U.S. patent application number 16/477416 was filed with the patent office on 2020-01-23 for prophylactic and therapeutic drug for nonalcoholic fatty liver disease.
This patent application is currently assigned to Kowa Company, Ltd.. The applicant listed for this patent is Kowa Company, Ltd.. Invention is credited to Masato Asahiyama, Yusuke Sasaki, Toshiya Tanaka.
Application Number | 20200022960 16/477416 |
Document ID | / |
Family ID | 62840012 |
Filed Date | 2020-01-23 |
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United States Patent
Application |
20200022960 |
Kind Code |
A1 |
Sasaki; Yusuke ; et
al. |
January 23, 2020 |
PROPHYLACTIC AND THERAPEUTIC DRUG FOR NONALCOHOLIC FATTY LIVER
DISEASE
Abstract
The present invention addresses the problem of providing a
medicinal composition and a drug combination by which nonalcoholic
fatty liver disease and nonalcoholic steatohepatitis can be
prevented and/or treated. The present invention provides a
combination of a peroxisome proliferator-activated receptor (PPAR)
.alpha. agonist with a sodium glucose cotransporter 2 (SGLT2)
inhibitor, which is to be used for preventing and/or treating
nonalcoholic fatty liver disease and nonalcoholic
steatohepatitis.
Inventors: |
Sasaki; Yusuke; (Tokyo,
JP) ; Asahiyama; Masato; (Shizuoka, JP) ;
Tanaka; Toshiya; (Tokyo, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Kowa Company, Ltd. |
Nagoya-shi |
|
JP |
|
|
Assignee: |
Kowa Company, Ltd.
Nagoya-shi
JP
|
Family ID: |
62840012 |
Appl. No.: |
16/477416 |
Filed: |
January 11, 2018 |
PCT Filed: |
January 11, 2018 |
PCT NO: |
PCT/JP2018/000398 |
371 Date: |
July 11, 2019 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 1/16 20180101; A61K
31/381 20130101; A61P 35/00 20180101; A61K 31/7034 20130101; A61K
45/06 20130101; A61K 31/7048 20130101; A61K 31/423 20130101; A61P
43/00 20180101 |
International
Class: |
A61K 31/423 20060101
A61K031/423; A61P 1/16 20060101 A61P001/16 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 11, 2017 |
JP |
2017-002731 |
Claims
1. A prophylactic and/or therapeutic agent for liver disease,
comprising a combination of a PPAR.alpha. agonist with an SGLT2
inhibitor.
2. The prophylactic and/or therapeutic agent according to claim 1,
wherein the liver disease comprises nonalcoholic fatty liver
disease.
3. The prophylactic and/or therapeutic agent according to claim 2,
wherein the nonalcoholic fatty liver disease comprises nonalcoholic
steatohepatitis.
4. The prophylactic and/or therapeutic agent according to claim 2,
having an effect to suppress hepatocyte ballooning in a subject
with nonalcoholic fatty liver disease.
5. The prophylactic and/or therapeutic agent according to claim 1,
wherein the liver disease comprises liver cirrhosis or
hepatocellular carcinoma.
6. The prophylactic and/or therapeutic agent according to claim 1,
wherein the PPAR.alpha. agonist is
(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]p-
henoxy]butyric acid or a salt thereof, or a solvate thereof.
7. The prophylactic and/or therapeutic agent according to claim 1,
wherein the SGLT2 inhibitor is selected from the group consisting
of dapagliflozin, canagliflozin, ipragliflozin, empagliflozin,
luseogliflozin, tofogliflozin, ertugliflozin, sotagliflozin,
bexagliflozin and remogliflozin.
8. The prophylactic and/or therapeutic agent according to claim 1,
being a combination drug.
9. The prophylactic and/or therapeutic agent according to claim 1,
being a kit.
10. A kit comprising a prophylactic and/or therapeutic agent of
claim 1.
