US20200022960A1 - Prophylactic and therapeutic drug for nonalcoholic fatty liver disease - Google Patents

Prophylactic and therapeutic drug for nonalcoholic fatty liver disease Download PDF

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US20200022960A1
US20200022960A1 US16/477,416 US201816477416A US2020022960A1 US 20200022960 A1 US20200022960 A1 US 20200022960A1 US 201816477416 A US201816477416 A US 201816477416A US 2020022960 A1 US2020022960 A1 US 2020022960A1
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liver disease
prophylactic
therapeutic agent
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fatty liver
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Yusuke Sasaki
Masato Asahiyama
Toshiya Tanaka
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Kowa Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—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
    • A61K31/351—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 not condensed with another ring
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • 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
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • 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

Definitions

  • the present invention relates to a prophylactic and/or therapeutic agent for nonalcoholic fatty liver disease.
  • Nonalcoholic fatty liver disease is a fatty liver disorder not associated with alcoholic hepatitis or viral hepatitis.
  • NAFLD is estimated to affect about 30% of the general population.
  • NAFLD is a generic term for a range of conditions from simple steatosis to nonalcoholic steatohepatitis (NASH).
  • Simple steatosis is accumulation of fat in hepatocytes and has a relatively good prognosis.
  • NASH includes both a fatty liver and liver inflammation and may lead to a relatively severe condition such as fibrosis of liver tissue, liver cirrhosis or hepatocellular carcinoma.
  • Non-Patent Documents 1, 2 and 3 The treatment for viral hepatitis such as hepatitis C has made rapid progress recently and therefore the number of patients with liver cancer caused by virus is expected to decrease in the future. In contrast, the number of patients with liver cancer based on NASH is expected to increase (Non-Patent Documents 1, 2 and 3).
  • NAFLD is considered to develop by a widely known mechanism of “two hit theory” in which NAFLD progresses from the stage of accumulation of fat in hepatocytes to the stage of liver inflammation/fibrosis (Non-Patent Document 4). Furthermore, “multiple-parallel hit theory” has been proposed recently, in which various factors are involved in progression of NAFLD in parallel (Non-Patent Document 5).
  • key factors are hepatocyte ballooning, Mallory-Denk body and fibrosis.
  • the NAFLD/NASH Clinical Practice Guideline of the Japanese Society of Gastroenterology defines the pathological diagnostic criterion for NASH as “NAFLD having hepatocyte ballooning degeneration with inflammation in addition to macrovesicular fatty change”.
  • NAFLD non-Patent Documents 3 and 6
  • Hepatocyte enlargement and ballooning degeneration are pathological findings that indicate fat accumulation causes degeneration of the cytoskeleton. These findings are key diagnosis criteria for NASH.
  • Drugs for the treatment target insulin resistance, lipid metabolism disorder, hypertension or oxidative stress.
  • Drugs used for insulin resistance include insulin sensitizing drug such as thiazolidine-based derivatives (pioglitazone, rosiglitazone, etc.) that are ligands for a nuclear receptor PPAR ⁇ involved in enhancement of insulin sensitivity, or biguanide-based drugs (metformin etc.).
  • Drugs used for lipid metabolism disorders include fibrate-based drugs (fenofibrate, bezafibrate, etc.) that are PPAR ⁇ agonists, statin-based preparations or intestinal cholesterol reabsorption inhibitors (ezetimibe etc.).
  • Drugs used for hypertension include angiotensin II type 1 receptor antagonists (ARBs) (Non-Patent Documents 1 and 3).
  • drugs used as an antioxidant include vitamin E.
  • An appropriate regimen for a patient may be selected depending on underlying disease from these drug treatments. However, any drug treatment requires further examination. Unfortunately, NAFLD has no currently available established drug treatment.
  • Patent Document 7 discloses that (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid or a salt thereof, or a solvate thereof has a selective PPAR ⁇ activating effect, and Patent Document 2 discloses that the compound is useful for prevention and treatment of nonalcoholic fatty liver disease.
