U.S. patent application number 15/801738 was filed with the patent office on 2018-07-05 for novel composition for nonalcoholic fatty liver disease (nafld).
The applicant listed for this patent is Cadila Healthcare Limited. Invention is credited to Rajendrakumar Hariprasad Jani, Pankaj Patel.
Application Number | 20180185330 15/801738 |
Document ID | / |
Family ID | 49253372 |
Filed Date | 2018-07-05 |
United States Patent
Application |
20180185330 |
Kind Code |
A1 |
Patel; Pankaj ; et
al. |
July 5, 2018 |
NOVEL COMPOSITION FOR NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)
Abstract
The present invention provides a compound of Formula (I) or
pharmaceutical acceptable thereof, wherein `R` is herein described.
In addition, the invention relates to composition comprising
effective therapeutic amount of compound of formula (I) and methods
of using the compounds for treating or prevention disorder such as
nonalcoholic fatty liver disease (NAFLD) including fatty liver
(steatosis), nonalcoholic steatohepatitis (NASH), and cirrhosis
(advanced scarring of the liver).
Inventors: |
Patel; Pankaj; (Admedabad,
IN) ; Hariprasad Jani; Rajendrakumar; (Ahmedabad,
IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cadila Healthcare Limited |
Ahmedabad |
|
IN |
|
|
Family ID: |
49253372 |
Appl. No.: |
15/801738 |
Filed: |
November 2, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15343859 |
Nov 4, 2016 |
9814697 |
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15801738 |
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14782609 |
Oct 6, 2015 |
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PCT/IN2013/000391 |
Jun 25, 2013 |
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15343859 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
Y10S 514/893 20130101;
A61K 31/40 20130101; A61P 1/16 20180101 |
International
Class: |
A61K 31/40 20060101
A61K031/40 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 22, 2013 |
IN |
1468/MUM/2013 |
Claims
1-26. (canceled)
27. A method of ameliorating fibrosis, comprising administering to
a subject in need thereof an effective amount of a pharmaceutical
composition comprising a pharmaceutically acceptable salt of
##STR00004## wherein R is --S-methyl, to ameliorate the
fibrosis.
28. The method of claim 27, wherein the pharmaceutically acceptable
salt is a metal cation salt.
29. The method of claim 27, wherein the pharmaceutically acceptable
salt is a metal cation salt selected from the group consisting of a
sodium salt, potassium salt, calcium salt, and magnesium salt.
30. The method of claim 27, wherein the pharmaceutically acceptable
salt is a magnesium salt.
31. A method of ameliorating fibrosis, comprising administering to
a subject in need thereof a therapeutically effective amount of
##STR00005## wherein R is --S-methyl, and M.sup.+ is a metal
cation, to ameliorate the fibrosis.
32. The method of claim 31, wherein M.sup.+ is Mg.sup.2+.
33. A method of treating cirrhosis, comprising administering to a
subject in need thereof a therapeutically effective amount of a
pharmaceutical composition comprising a pharmaceutically acceptable
salt of ##STR00006## wherein R is --S-methyl, to treat the
cirrhosis.
34. The method of claim 33, wherein the pharmaceutically acceptable
salt is a metal cation salt.
35. The method of claim 33, wherein the pharmaceutically acceptable
salt is a metal cation salt selected from the group consisting of a
sodium salt, potassium salt, calcium salt, and magnesium salt.
36. The method of claim 33, wherein the pharmaceutically acceptable
salt is a magnesium salt.
37. A method of treating cirrhosis, comprising administering to a
subject in need thereof a therapeutically effective amount of
##STR00007## wherein R is --S-methyl, and M.sup.+ is a metal
cation, to treat the cirrhosis.
38. The method of claim 37, wherein M.sup.+ is Mg.sup.2+.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to pharmaceutical compositions
containing the formula (I)
##STR00001##
for the reduction and removal of lipid accumulated in the liver
cells (hepatocytes) which is associated with nonalcoholic fatty
liver disease (NAFLD). The present invention further provides the
composition of formula (I) useful in the prevention and treatment
of nonalcoholic fatty liver disease (NAFLD)
BACKGROUND OF THE INVENTION
[0002] Nonalcoholic fatty liver disease (NAFLD) refers to a wide
spectrum of liver disease ranging from simple fatty liver
(steatosis), to nonalcoholic steatohepatitis (NASH), to cirrhosis
(irreversible, advanced scarring of the liver). All of the stages
of NAFLD have in common the accumulation of fat (fatty
infiltration) in the liver cells (hepatocytes). In NASH, the fat
accumulation is associated with varying degrees of inflammation,
fibrosis and scarring of the liver.