11. A method for treating a subject suffering from or susceptible
to a liver disease, the method comprising: administering to the
subject a PPAR.alpha. agonist and an SGLT2 inhibitor.
12. The method of claim 11 the subject is suffering from
nonalcoholic fatty liver disease.
13. The method of claim 11 wherein the subject is suffering from
nonalcoholic steatohepatitis.
14. The method of claim 11 wherein the subject is suffering from
liver cirrhosis.
15. The method of claim 11 wherein the subject is suffering from
hepatocellular carcinoma.
16. The method of claim 11 wherein the subject is identified as
suffering from liver disease and an effective amount of a
PPAR.alpha. agonist and an SGLT2 inhibitor is administered to the
identified subject.
Description
TECHNICAL FIELD
[0001] The present invention relates to a prophylactic and/or
therapeutic agent for nonalcoholic fatty liver disease.
BACKGROUND ART
[0002] Nonalcoholic fatty liver disease (NAFLD) 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. 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).
[0003] 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). In diagnosis of NASH, 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".
[0004] Matteoni et al. classified NAFLD patients into four stages
based on the pathological findings in light of their prognosis, and
defined Types 3 and 4 as NASH (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.
[0005] Treatment for NAFLD bases principally on care about obesity,
diabetes, dyslipidemia and hypertension through improvement of
lifestyle such as diet therapy and exercise therapy. In addition to
improvement of lifestyle, drug treatments are performed in clinical
practice. 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.gamma. 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.alpha. 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).
[0006] In addition, for oxidative stress, drugs used as an
antioxidant include vitamin E.
[0007] 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.
[0008] Regarding fibrate-based drugs, fenofibrate is reported to be
investigated for the effect on NAFLD in clinical trials (Non-Patent
Document 7). In addition, Patent Document 1 discloses that
(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]p-
henoxy]butyric acid or a salt thereof, or a solvate thereof has a
selective PPAR.alpha. activating effect, and Patent Document 2
discloses that the compound is useful for prevention and treatment
of nonalcoholic fatty liver disease. Meanwhile, as for sodium
glucose cotransporter 2 (SGLT2) inhibitors, remogurifurojin has
been performed clinical investigation and is reported to have
curative effect on NASH (Non-Patent Document 8). Along with a
worldwide increase in patients with metabolic syndrome, the number
of NASH patients is also predicted to increase. Since NASH is
thought to be a cause of nonviral hepatocellular carcinoma, which
is a major factor for cancer-related death (Non-Patent Document 9),
more effective treatment is desired to be established.
CITATION LIST
Patent Document
[0009] Patent Document 1: WO 2005/023777 [0010] Patent Document 2:
WO 2015/005365
Non-Patent Document
[0010] [0011] Non-Patent Document 1: Chalasani N. et al.
Hepatology, 55, 2005-23 (2012) [0012] Non-Patent Document 2: Musso
G. et al. Nat. Rev. Drug Discov. 15 (4), 249-74 (2016.1) [0013]
Non-Patent Document 3: NAFLD/NASH Clinical Practice Guideline, 2014
of the Japanese Society of Gastroenterology [0014] Non-Patent
Document 4: Day C P. et al, Gastroenterology, 114 (4), 842-5 (1998)
[0015] Non-Patent Document 5: Tilg H. et al. Hepatology, 52,
1836-46 (2010) [0016] Non-Patent Document 6: Matteoni C A. et al.
Gastroenterology, 116, 1413-9 (1999) [0017] Non-Patent Document 7:
Fernandez-Miranda C. et al. Dig. Liver Dis., 40, 200-5 (2008)
[0018] Non-Patent Document 8: Wilkison W. et al. Abstract 0047.
International Liver Congress; Apr. 22-26, 2015 [0019] Non-Patent
Document 9: Fujii M. et al. Med. Mol. Morphol, 46, 141-52
(2013)
SUMMARY OF INVENTION
Technical Problem
[0020] 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.