  • Non-Patent Document 8 sodium glucose cotransporter 2 (SGLT2) inhibitors
  • SGLT2 sodium glucose cotransporter 2
  • An object of the present invention is to provide a pharmaceutical composition and/or a combination of drugs that have preventing and/or improving effect on enlargement of lipid droplets in hepatocytes and/or ballooning of hepatocytes and therefore are capable of preventing and/or treating NAFLD and NASH.
  • NASH-HCC mouse model a combination of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid (hereinafter, also referred to as Compound 1) that is a PPAR ⁇ agonist with an SGLT2 inhibitor, which is disclosed in Expert Opin. Investig.
  • Drugs (2013) 22(4): 463-486 etc. exerts strong effects to reduce the size of lipid droplet in hepatocyte and/or to suppress ballooning of hepatocyte, and as a result, to prevent and/or treat NAFLD and NASH.
  • the present invention has been accomplished on the basis of these findings.
  • the present invention relates to a composition, kit or the like, characterized by a combination of a PPAR ⁇ agonist with an SGLT2 inhibitor. More specifically, the present invention relates to the following items [1] to [52].
  • a prophylactic and/or therapeutic agent for liver disease including a combination of a PPAR ⁇ agonist with an SGLT2 inhibitor.
  • liver disease comprises nonalcoholic fatty liver disease.
  • liver disease comprises liver cirrhosis or hepatocellular carcinoma.
  • the prophylactic and/or therapeutic agent according to any of the items [1] to [6], wherein the SGLT2 inhibitor is selected from dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, luseogliflozin, tofogliflozin, ertugliflozin, sotagliflozin, bexagliflozin or remogliflozin.
  • the SGLT2 inhibitor is selected from dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, luseogliflozin, tofogliflozin, ertugliflozin, sotagliflozin, bexagliflozin or remogliflozin.
  • a medicament for use in prevention and/or treatment of liver disease including a combination of a PPAR ⁇ agonist with an SGLT2 inhibitor.
  • liver disease comprises nonalcoholic fatty liver disease.
  • liver disease comprises liver cirrhosis or hepatocellular carcinoma.
  • the medicament according to any of the items [10] to [15], wherein the SGLT2 inhibitor is selected from dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, luseogliflozin, tofogliflozin, ertugliflozin, sotagliflozin, bexagliflozin or remogliflozin.
  • the SGLT2 inhibitor is selected from dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, luseogliflozin, tofogliflozin, ertugliflozin, sotagliflozin, bexagliflozin or remogliflozin.
  • a pharmaceutical composition for preventing and/or treating liver disease including a PPAR ⁇ agonist, an SGLT2 inhibitor and a pharmaceutically acceptable carrier.
  • liver disease comprises nonalcoholic fatty liver disease.
  • composition according to the item [20] having an effect to suppress hepatocyte ballooning in a subject with nonalcoholic fatty liver disease.
  • liver disease comprises liver cirrhosis or hepatocellular carcinoma.
  • composition according to any of the items [19] to [24], wherein the SGLT2 inhibitor is selected from dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, luseogliflozin, tofogliflozin, ertugliflozin, sotagliflozin, bexagliflozin or remogliflozin.
  • the SGLT2 inhibitor is selected from dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, luseogliflozin, tofogliflozin, ertugliflozin, sotagliflozin, bexagliflozin or remogliflozin.
  • a method for preventing and/or treating liver disease including the process of administering to a subject in need of treatment an effective amount of a PPAR ⁇ agonist and the process of administering to the subject an effective amount of an SGLT2 inhibitor.
  • liver disease comprises nonalcoholic fatty liver disease.
  • liver disease comprises liver cirrhosis or hepatocellular carcinoma.
  • the SGLT2 inhibitor is selected from dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, luseogliflozin, tofogliflozin, ertugliflozin, sotagliflozin, bexagliflozin or remogliflozin.
  • liver disease comprises nonalcoholic fatty liver disease.
  • nonalcoholic fatty liver disease comprises nonalcoholic steatohepatitis.
  • liver disease comprises liver cirrhosis or hepatocellular carcinoma.