[0003] NASH and NAFLD are frequently reported in both men and
women, although it most often appears in women and is especially
prevalent in the obese. Although the disease has been observed to
be accompanied by several other pathological conditions, including
diabetes mellitus, hyperlipidemia, hyperglycemia, all part of the
"metabolic syndrome," the cause and progression of the disease, as
well as the causal or temporal relation to these conditions, is not
well understood.
[0004] However, in patients suffering from NAFLD and NASH in
particular, certain characteristics of liver tissue and
abnormalities of function are typical. Specifically, fatty
deposits, tissue degeneration, inflammation, cell degeneration,
fibrosis, cirrhosis, elevation of free fatty acids and other such
abnormalities have come to be associated with nonalcoholic
steatohepatitis and are frequently seen in patients suffering from
different forms of NAFLD.
[0005] The physiological condition that most commonly accompanies
NASH is obesity, with approximately 70% and above of NASH sufferers
also displaying clinically diagnosed obesity. NASH is particularly
prevalent in obese patients who have undergone jejunal bypass to
treat the obesity. In NASH patients, the extent of obesity tends to
be generally correlated with the amount of steatosis and to be
unrelated to non-insulin-dependent diabetes mellitus. However,
non-insulin-dependent diabetes mellitus increases the prevalence of
steatohepatitis especially in patients requiring insulin. Unless a
massive amount of the excess body weight is eliminated, weight loss
in patients before death does not appear to alleviate the steatosis
and, somewhat paradoxically, obese patients who lost weight before
death can have a higher incidence of steatohepatitis.
[0006] Even in NASH patients who do not consume any alcohol at all,
liver biopsy specimens tend to mimic those seen in patients
suffering from alcoholic hepatitis. However, a comparison of the
two conditions reveals a higher incidence of vacuolation
(indicative of diabetes) and steatosis in NASH as compared to
alcoholic hepatitis. Patients suffering from alcoholic hepatitis
also have a higher incidence of periportal and pericellular
fibrosis and proliferation of the bile ducts. Overall, the symptoms
and histological damage observed in alcoholic hepatitis patients
are more severe than in NASH.
[0007] Currently, there is no established therapy for patients
suffering from NASH. Weight loss is a common prescription, simply
because obesity is frequently detected in patients suffering from
NASH. The effect of a reduction in weight loss on NASH cannot be
determined with certainty, however, because obese patients seldom
maintain significant weight reduction. Thus, there is a need to
find a treatment for NAFLD and particularly NASH.
OBJECTS OF THE INVENTION
[0008] In one embodiment, the present invention discloses a
pharmaceutical composition containing the compound of the Formula
(I)
##STR00002##
for reduction and removal of lipid accumulated in the liver cells
(hepatocytes), required for treating and preventing certain
diseases and conditions related to nonalcoholic fatty liver disease
(NAFLD) including fatty liver (steatosis), nonalcoholic
steatohepatitis (NASH), and cirrhosis (advanced scarring of the
liver) in patient in need of such treatment.
[0009] In another embodiment the present invention provides a
method and a formulation comprising an effective amount of compound
of Formula (I) for treating nonalcoholic fatty liver disease
(NAFLD) including fatty liver (steatosis), nonalcoholic
steatohepatitis (NASH), and cirrhosis (advanced scarring of the
liver).
[0010] The method comprises administering to a subject an effective
amount of a compound of formula (I) as a pharmaceutical
formulation, as disclosed hereinafter including pharmaceutically
acceptable salts of the compound of formula (I).
[0011] In yet another embodiments the invention further provides a
pharmaceutical composition containing effective amount of compound
of formula (I) suitable for treatment of nonalcoholic fatty liver
disease (NAFLD) including fatty liver (steatosis), nonalcoholic
steatohepatitis (NASH), and cirrhosis (advanced scarring of the
liver).
[0012] In another embodiment the present invention provides a
method of treating alcoholic steatohepatitis in a subject,
comprising administering to the subject an effective amount of a
compound according to Formula (I), or a pharmaceutically acceptable
salt thereof as a suitable pharmaceutically acceptable
composition.
[0013] In another embodiment the present invention provides a
method of treating liver failure in a subject, comprising
administering to the subject an effective amount of a compound
according to Formula (I), or a pharmaceutically acceptable salt
thereof. The above and other embodiments of the present invention
are disclosed further hereinafter.
DESCRIPTION OF THE FIGURES
[0014] FIG. 1: Effect of Saroglitazar on ALT in PP population
[0015] FIG. 2: Effect of Saroglitazar on liver function test in
Safety Population
[0016] FIG. 3: Effect of Saroglitazar on C-Peptide and HOMA
Function in PP population
[0017] FIG. 4: Effect of Saroglitazar on Triglycerides in PP
population
DETAILED DESCRIPTION OF THE INVENTION
[0018] The present invention describes a pharmaceutical composition
for reduction and removal of lipid accumulated in the liver cells
(hepatocytes), required for treating and preventing certain
diseases and conditions in subject suffering from nonalcoholic
fatty liver disease (NAFLD) including fatty liver (steatosis),
nonalcoholic steatohepatitis (NASH), and cirrhosis (advanced
scarring of the liver) and methods for ameliorating and/or treating
such disease conditions.