Solution to Problem
[0021] In view of the above-mentioned problems, in order to find a
mean useful for prevention and/or treatment of nonalcoholic fatty
liver disease (NAFLD), in particular, severe nonalcoholic
steatohepatitis (NASH), the present inventors have conducted
intensive studies using a NASH-HCC mouse model. They have found
that a combination of
(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]p-
henoxy]butyric acid (hereinafter, also referred to as Compound 1)
that is a PPAR.alpha. 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.
[0022] In other words, the present invention relates to a
composition, kit or the like, characterized by a combination of a
PPAR.alpha. agonist with an SGLT2 inhibitor. More specifically, the
present invention relates to the following items [1] to [52].
[0023] [1] A prophylactic and/or therapeutic agent for liver
disease, including a combination of a PPAR.alpha. agonist with an
SGLT2 inhibitor.
[0024] [2] The prophylactic and/or therapeutic agent according to
the item [1], wherein the liver disease comprises nonalcoholic
fatty liver disease.
[0025] [3] The prophylactic and/or therapeutic agent according to
the item [2], wherein the nonalcoholic fatty liver disease
comprises nonalcoholic steatohepatitis.
[0026] [4] The prophylactic and/or therapeutic agent according to
the item [2], having an effect to suppress hepatocyte ballooning in
a subject with nonalcoholic fatty liver disease.
[0027] [5] The prophylactic and/or therapeutic agent according to
the item [1], wherein the liver disease comprises liver cirrhosis
or hepatocellular carcinoma.
[0028] [6] The prophylactic and/or therapeutic agent according to
any of the items [1] to [5], wherein the PPAR.alpha. agonist is
(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]p-
henoxy]butyric acid or a salt thereof, or a solvate thereof.
[0029] [7] 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.
[0030] [8] The prophylactic and/or therapeutic agent according to
any of the items [1] to [7], being a combination drug.
[0031] [9] The prophylactic and/or therapeutic agent according to
any of the items [1] to [7], being a kit.
[0032] [10] A medicament for use in prevention and/or treatment of
liver disease, including a combination of a PPAR.alpha. agonist
with an SGLT2 inhibitor.
[0033] [11] The medicament according to the item [10], wherein the
liver disease comprises nonalcoholic fatty liver disease.
[0034] [12] The medicament according to the item [11], wherein the
nonalcoholic fatty liver disease comprises nonalcoholic
steatohepatitis.
[0035] [13] The medicament according to the item [11], having an
effect to suppress hepatocyte ballooning in a subject with
nonalcoholic fatty liver disease.
[0036] [14] The medicament according to the item [10], wherein the
liver disease comprises liver cirrhosis or hepatocellular
carcinoma.
[0037] [15] The medicament according to any of the items [10] to
[14], wherein the PPAR.alpha. agonist is
(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]p-
henoxy]butyric acid or a salt thereof, or a solvate thereof.
[0038] [16] 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.
[0039] [17] The medicament according to any of the items [10] to
[16], being a combination drug.
[0040] [18] The medicament according to any of the items [10] to
[16], being a kit.
[0041] [19] A pharmaceutical composition for preventing and/or
treating liver disease, including a PPAR.alpha. agonist, an SGLT2
inhibitor and a pharmaceutically acceptable carrier.
[0042] [20] The pharmaceutical composition according to the item
[19], wherein the liver disease comprises nonalcoholic fatty liver
disease.
[0043] [21] The pharmaceutical composition according to the item
[20], wherein the nonalcoholic fatty liver disease comprises
nonalcoholic steatohepatitis.
[0044] [22] The pharmaceutical composition according to the item
[20], having an effect to suppress hepatocyte ballooning in a
subject with nonalcoholic fatty liver disease.
[0045] [23] The pharmaceutical composition according to the item
[19], wherein the liver disease comprises liver cirrhosis or
hepatocellular carcinoma.
[0046] [24] The pharmaceutical composition according to any of the
items [19] to [23], wherein the PPAR.alpha. agonist is
(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]p-
henoxy]butyric acid or a salt thereof, or a solvate thereof.
