compounds from Table 3 can reduce TG content in fatty liver cells
  • Table 3-2 Part of the test compound (bioflavonoids) from Table 3 reduces TG content in fatty liver cells
  • Table 3-3 Part of the test compound (excipient) from Table 3 reduces TG content in fatty liver cells
  • the other animals were given fatty liver treatment. After 8 weeks, the animals in each group were given different treatments for 4 weeks or 8 weeks, respectively.
  • the group and the high-fat control group were given deionized water, the silymarin was given to the control group, and the test group was given different test compounds, including puerarin, phlorizin, eriodicty, sucralose, mannitol, saccharin, orange peel, A combination of menthol, or a portion of the test compound.
  • Table 4-1 Results of liver weight and body fat weight analysis of test compounds.
  • test compounds are safe and sound.
  • test compound has the effect of reducing liver lipids
  • Figure 1 shows that in mice with induced fatty liver, liver cells in the hilar region (including bile duct, portal vein, and hepatic artery) are covered with many large vesicular fat droplets, and hepatocytes appear ballooning, which successfully induces fatty liver animal models.
  • Table 5-1 Test compounds reduce liver lipids in animals (during 4 weeks of dosing)
  • Table 5-2 Test compounds reduce liver lipids in animals (during 8 weeks of dosing)
  • orange peel, eriodictyol, phloridin, mannitol, menthol, sucralose, and saccharin can significantly reduce total cholesterol in the liver; in particular, saccharin treatment for 4 weeks, excellent results, can be reduced by about 56% Total liver cholesterol (p ⁇ 0.005).
  • a combination of saccharin and mannitol When a combination of two test compounds is administered, a combination of saccharin and mannitol, a combination of menthol and mannitol, a combination of sucralose and mannitol, a combination of eriodictyol and mannitol, or eriodictyol and three
  • the combination of sucralose can effectively reduce the triglyceride in the liver; in particular, the combination of menthol and mannitol for 4 weeks, the excellent effect, can reduce the liver triglyceride content of about 77% (p ⁇ 0.005)
  • the combination of eriodictin and sucralose for 8 weeks achieved excellent results, reducing the liver triglyceride content by about 78% (p ⁇ 0.005).
  • the combination of sucralose and mannitol, the combination of eriodictyol and mannitol, or the combination of eriodicty and sucralose can significantly reduce total cholesterol in the liver; among them, eriodictin and sucralose At 8 weeks of combined treatment, an excellent effect was achieved, which reduced the total cholesterol content of the liver by about 77% (p ⁇ 0.005).
  • a combination of menthol, mannitol, eriodictyol, sucralose, mannitol, and eriodictol can effectively reduce triglycerides in the liver; in particular, three When the combination of sucralose, mannitol, and eriodictin was treated for 8 weeks, the excellent effect was obtained, and the liver triglyceride content was reduced by about 79% (p ⁇ 0.005). In addition, the combination of sucralose, mannitol, and eriodictol can significantly reduce total cholesterol in the liver.
  • test compound has the effect of reducing liver damage
  • FIG. 1 shows liver tissue damage in fatty liver animals, including liver cells in the hilar region (including bile duct, portal vein, and hepatic artery), which are covered with many large vesicular fat droplets, and the hepatocytes appear ballooning.
  • liver tissue sections showed a significant reduction in large vesicular fat droplets in liver cells, of which mice treated with silymarin were still observed.
  • liver tissue type of mice treated with menthol, eriodictol, or mannitol was closer to the blank group, indicating that fatty liver disease was mild.
  • NAS score results are shown in Table 6.
  • Test compounds can reduce liver damage in animals
  • the NAS Nonalcoholic Fatty Liver Disease Activity Score
  • the NAS Nonalcoholic Fatty Liver Disease Activity Score
  • liver tissue damage was induced in mice with fatty liver (increased NAS score). Strugram and mannitol significantly reduced liver damage when administered to a single test compound. It is worth noting that the combination of menthol and mannitol gave excellent results when administered a combination of the two test compounds, and almost no liver damage was observed, and the NAS score was the same as that of the blank group.