[0019] The formulation comprises compound of formula (I) and the
method comprises administering to a subject in need thereof an
effective amount of a compound according to Formula (I), or a
pharmaceutically acceptable salt thereof.
##STR00003##
wherein `R` is selected from hydroxy, hydroxyalkyl, acyl, alkoxy,
alkylthio, thioalkyl, aryloxy, arylthio and M.sup.+ represents
suitable metal cations such as Na.sup.+, K.sup.+, Ca.sup.+2,
Mg.sup.+2 and the like.
Definitions and Abbreviations
[0020] As used above, and throughout this disclosure, the following
terms, unless otherwise indicated, shall be understood to have the
following
Meanings:
[0021] "Patient" includes both human and animals. "Mammal" means
humans and other mammalian animals.
[0022] A "subject" is a mammal, preferably a human, but can also be
an animal in need of veterinary treatment, e.g., companion animals
(e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep,
pigs, horses, and the like) and laboratory animals (e.g., rats,
mice, guinea pigs, and the like).
[0023] As used herein "treating" includes achieving, partially or
substantially, one of more of the following results: partially or
totally reducing the extent of the disease, disorder or syndrome
(e.g., reducing fat deposits, increasing insulin
activity/sensitivity, reducing weight); ameliorating or improving a
clinical symptom or indicator associated with the disorder;
delaying, inhibiting or preventing the progression of the disease,
disorder or syndrome; or partially or totally delaying, inhibiting
or preventing the onset or development of disorder. Delaying,
inhibiting or preventing the progression of the disease, disorder
or syndrome includes for, example, delaying, inhibiting or
preventing the progression of fatty liver to NASH; delaying,
inhibiting or preventing the progression of NASH to cirrhosis,
end-stage liver disease and/or hepatocellular carcinoma; and
delaying, inhibiting or preventing the progression of pre-diabetes
to diabetes.
[0024] The term "alkyl" used herein, either alone or in combination
with other radicals, denotes a linear or branched radical
containing one to twelve carbons, such as methyl, ethyl, n-propyl,
iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, t-amyl, n-pentyl,
n-hexyl, iso-hexyl, heptyl, octyl and the like.
[0025] The term "alkoxy" used herein, either alone or in
combination with other radicals, denotes a radical alkyl, as
defined above, attached directly to an oxygen atom, such as
methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy,
iso-butoxy, pentyloxy, hexyloxy, and the like.
[0026] The term "aryl" or "aromatic" used herein, either alone or
in combination with other radicals, refers to an optionally
substituted aromatic system containing one, two or three rings
wherein such rings may be attached together in a pendant manner or
may be fused, such as phenyl, naphthyl, tetrahydronaphthyl, indane,
biphenyl, and the like. The term `aralkyl" denotes an alkyl group,
as defined above, attached to an aryl, such as benzyl, phenethyl,
naphthylmethyl, and the like. The term "aryloxy" denotes an aryl
radical, as defined above, attached to an alkoxy group, such as
phenoxy, naphthyloxy and the like, which may be substituted. The
term "aralkoxy" denotes an arylalkyl moiety, as defined above, such
as benzyloxy, phenethyloxy, naphthylmethyloxy, phenylpropyloxy, and
the like, which may be substituted.
[0027] The term "acyl" used herein, either alone or in combination
with other radicals, refers to a radical containing one to eight
carbons such as formyl, acetyl, propanoyl, butanoyl, iso-butanoyl,
pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, which may be
substituted.
[0028] The term "hydroxyalkyl" used herein, either alone or in
combination with other radicals, refers to an alkyl group, as
defined above, substituted with one or more hydroxy radicals, such
as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl,
hydroxypentyl, hydroxyhexyl and the like.
[0029] The term "thio(C.sub.1-C.sub.12)alkyl" or
"thio((C.sub.1-C.sub.6)alkyl" used herein, either alone or in
combination with other radicals, represents an alkyl group, as
defined above, attached to a group of formula --SR', where R'
represents hydrogen, alkyl or aryl group, e.g. thiomethyl,
methylthiomethyl, phenylthiomethyl and the like, which may be
substituted Effective amount" or "therapeutically effective amount"
is meant to describe an amount of compound or a composition of the
present invention effective in inhibiting the above-noted diseases
and thus producing the desired therapeutic, ameliorative,
inhibitory or preventative effect.