[0047] [25] The pharmaceutical 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.
[0048] [26] 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.alpha. agonist and the
process of administering to the subject an effective amount of an
SGLT2 inhibitor.
[0049] [27] The preventing and/or treating method according to the
item [26], wherein the liver disease comprises nonalcoholic fatty
liver disease.
[0050] [28] The preventing and/or treating method according to the
item [27], wherein the nonalcoholic fatty liver disease comprises
nonalcoholic steatohepatitis.
[0051] [29] The preventing and/or treating method according to the
item [27], for suppressing ballooning of hepatocytes in the subject
with nonalcoholic fatty liver disease.
[0052] [30] The preventing and/or treating method according to the
item [26], wherein the liver disease comprises liver cirrhosis or
hepatocellular carcinoma.
[0053] [31] The preventing and/or treating method according to any
of the items [26] to [30], wherein the PPAR.alpha. agonist is
(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]p-
henoxy]butyric acid or a salt thereof, or a solvate thereof.
[0054] [32] The preventing and/or treating method according to any
of the items [26] to [31], wherein the SGLT2 inhibitor is selected
from dapagliflozin, canagliflozin, ipragliflozin, empagliflozin,
luseogliflozin, tofogliflozin, ertugliflozin, sotagliflozin,
bexagliflozin or remogliflozin.
[0055] [33] The preventing and/or treating method according to any
of the items [26] to [32], wherein the PPAR.alpha. agonist and the
SGLT2 inhibitor are simultaneously administered.
[0056] [34] The preventing and/or treating method according to any
of the items [26] to [32], wherein the PPAR.alpha. agonist and the
SGLT2 inhibitor are separately administered at intervals.
[0057] [35] Use of a PPAR.alpha. agonist and an SGLT2 inhibitor for
manufacture of a prophylactic and/or therapeutic agent for liver
disease.
[0058] [36] The use according to the item [35], wherein the liver
disease comprises nonalcoholic fatty liver disease.
[0059] [37] The use according to the item [36], wherein the
nonalcoholic fatty liver disease comprises nonalcoholic
steatohepatitis.
[0060] [38] The use according to the item [36], wherein the agent
has an effect to suppress hepatocyte ballooning in a subject with
nonalcoholic fatty liver disease.
[0061] [39] The use according to the item [35], wherein the liver
disease comprises liver cirrhosis or hepatocellular carcinoma.
[0062] [40] The use according to any of the items [35] to [39],
wherein the PPAR.alpha. agonist is
(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]p-
henoxy]butyric acid or a salt thereof, or a solvate thereof.
[0063] [41] The use according to any of the items [35] to [40],
wherein the SGLT2 inhibitor is selected from dapagliflozin,
canagliflozin, ipragliflozin, empagliflozin, luseogliflozin,
tofogliflozin, ertugliflozin, sotagliflozin, bexagliflozin or
remogliflozin.
[0064] [42] The use according to any of the items [35] to [41],
wherein the agent is a combination drug.
[0065] [43] The use according to any of the items [35] to [41],
wherein the agent is a kit.
[0066] [44] A combination of a PPAR.alpha. agonist with an SGLT2
inhibitor for preventing and/or treating liver disease.
[0067] [45] The combination according to the item [44], wherein the
liver disease comprises nonalcoholic fatty liver disease.
[0068] [46] The combination according to the item [45], wherein the
nonalcoholic fatty liver disease comprises nonalcoholic
steatohepatitis.
[0069] [47] The combination according to the item [45], having an
effect to suppress hepatocyte ballooning in a subject with
nonalcoholic fatty liver disease.
[0070] [48] The combination according to the item [44], wherein the
liver disease comprises liver cirrhosis or hepatocellular
carcinoma.
[0071] [49] The combination according to any of the items [44] to
[48], wherein the PPAR.alpha. agonist is
(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]p-
henoxy]butyric acid or a salt thereof, or a solvate thereof.