  • the SGLT2 inhibitor is selected from dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, luseogliflozin, tofogliflozin, ertugliflozin, sotagliflozin, bexagliflozin or remogliflozin.
  • liver disease comprises nonalcoholic fatty liver disease.
  • liver disease comprises liver cirrhosis or hepatocellular carcinoma.
  • the SGLT2 inhibitor is selected from dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, luseogliflozin, tofogliflozin, ertugliflozin, sotagliflozin, bexagliflozin or remogliflozin.
  • the therapeutic agent, medicament, pharmaceutical composition, treating method, use or combination of the present invention can suppress enlargement of lipid droplets in hepatocytes and/or ballooning of hepatocytes in a patient with nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). Accordingly, the present invention can provide new prevention and/or treatment of NAFLD and NASH. In particular, the present invention can provide prevention and/or treatment of highly severe NASH.
  • NAFLD nonalcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • FIG. 1 shows the lipid droplet size (pmt) in hepatocytes when Compound 1 (0.1 mg/kg), tofogliflozin (10 mg/kg) or a combination of Compound 1 (0.1 mg/kg) and tofogliflozin (10 mg/kg) of the present invention is administered.
  • FIG. 2 shows ballooning of hepatocytes when Compound 1 (0.1 mg/kg), tofogliflozin (10 mg/kg) or a combination of Compound 1 (0.1 mg/kg) and tofogliflozin (10 mg/kg) of the present invention is administered.
  • FIG. 3 shows ballooning of hepatocytes when Compound 1 (0.1 mg/kg), ipragliflozin (3 mg/kg) or a combination of Compound 1 (0.1 mg/kg) and ipragliflozin (3 mg/kg) of the present invention is administered.
  • PPAR ⁇ agonist means a generic term of compounds activating a PPAR ⁇ -type receptor.
  • PPAR ⁇ -type receptor is a type of peroxisome proliferator-activated receptors (PPAR) which are one kind of nuclear receptors.
  • PPAR ⁇ -type receptor involves in fat oxidation.
  • fibrates such as fenofibrate, clofibrate, bezafibrate, clinofibrate, ciprofibrate, etofibrate and gemfibrozil, and WY-14643 (pirinixic acid), GW-7647 (2-(4-(2-(1-(1-cyclohexane butyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionate), and pemafibrate.
  • SGLT2 inhibitor means a generic term of compounds having an inhibitory effect on a sodium glucose cotransporter 2 (SGLT2) involved in glucose reabsorption in the kidney.
  • SGLT2 sodium glucose cotransporter 2
  • dapagliflozin canagliflozin, ipragliflozin (ASP1941), empagliflozin (BI 10773), luseogliflozin (TS-071), tofogliflozin (CSG452), ertugliflozin (PF-04971729), sotagliflozin (LX-4211), bexagliflozin (EGT-1442) and remogliflozin (KGT-1681).
  • SGLT2 inhibitor means a generic term of compounds having an inhibitory effect on a sodium glucose cotransporter 2 (SGLT2) involved in glucose reabsorption in the kidney.
  • dapagliflozin canagliflozin
  • ipragliflozin i
  • Ipragliflozin is a common name for a compound (1S)-1,5-anhydro-1-C- ⁇ 3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl ⁇ -D-glucitol.
  • Ipragliflozin can be used, for example, as ipragliflozin L-proline (1:1).
  • Tofogliflozin is a common name for a compound (1S,3′R,4'S,5'S,6′R)-6-[(4-ethylphenyl)methyl]-6′-(hydroxymethyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[2-benzofuran-1,2′-pyran]-3′,4′,5′-triol.
  • Tofogliflozin can be used, for example, as tofogliflozin monohydrate.
  • Ipragliflozin can be produced, for example, according to the method described in WO 2004/080990 or according to any publicly known method described in documents.
  • Tofogliflozin can be produced, for example, according to the method described in WO 2006/080421 or according to any publicly known method described in documents.
  • the liver disease includes fatty liver, hepatitis, NAFLD, NASH, liver cirrhosis and liver cancer such as hepatocellular carcinoma.