[0030] One or more compounds of the invention may exist in
unsolvated as well as solvated forms with pharmaceutically
acceptable solvents such as water, ethanol, and the like, and it is
intended that the invention embrace both solvated and unsolvated
forms. "Solvate" means a physical association of a compound of this
invention with one or more solvent molecules. This physical
association involves varying degrees of ionic and covalent bonding,
including hydrogen bonding. In certain instances the solvate will
be capable of isolation, for example when one or more solvent
molecules are incorporated in the crystal lattice of the
crystalline solid. "Solvate" encompasses both solution-phase and
isolatable solvates.
[0031] One or more compounds of the invention may optionally be
converted to a solvate. Preparation of solvates is generally known.
Thus, for example, M. Caira et al, J. Pharmaceutical Sci, 93(3),
601-611 (2004) describe the preparation of the solvates of the
antifungal fluconazole in ethyl acetate as well as from water.
Similar preparations of solvates, hemisolvate, hydrates and the
like are described by E. C. van Tonder et al, AAPS PharmSciTech.,
5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun.,
603-604 (2001)
[0032] The compounds of Formula (I) can form salts which are also
within the scope of this invention. Reference to a compound of
Formula (I) herein is understood to include reference to salts
thereof, unless otherwise indicated. The term "salt(s)", as
employed herein, denotes acidic salts formed with inorganic and/or
organic acids, as well as basic salts formed with inorganic and/or
organic bases. In addition, when a compound of Formula (I) contain
both a basic moiety, such as, but not limited to a pyridine or
imidazole, and an acidic moiety, such as, but not limited to a
carboxylic acid, zwitterions ("inner salts") may be formed and are
also included within the term "salt(s)" as used herein.
[0033] Pharmaceutically acceptable (i.e., non-toxic,
physiologically acceptable) salts are preferred, although other
salts are also useful. Salts of the compounds of the Formula (I)
may be formed, for example, by reacting a compound of Formula I
with an amount of acid or base, such as an equivalent amount, in a
medium such as one in which the salt precipitates or in an aqueous
medium followed by lyophilization.
[0034] Exemplary acid addition salts include acetates, ascorbates,
benzoates, benzenesulfonates, bisulfates, borates, butyrates,
citrates, camphorates, camphorsulfonates, fumarates,
hydrochlorides, hydrobromides, hydroiodides, lactates, maleates,
methanesulfonates, naphthalenesulfonates, nitrates, oxalates,
phosphates, propionates, salicylates, succinates, sulfates,
tartarates, thiocyanates, toluenesulfonates (also known as
tosylates) and the like.
[0035] Exemplary basic salts include ammonium salts, alkali metal
salts such as sodium, lithium, and potassium salts, alkaline earth
metal salts such as calcium and magnesium salts, salts with organic
bases (for example, organic amines) such as dicyclohexylamines,
t-butyl amines, and salts with amino acids such as arginine, lysine
and the like. Basic nitrogen-containing groups may be quarternized
with agents such as lower alkyl halides (e.g., methyl, ethyl, and
butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.,
dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g.,
decyl, lauryl, and stearyl chlorides, bromides and iodides),
aralkyl halides (e.g., benzyl and phenethyl bromides), and
others.
[0036] All such acid salts and base salts are intended to be
pharmaceutically acceptable salts within the scope of the invention
and all acid and base salts are considered equivalent to the free
forms of the corresponding compounds for purposes of the
invention
[0037] Polymorphic forms of the compounds of Formula (I), and of
the salts, solvates, esters and prodrugs of the compounds of
Formula (I) are intended to be included in the present
invention.
[0038] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts
[0039] In the embodiments the present invention provides a suitable
pharmaceutical composition of compounds of formula (I) or their
derivatives, which comprises one or more pharmaceutical excipients,
antioxidants and chelating agents, wherein the pH of the
composition is above 6, preferably in the range from about pH 6 to
pH of about 10.
[0040] In such embodiments the pharmaceutical composition of the
present invention essentially comprises of [0041] the
pharmaceutically active substance; [0042] Suitable additives;
[0043] a suitable stabilizer; [0044] optionally with one or more
pharmaceutically acceptable excipients. One function of the liver
is to process fats and proteins from digested food.
[0045] Fatty liver disease covers a range of conditions where there
is a build-up of fat in the liver cells. The liver cells
(hepatocytes) normally contain some fat and related fatty chemicals
(triglycerides, fatty acids, etc). Excess fat is normally passed
out of liver cells, into the bloodstream, and then taken up and
stored in fat cells (adipose cells) throughout the body. In fatty
liver disease, excess fat builds up in liver cells. This is thought
to happen if there is some problem or disruption in the normal
processing of fat and related fatty chemicals in the liver cells.
Simple fatty liver (also called "hepatic steatosis") is present
when the fat content inside liver cells makes up more than 5-10% of
the liver's weight. Simple fatty liver is not associated with
serious damage or harm to the liver.