[0072] [50] The combination according to any of the items [44] to
[49], wherein the SGLT2 inhibitor is selected from dapagliflozin,
canagliflozin, ipragliflozin, empagliflozin, luseogliflozin,
tofogliflozin, ertugliflozin, sotagliflozin, bexagliflozin or
remogliflozin.
[0073] [51] The combination according to any of the items [44] to
[50], being a combination drug.
[0074] [52] The combination according to any of the items [44] to
[50], being a kit.
Advantageous Effects of Invention
[0075] 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.
BRIEF DESCRIPTION OF DRAWINGS
[0076] 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.
[0077] 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.
[0078] 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.
DESCRIPTION OF EMBODIMENTS
[0079] In the present invention, PPAR.alpha. agonist means a
generic term of compounds activating a PPAR.alpha.-type receptor.
PPAR.alpha.-type receptor is a type of peroxisome
proliferator-activated receptors (PPAR) which are one kind of
nuclear receptors. PPAR.alpha.-type receptor involves in fat
oxidation. Specifically included are 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.
(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]p-
henoxy]butyric acid (Compound 1), which is also known as the common
name pemafibrate, is used in the present invention. It can be
produced, for example, according to the method described in WO
2005/023777 or according to any publicly known method described in
documents.
[0080] In the present invention, 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. Specifically included are 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). Each of these compounds may be used as a
pharmaceutically acceptable salt and/or solvate as appropriate, but
the present invention includes all of them.
[0081] 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).
[0082] 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.
[0083] 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.
[0084] 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.
[0085] In the present invention, the liver disease includes fatty
liver, hepatitis, NAFLD, NASH, liver cirrhosis and liver cancer
such as hepatocellular carcinoma.
[0086] 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.
[0087] The "solvate" of the present invention includes a hydrate
and alcoholate (such as ethanolate).
[0088] A combination drug is a pharmaceutical product including two
or more active ingredients in a single dosage form. In the present
invention, an example of the combination drug may be a tablet
including the PPAR.alpha. agonist and the SGLT2 inhibitor in an
effective amount.
[0089] A kit is a set of two or more pharmaceutical products. Each
of the pharmaceutical products may be taken or administered
simultaneously or separately at intervals. In the present
invention, an example of the kit may be a combination of a
pharmaceutical product containing an effective amount of the
PPAR.alpha. agonist with a pharmaceutical product containing an
effective amount of the SGLT2 inhibitor.
[0090] NASH is characterized by hepatocyte ballooning in addition
to enlargement of lipid droplets in hepatocytes (see Non-Patent
Documents 3 and 6). As described in the Examples below, 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. In addition, 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. Accordingly, the combined use of the
PPAR.alpha. agonist with the SGLT2 inhibitor of the present
invention is useful as a prophylactic and/or therapeutic agent for
NASH in mammals including humans.
[0091] The therapeutic agent, medicament and the like obtained by
combining the PPAR.alpha. 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.
[0092] The therapeutic agents, medicaments and the like obtained by
combining the PPAR.alpha. 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. When
Compound 1 as a PPAR.alpha. agonist is administered to an adult,
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. When ipragliflozin is used as
an SGLT2 inhibitor, the daily dose may range from 0.1 to 1000 mg,
preferably from 1 to 200 mg. When 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.
EXAMPLES
[0093] Hereinafter, the present invention is described more
specifically with reference to Examples, but the present invention
is not limited to the Examples at all.
Example 1 Effect of Compound 1 Combined with Tofogliflozin on NASH
Mouse Model
[0094] 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.
[0095] In this examination, 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.
[0096] 1) Used Animal:
[0097] 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 .mu.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.
[0098] 2) Manner of Grouping:
[0099] NASH-HCC mice were separated into four groups which included
a control group, a group administered 0.1 mg/kg of Compound 1, a
group administered 10 mg/kg of tofogliflozin and a group
administered in their combination (0.1 mg/kg of Compound 1 and 10
mg/kg of tofogliflozin) (n=5 to 7). 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.