  • Table 8-1 Test compounds reduce liver damage in animals (during 4 weeks of dosing)
  • Table 8-2 Test compounds reduce liver damage in animals (during 8 weeks of dosing)
  • ALT and AST are the most commonly used enzyme indicators to reflect liver biochemical damage. These enzymes are normally present in hepatocytes, and are leaked when the liver cells are destroyed. The rise in serum ALT and AST values usually reflects liver inflammation and liver function damage.
  • liver function was impaired in induced fatty liver animals (increased ALT and AST values).
  • mannitol was treated for 4 weeks, an excellent effect was obtained, which was reduced by about 64% ALT value (p ⁇ 0.005) and about 60% AST value (p ⁇ 0.005).
  • the combination of menthol and mannitol or the combination of eriodictin and sucralose can significantly reduce the ALT value; the combination of menthol and mannitol, the combination of sucralose and mannitol , or a combination of saccharin and mannitol, can significantly reduce the AST value.
  • the combination of menthol and mannitol was treated for 4 weeks, an excellent effect was obtained, and the ALT value (p ⁇ 0.005) and the AST value of about 62% (p ⁇ 0.005) were reduced by about 76%.
  • sucralose, mannitol, and eriodictol significantly reduced the ALT value (p ⁇ 0.005) when a combination of the three test compounds was administered.
  • Table 9-1 Test compounds increase liver antioxidant capacity (Gpx and GSH)
  • Gpx, GSH, Grd, and SOD are members of the common liver antioxidant system that reduces the oxidative stress in the liver and protects the liver from oxidative stress.
  • An increase in the values of Gpx, GSH, Grd, and SOD represents that the liver maintains better antioxidant activity.
  • mice induced by fatty liver were decreased.
  • orange peel, puerarin, eriodictyol, phlorizin, mannitol, and sucralose can significantly improve the antioxidant activity of the viscera.
  • mannitol was treated for 4 weeks, an excellent effect was obtained, and the levels of Gpx, GSH, Grd, and SOD were greatly increased (p ⁇ 0.005).
  • the compounds provided by the present invention can reduce liver fat content, reduce liver damage and increase liver antioxidant activity.
  • These compounds are low-molecular natural plant phenolic compounds, which are widely found in fruits and vegetables, grains, rhizomes, flowers, teas and red wines.
  • liver fat and improve related diseases such as Fatty liver, acute and chronic alcoholic fatty liver, acute and chronic non-alcoholic fatty liver disease (NAFLD), acute and chronic alcoholic hepatitis, acute and chronic nonalcoholic steatohepatitis, non-alcoholic liver
  • NAFLD non-alcoholic fatty liver disease
  • acute and chronic alcoholic hepatitis acute and chronic nonalcoholic steatohepatitis
  • non-alcoholic liver The potential of health foods or drugs for conditions such as cirrhosis, alcoholic cirrhosis (ICD-9-CM Diagnosis Code 571.8, 571.0, 571.1, 571.2, 571.3, 571.4, 571.5, 571.9).

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US15/564,507 US10925854B2 (en) 2015-11-19 2016-03-31 Methods and compositions for preventing or treating fatty liver, protecting liver function or ameliorating liver diseases caused by fatty liver or other associated disorders
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ES21173210T ES3044383T3 (en) 2015-09-24 2016-09-26 Mannitol for use in treating hepatotoxicity and fatty liver diseases
MX2018003700A MX395231B (es) 2015-09-24 2016-09-26 Compuestos eficaces en el tratamiento de la hepatotoxicidad y enfermedades de hígado graso, y uso de los mismos.
US15/564,526 US10456371B2 (en) 2015-09-24 2016-09-26 Substituted esters containing polyols and saccharides for treating hepatotoxicity and fatty liver diseases
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HRP20250899TT HRP20250899T1 (hr) 2015-09-24 2016-09-26 Manitol za uporabu u liječenju hepatotoksičnosti i masnih bolesti jetre
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