[0046] Nonalcoholic fatty liver disease (NAFLD) refers to a wide
spectrum of liver disease ranging from: i) simple fatty liver
(steatosis), in which there are fat deposits on the liver; ii)
nonalcoholic steatohepatitis (NASH) in which there are fat deposits
on the liver along with inflammation and damage of the liver; and
iii) cirrhosis in which there is irreversible, advanced scarring of
the liver.
[0047] All of the stages of NAFLD have in common the accumulation
of fat (fatty infiltration) in the liver cells (hepatocytes). Fatty
liver (steatosis) can progress to nonalcoholic steatohepatitis
(NASH). In NASH, the fat accumulation is associated with varying
degrees of inflammation and scarring of the liver, and in many
cases insulin resistance, dyslipidemia and hypertension. NASH can
progresses to, fibrosing, steatohepatitis and may trigger
cirrhosis, end-stage liver disease, acute live failure and
hepatocellular carcinoma. It most often occurs in people with
excess body weight, elevated blood lipids, such as cholesterol and
triglycerides, and insulin resistance.
[0048] The present invention also provides methods of treating
liver failure. Acute liver failure occurs when the cells in the
liver die or become damaged in a short period of time. This causes
the liver to fail to work normally and can be fatal.
[0049] Any progressive liver disease, such as cirrhosis, can result
in liver failure. Signs of liver failure include encephalopathy
(altered brain function, jaundice, ascites, fetor hepaticus and
failure of coagulation).
[0050] Many people with simple fatty liver have other conditions
where fatty liver is a complication. Many cases of simple fatty
liver develop in people who drink more alcohol than the recommended
limits. Over half of people who drink heavily develop simple fatty
liver. In these cases simple fatty liver can progress to alcoholic
steatohepatitis. In this condition the excess fat in the liver
cells is associated with, or may cause, inflammation of the liver.
Alcoholic steatohepatitis, may eventually cause scarring
(cirrhosis) of the liver.
[0051] Effective amounts of such compounds are administered to a
subject with one or more of these conditions.
[0052] In an embodiments the compounds according to Formula (I) can
be used alone or in combination e.g., as an adjunct therapy, with
at least one other therapeutic agent Compounds according to formula
(I) can be subject with NASH, a compound according to formula (I)
can be co-administered with a therapeutic agent used to reduce one
or more of the symptoms of NASH or NAFLD including, but not limited
to, an agent used to control blood glucose levels, an agent used to
control lipid levels, e.g., an agent used to lower or control
cholesterol, an antioxidant, an appetite suppressing agent, an
anti-obesity agent, to control blood glucose levels, such as,
sulfonylureas, an antibiotic/probiotic or an anti-inflammatory
agent. Examples of such agents are listed herein and includes
chlorpropamide, glipizide, glyburide, and glimepiride;
meglitinides, such as, repaglinide and nateglinide; biguanides,
such as, metformin and acarbose; thiazolidinediones, such as,
rosiglitazone, and pioglitazone; and insulin and its derivatives,
such as, pramlintide, exenatide, hutnalog, novolog, humulin,
novolin, ultralente, and lanrus; an agent used to control lipid
levels, such as, vytorin, Clofibrate and Gemfibrozil, a plasma
HDL-raising agent, a cholesterol lowering agent, a cholesterol
biosynthesis inhibitor, for example an HMG-CoA reductase inhibitor
(such as a statin, such as, Atorvastatin, Fluvastatin, Lovastatin,
Pravastatin, Rosuvastatin, Simvastatin); an HMG-CoA synthase
inhibitor, an acyl-coenzyme A: cholesterol acyltransferase (ACAT)
inhibitor, such as, melinamide; probucol, niacin (nicotinic acid,
Vitamin-B-3), nicotinic acid and the salts thereof and niacinamide;
a cholesterol absorption inhibitor such as ezetimibe; a bile acid
sequestrant, such as, cholestyramine, colestipol, and Colesevelam;
fibrates such as clofibrate, fenofibrate, and gemfibrizol, vitamin
B6 (also known as pyridoxine) and physiologically acceptable salts
thereof, such as the HCl salt; vitamin B12 (also known as
cyanocobalamin), and angiotensin II antagonist converting enzyme
inhibitor; a beta-blocker; an agent used to reduce weight or
suppress appetite, such as, sibutramine, orlistat and the like.
[0053] In an embodiment, when methods of the present invention is
used to treat a subject with alcoholic steatohepatitis, a compound
according to formula (I) can be co-administered with a therapeutic
agent used to reduce one or more of the symptoms of alcoholic
steatohepatitis including, but not limited to, an agent used to
control blood glucose levels, an agent used to control lipid
levels, e.g., an agent used to lower control cholesterol, an
antioxidant, an appetite suppressing agent, an anti-obesity agent,
an antibiotic or an anti-inflammatory agent, such as those
described above.