  • the “salt” of the present invention is not particularly limited as long as it is pharmaceutically acceptable. It includes alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; inorganic base salts such as ammonium salt; organic base salts such as trialkylamine salt; mineral acid salts such as hydrochloride salt and sulfate salt; and organic acid salts such as acetate salt.
  • alkali metal salts such as sodium salt and potassium salt
  • alkaline earth metal salts such as calcium salt and magnesium salt
  • inorganic base salts such as ammonium salt
  • organic base salts such as trialkylamine salt
  • mineral acid salts such as hydrochloride salt and sulfate salt
  • organic acid salts such as acetate salt.
  • the “solvate” of the present invention includes a hydrate and alcoholate (such as ethanolate).
  • a combination drug is a pharmaceutical product including two or more active ingredients in a single dosage form.
  • an example of the combination drug may be a tablet including the PPAR ⁇ agonist and the SGLT2 inhibitor in an effective amount.
  • kits are a set of two or more pharmaceutical products. Each of the pharmaceutical products may be taken or administered simultaneously or separately at intervals.
  • an example of the kit may be a combination of a pharmaceutical product containing an effective amount of the PPAR ⁇ agonist with a pharmaceutical product containing an effective amount of the SGLT2 inhibitor.
  • NASH is characterized by hepatocyte ballooning in addition to enlargement of lipid droplets in hepatocytes (see Non-Patent Documents 3 and 6).
  • the combined use of Compound 1 with ipragliflozin significantly inhibited ballooning of hepatocytes in a NASH-HCC mouse that is a model animal for NASH.
  • the combined use of Compound 1 with tofogliflozin significantly inhibited ballooning of hepatocytes in a NASH-HCC mouse and inhibited enlargement of lipid droplets in the hepatocytes.
  • the combined use of the PPAR ⁇ agonist with the SGLT2 inhibitor of the present invention is useful as a prophylactic and/or therapeutic agent for NASH in mammals including humans.
  • the therapeutic agent, medicament and the like obtained by combining the PPAR ⁇ agonist with the SGLT2 inhibitor of the present invention can be used alone or in combination with other pharmaceutically acceptable carriers to prepare a dosage form such as tablets, capsules, granules, powders, lotions, ointments, injections or suppositories. These preparations can be produced according to a known method.
  • the therapeutic agents, medicaments and the like obtained by combining the PPAR ⁇ agonist with the SGLT2 inhibitor of the present invention are administered orally or parenterally.
  • Those skilled in the art can appropriately set the dose depending on the body weight, age, sex, symptom and the like of a patient.
  • the daily dose may range from 0.01 to 1000 mg, preferably from 0.01 to 10 mg, more preferably from 0.05 to 5 mg, and it is administered preferably in 1 to 3 divided doses.
  • the daily dose may range from 0.1 to 1000 mg, preferably from 1 to 200 mg.
  • tofogliflozin is used as the SGLT2 inhibitor
  • the daily dose may range from 0.1 to 500 mg, preferably from 1 to 100 mg. In either case, the daily dose is administered in 1 to 3 divided doses.
  • a NASH-HCC mouse is a model animal that develops liver cirrhosis from fatty liver via NASH when it is fed with a high fat diet, and subsequently develops hepatocellular carcinoma (Non-Patent Document 9).
  • the effect of compound 1 combined with tofogliflozin was examined using the NASH-HCC mouse model.
  • Compound 1 was prepared according to the method described in the Patent Document 1. Tofogliflozin monohydrate (Chugai Pharmaceutical Co., Ltd.) was used as a concrete example of tofogliflozin.
  • NASH-HCC mice were prepared with reference to Non-Patent Document 9, and were used for this experiment. Specifically, male C57BL/6J mice were subcutaneously administered 200 ⁇ g of streptozotocin on the second day after birth. The mice were fed ad libitum with a high-fat diet (HFD-32, Clea Japan, Inc.) for 2 weeks starting from 4-week-old. The mice were separated into four groups as described in below 2) and were administered drugs from 6-week-old to 9-week-old as described in below 3). Daily food consumption of the mice in each group were measured while the drugs were administered so that the mice of all groups were fed with the same amount of food as those for the control group.