[0100] 3) Drug Administration:
[0101] 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.
[0102] 4) Method of Observation and Examination:
[0103] After the administration period, the liver of each mouse was
excised under anesthesia and was fixed with 10% neutral buffered
formalin solution to prepare hematoxylin-eosin stained specimens.
Using the 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).
[0104] Ballooning of hepatocytes in each mouse was scored under
blind conditions according to the following criteria (Kleiner et
al., Hepatology 41, 1313-21, 2005).
[0105] No balloon cells: 0
[0106] Balloon cell is rare (Few balloon cells): 1
[0107] Many Balloon cells or prominent (Ballooning): 2 Then, the
mean value of the scores (ballooning score) was calculated in each
group and the values were shown (FIG. 2).
[0108] 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). The Steel test (N=5 to 7) was
performed using EZR, the drug administration group was labeled with
the mark * in figures when the group had the significant difference
at p<0.05 with respect to the control group, and labeled with
the mark ** when the group had the significant difference at
p<0.01.
[0109] 5) Result
[0110] As shown in FIG. 1, the median of lipid droplet size was
1.17 (.mu.m.sup.2) in the control group, 1.00 (.mu.m.sup.2) in the
group administered 0.1 mg/kg of Compound 1 and 1.00 (.mu.m.sup.2)
in the group administered 10 mg/kg of tofogliflozin. Although there
was a tendency of the size of lipid droplets in hepatocytes to
decrease, there was no statistically significant difference. In
contrast with the single administration groups, the median of lipid
droplet size was 0.89 (.mu.m.sup.2) in their combination use group,
and a significant decrease (p=0.037) was observed with respect to
the control group.
[0111] In addition, as shown in FIG. 2, the ballooning score was
1.33 in the control group, 0.60 in the group administered 0.1 mg/kg
of Compound 1 and 0.71 in the group administered 10 mg/kg of
tofogliflozin. Although there was a tendency of ballooning of
hepatocytes to be suppressed, there was no statistically
significant difference. In contrast with the single administration
groups, the ballooning score was 0.14 in their combination use
group, and a marked suppression (p=0.0089) of ballooning of
hepatocytes was observed with respect to the control group.
Example 2 Effect of Compound 1 Combined with Ipragliflozin on NASH
Mouse Model
[0112] The effect of Compound 1 combined with ipragliflozin was
examined in NASH-HCC mice (Non-Patent Document 9).
[0113] In this examination, 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.
[0114] 1) Used Animals:
[0115] NASH-HCC mice were prepared in the same manner as in 1) of
Example 1, and were used for this experiment.
[0116] 2) Manner of Grouping:
[0117] NASH-HCC mice were separated into four groups which included
a control group, a group administrated 0.1 mg/kg of Compound 1, a
group administrated 3 mg/kg of ipragliflozin and a group
administrated in their combination (0.1 mg/kg of Compound 1 and 3
mg/kg of ipragliflozin) (n=8). 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.
[0118] 3) Drug Administration:
[0119] 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.
[0120] 4) Method of Observation and Examination:
[0121] Observation and examination was carried out in the same
manner as in 4) of Example 1.
[0122] 5) Result
[0123] As shown in FIG. 3, the ballooning score was 1.50 in the
control group, 1.35 in the group administrated 0.1 mg/kg of
Compound 1 and 0.88 in the group administrated 3 mg/kg of
ipragliflozin. Although there was a tendency of ballooning of
hepatocytes to be suppressed, there was no statistically
significant difference. In contrast with the single administration
group, the ballooning score was 0.38 in their combined use group,
and a marked suppression (p=0.009) of ballooning of hepatocytes was
observed with respect to the control group.
[0124] As is evident from the above results, 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.
INDUSTRIAL APPLICABILITY
[0125] Since a combination of a PPAR.alpha. agonist and an SGLT2
inhibitor exhibits a prophylactic and/or therapeutic effect on
NAFLD and NASH, the present invention has industrial
applicability.
* * * * *