[0054] In another embodiments when used in the methods of the
present invention to treat a subject with liver failure, a compound
according to formula (I) can be co-administered with a therapeutic
agent used to reduce one or more of the symptoms of alcoholic
steatohepatitis including, but not limited to, an agent used to
control blood glucose levels, an agent used to control lipid
levels, such as those described above.
[0055] In a further embodiment, the present invention discloses a
suitable pharmaceutical composition of the compound of formula (I),
for the treatment of one or more of the diseases disclosed above. A
preferred pharmaceutical composition of the compound of formula (I)
comprises of [0056] the pharmaceutically active substance; [0057]
Suitable additives; [0058] a suitable stabilizer; [0059] optionally
with one or more pharmaceutically acceptable excipients. Each of
the components may be selected from those known in the art.
[0060] In an embodiment suitable stabilizers may be selected from
the classes of antioxidants or chelating agents.
[0061] In an embodiment the pharmaceutical excepients according to
the present invention can be selected from solubilizers, diluents,
fillers, disintegrants, binder, lubricants, glidants, wetting
agents, solvents and the like as is known in the art.
[0062] In an embodiment suitable additives are selected from sodium
benzoate, sodium hydroxide, sodium sulfite and sodium
carbonate.
[0063] In an embodiment antioxidants used according to the present
invention include, but are not limited to citric acid, alpha
tocopherol, sodium sulphite, sodium metabisulphite, butylated
hydroxy anisole (BHA), BHT (2,6-di-tert-butyl-4-methylphenol),
monothioglycerol, Vitamin C (ascorbic acid), and propyl gallate and
combinations thereof and other similar material known to those of
ordinary skilled in the art.
[0064] Chelating agent used according to the present invention
include, but are not limited to Disodium EDTA, citric acid and or
its salts, maleic acid, chlorambutol, chlorhexidine or its salts,
chlorocresol, combinations thereof and other similar material known
to those of ordinary skill in the art.
[0065] As used herein, the term "binders" is intended to mean
substances used to cause adhesion of powder particles in tablet
granulations. Such compounds include, by way of example and without
limitation, acacia alginic acid, tragacanth, carboxymethylcellulose
sodium, poly (vinylpyrrolidone), compressible sugar (e.g., NuTab),
ethylcellulose, gelatin, liquid glucose, methyl cellulose, povidone
and pregelatinized starch, combinations thereof and other similar
material known to those of ordinary skill in the art.
[0066] When needed, other binders may also be included in the
present invention. Exemplary binders include starch, poly(ethylene
glycol), guar gum, polysaccharide, bentonites, sugars, invert
sugars, poloxamers (PLURONIC F68, PLURONIC F127), collagen,
albumin, celluloses in non-aqueous solvents, and the like or their
suitable combinations. Other binders which may be included may be,
for example, polypropylene glycol), polyoxyethylene-polypropylene
copolymer, polyethylene ester, polyethylene sorbitan ester,
poly(ethylene oxide), microcrystalline cellulose,
poly(vinylpyrrolidone), combinations thereof and other such
materials known to those of ordinary skill in the art. As used
herein, the term "diluent" or "filler" is intended to mean inert
substances used as fillers to create the desired bulk, flow
properties, and compression characteristics in the preparation of
tablets and capsules. Such compounds include, by way of example and
without limitation, dibasic calcium phosphate, kaolin, sucrose,
mannitol, microcrystalline cellulose, powdered cellulose,
precipitated calcium carbonate, sorbitol, starch, combinations
thereof and other such materials known to those of ordinary skill
in the art.
[0067] As used herein, the term "glidant" is intended to mean
agents used in tablet and capsule formulations to improve
flow-properties during tablet compression and to produce an
anti-caking effect. Such compounds include, by way of example and
without limitation, colloidal silica, calcium silicate, magnesium
silicate, silicon hydrogel, cornstarch, talc, combinations thereof
and other such materials known to those of ordinary skill in the
art.
[0068] In an embodiment, the term "lubricant" is intended to mean
substances used in tablet formulations to reduce friction during
tablet compression. Such compounds include, by way of example and
without limitation, calcium stearate, magnesium stearate, mineral
oil, stearic acid, zinc stearate, suitable combinations thereof and
other such materials known to those of ordinary skill in the
art.
[0069] In an embodiment, the term "disintegrant" is intended to
mean a compound used in solid dosage forms to promote the
disruption of the solid mass into smaller particles which are more
readily dispersed or dissolved. Exemplary disintegrants include, by
way of example and without limitation, starches such as corn
starch, potato starch, pregelatinized and modified starched
thereof, sweeteners, clays, such as bentonite, microcrystalline
cellulose (e.g. Avicel.TM.), carsium (e.g. Amberlite.TM.),
alginates, sodium starch glycolate, gums such as agar, guar, locust
bean, karaya, pectin, tragacanth, combinations thereof and other
such materials known to those of ordinary skill in the art.