  • HFD-32 high-fat diet
  • the mice were separated immediately before starting drug administration (at 6-week-old). There was no difference in the mean of body weight between the groups.
  • the control group was administered 3% gum arabic aqueous solution.
  • Compound 1 and/or tofogliflozin was dissolved in 3% gum arabic aqueous solution, and was administered to the group administered Compound 1, the group administered tofogliflozin or the group administered in their combination, respectively.
  • the mice of each group were orally administered the solution in 5 mL/kg body weight once a day. The administration period was for 3 weeks starting from 6-week-old as described above.
  • the liver of each mouse was excised under anesthesia and was fixed with 10% neutral buffered formalin solution to prepare hematoxylin-eosin stained specimens.
  • the lipid droplet size in hepatocyte was analyzed by image analysis software Image J. The area of 6000 to 10,000 lipid droplets was measured in each specimen. The median of the lipid droplet area was calculated for each mouse and then the median and quartile were calculated for each group based on the median for each mouse in the group. These data were expressed in a box-and-whisker plot ( FIG. 1 ).
  • Ballooning of hepatocytes in each mouse was scored under blind conditions according to the following criteria (Kleiner et al., Hepatology 41, 1313-21, 2005).
  • Balloon cell is rare (Few balloon cells): 1
  • Ballooning score was calculated in each group and the values were shown ( FIG. 2 ).
  • Statistical processing was performed using statistical software EZR, which extends the functions of R and R commander.
  • the software is distributed free of charge on the website of Jichi Medical University Saitama Medical Center (Bone Marrow Transplantation (2013) 48, 452-458).
  • Non-Patent Document 9 The effect of Compound 1 combined with ipragliflozin was examined in NASH-HCC mice.
  • Compound 1 was prepared according to the method described in the Patent Document 1.
  • Ipragliflozin (Shanghai Haoyuan Chamexpress Co., Ltd., Shanghai, China) was used as a concrete example of ipragliflozin.
  • NASH-HCC mice were prepared in the same manner as in 1) of Example 1, and were used for this experiment.
  • the mice were separated immediately before starting drug administration (at 6-week-old). There was no difference in the mean of body weight between the groups.
  • the control group was administered 3% gum arabic aqueous solution.
  • Compound 1 and/or ipragliflozin was dissolved in 3% gum arabic aqueous solution, and was administered to the group administered Compound 1, the group administered ipragliflozin or the group administered in their combination, respectively.
  • the mice of each group were orally administered the solution in 5 mL/kg body weight once a day. The administration period was for 3 weeks starting from 6-week-old.
  • a combined use of Compound 1 with an SGLT2 inhibitor such as tofogliflozin or ipragliflozin of the present invention provides a remarkable effect to reduce lipid droplet size in hepatocytes and to suppressballooning of hepatocytes in the NASH mouse model.
  • Reduction of lipid droplet size in hepatocytes and suppression of ballooning of hepatocytes correspond to improvement of the condition of NAFLD and NASH, which in turn leads to prevention of liver cirrhosis and hepatocellular carcinoma that are terminal diseases of NAFLD and NASH.
  • the present invention Since a combination of a PPAR ⁇ agonist and an SGLT2 inhibitor exhibits a prophylactic and/or therapeutic effect on NAFLD and NASH, the present invention has industrial applicability.

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BR112019020485A2 (pt) 2017-04-03 2020-05-12 Coherus Biosciences, Inc. Agonista ppary para tratamento de paralisia supranuclear progressiva
JP2022516509A (ja) * 2018-12-31 2022-02-28 コヒラス・バイオサイエンシズ・インコーポレイテッド 非アルコール性脂肪性肝疾患（ｎａｆｌｄ）を治療するための組成物および方法
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EP3569250A1 (en) 2019-11-20
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BR112019013539A2 (pt) 2020-01-07
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CN110167595A (zh) 2019-08-23
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JP7202892B2 (ja) 2023-01-12
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