[0070] In an embodiment, the term "wetting agent" is intended to
mean a compound used to aid in attaining intimate contact between
solid particles and liquids. Exemplary wetting agents include, by
way of example and without limitation, poloxamers, gelatin, casein,
Glycerol mono-oleate, lecithin (phosphatides), gum acacia,
cholesterol, tragacanth, stearic acid, benzalkonium chloride,
calcium stearate, glycerol monostearate, cetostearyl alcohol,
sodium lauryl sulphate, sodium dodecyl sulfate, salts of bile acids
(taurocholate, glycocholate, cholate, deoxycholate, etc.),
cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene
alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000),
polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan
fatty acid esters, (e.g., TWEEN), polyethylene glycols,
polyoxyethylene stearates colloidal silicon dioxide, phosphates,
sodium dodecylsulfate, carboxymethylcellulose calcium, carboxy
methylcellulosesodium, methyl cellulose, hydroxyethylcellulose,
hydroxylpropylcellulose, hydroxy propyl methyl cellulose phthalate,
noncrystalline cellulose, magnesium aluminum silicate,
triethanolamine, polyvinyl alcohol, and poly vinyl pyrrolidone
(PVP) and their suitable combinations and other such materials
known to those of ordinary skill in the art. Tyloxapol (a nonionic
liquid polymer of the alkyl aryl polyether alcohol type, also known
as superinone or triton) is another useful wetting agent which may
be used. The stable pharmaceutical composition according to the
present invention may be in the form of tablet or capsule or a
powder or a suspension in a liquid or an aerosol formulation or
solutions, preferably in the form of tablet or capsule.
[0071] In another embodiment of the present invention, is a
described process for the preparation of a stable pharmaceutical
composition of compounds of formula (I) or their derivatives.
[0072] The stable pharmaceutical composition may be made by direct
compression, wet granulation or dry granulation methods by
techniques known to persons skilled in the art. Thus, for
example,
[0073] In wet granulation process, the drug is mixed with one or
more pharmaceutical excepients and granulated with suitable binding
solution as described earlier, to form wet granules, the wet
granules are dried and optionally sieved. The dried granules are
mixed with one or more suitable excipients from those described
elsewhere and then compressed into tablets or filled into
capsules.
[0074] In direct compression process, the drug is mixed with all
the pharmaceutical excipients required and then is either
compressed, into tablets or filled in capsules.
[0075] In dry granulation process the drug is mixed with one or
more pharmaceutical excipients and compressed into slugs and these
slugs are passed through required sieve. The sieved granules are
mixed with one or more suitable excipients from those described
elsewhere and then compressed into tablets or filled into
capsules.
[0076] One or more solvents used in the formulation are selected
from acetone, chloroform, dichloromethane, ethyl alcohol, ethyl
acetate, methyl alcohol, isopropyl alcohol and combinations thereof
and other such materials known to those of ordinary skill in the
art.
[0077] In an embodiment, the compound of formula (I) or
pharmaceutical compositions containing the compound of formula (I)
is given to a subject in need thereof at a dose of about 0.5 mg to
5 g. A skilled person is aware how to decide the optimum dose based
on the patient profile, the severity of disease, the presence of
secondary medicines and the like.
[0078] The compound of formula (I), when R is --SMe and M.sup.+ is
Mg, is commercially known as Saroglitazar. This compound
(Saroglitazar) is dosed to patients in need thereof for the
treatment of one or more of the diseases described above as per the
following general protocol:
Study Design and Protocol:
[0079] Title of the Study--"A prospective, multi-centric,
open-label, single arm study to evaluate the safety and efficacy of
4 mg of Saroglitazar in a pharmaceutical composition as described
above in Non-alcoholic steatohepatitis."
Objectives:
[0080] To evaluate the safety and efficacy of 4 mg of compound of
Saroglitazar in Non-alcoholic steatohepatitis (NASH).
The following effficacy parameters were measured:
Primary Efficacy (Time Frame 6 and 12 Weeks):
[0081] 1. Change in alanine aminotransferase (ALT) from
baseline
Secondary Efficacy (Time Frame 6 and 12 Weeks):
[0082] Sustained reduction in ALT level. [0083] C-peptide test for
homeostasis model assessment (HOMA) beta and HOMA IR [0084]
Triglyceride (TG)
Criteria for Safety:
[0084] [0085] 1. General and Systemic Clinical Examination:
Cardiovascular system (CVS), respiratory system (RS),
gastro-intestinal system (GIS), central nervous system (CNS) etc.
[0086] 2. Laboratory Investigations: Complete blood count (CBC),
aspartate aminotransferase (AST), ALT, alkaline phosphatase (ALP),
serum bilirubin, .gamma.-glutamyl transpeptidase (GGT), Serum
proteins, blood urea nitrogen (BUN), Serum creatinine, creatinine
phosphokinase (CPK), fasting plasma glucose (FPG). [0087] 3.
Frequency and severity of adverse events (AEs) for all subjects
enrolled were recorded. All AEs, were classified using [0088]
causality [0089] severity [0090] seriousness
Methodology:
[0091] It is an interventional, single arm, safety and efficacy
study to explore effect of compound of Saroglitazar suitably
formulated as described above, on NASH.
[0092] Subjects was diagnosed by biopsy as suffering from NASH in
last one year and willing to participate in study were invited for
screening programme for inclusion in the study.
Subjects satisfying inclusion exclusion criteria will be enrolled
in the study.
[0093] All subjects were given suitable formulation of compound of
Saroglitazar 4 mg for 12 weeks. Lifestyle modification was
continued as before the study. Patient was monitored for safety and
efficacy of Saroglitazar.
Study Schedules:
[0094] Informed consent was obtained before any trial related
activity. [0095] Visit 1, Screening Visit/Enrolment [Week -1 to
0]
[0096] Subjects were screened for the inclusion and exclusion
criteria and those qualifying were invited to participate in the
study. Clinical evaluation was done for baseline characteristics
and anthropometry
[0097] After Clinical evaluations, all baseline safety and efficacy
parameters were recorded as per Table (I) given below. All
laboratory investigations were carried out after overnight
fasting.
During the 12 week program, a designated person from the centre
could interview the subjects for his/her general health,
telephonically. Enrolled Subjects would receive the study
medication for next two weeks. Patients were advised to follow same
lifestyle modifications during study period as before the
study.
[0098] Visit 2, [Week 2]
[0099] Subjects were clinically examined and given the study
medications for four weeks and also safety parameters were assessed
as per Table (I) given below.
[0100] Visit 3 [Week 6]
[0101] Subjects were clinically examined and given the study
medications for next 6 weeks.
Safety and efficacy parameters were assessed as per Table (I) given
below.
[0102] Visit 4 [Week 12]
[0103] Subjects were clinically examined and safety and efficacy
parameters were assessed as per Table (I) given below.
[0104] If further investigations are required in case of any AE,
investigator will be advised to assess the AE and take necessary
action, if required. Subjects will be advised to contact the
investigator for any complaints within next two weeks.
[0105] During the above period, if any subject misses the drug
administration up to 3 consecutive days, it will not be considered
drop-out or protocol deviation.
Visit and Investigation Schedule
TABLE-US-00001 [0106] Screening/ Enrolment Visit 1 Visit2 Visit 3
Visit 4 Activity (Week 0) (Week 2) (Week 6) (Week 12/) Demographics
Informed Consent Inclusion/Exclusion criteria Medical History
Clinical Examination Laboratory studies (efficacy-Lipid profile, C
peptide, ALT) Laboratory studies* ECG USG Pregnancy test for female
subjects (advise for contraception) Dispensing of Study Medication
Study Medication capsule Count Recording of Adverse Events Global
Tolerability Assessments Study Completion *Laboratory Tests:
Biochemistry (laboratory) parameters to be performed include
following tests: Liver Function test (LFT): AST, ALT, ALP, total
bilirubin, serum proteins, total albumin and globulin, GGT Renal
function test: Blood urea nitrogen (BUN), Serum creatinine and
calculated GFR Creatinine phosphokinase (CPK) CBC
Criteria for Inclusion/Exclusion:
Inclusion Criteria
[0107] Subject has given informed consent for participation in this
trial [0108] Biopsy proven NASH (Biopsy done in last one year).
[0109] ALT>than 1.5 times upper normal limit. [0110] Patient
presently on lifestyle modification for NASH for at least one
month. [0111] BMI between 23 to 40 kg/m.sup.2 [0112] Compensated
liver disease with the following hematologic, biochemical, and
serological criteria on entry into protocol: [0113] Hemoglobin
>9 gm/dL [0114] White blood cell (WBC)>2.5 K/UL [0115]
Neutrophil count >1.5 K/UL [0116] Platelets >100 K/UL [0117]
Serum bilirubin, <1.5 mg % [0118] Albumin >3.2 g/dL [0119]
Serum creatinine within normal limits
Exclusion Criteria:
[0119] [0120] Pregnancy and lactation [0121] Subjects with history
of gall stone [0122] Subjects with history of myopathies or
evidence of active muscle diseases [0123] Subject with history of
alcohol consumption >than 20 gm/week and/or drug abuse [0124]
Known allergy, sensitivity or intolerance to the study drugs and
their formulation ingredients. [0125] Participation in any other
clinical trial in past 3 months [0126] History of malignancy;
active neoplasm. [0127] Previous liver biopsy that demonstrated
presence of cirrhosis or radiologic imaging consistent with
cirrhosis or portal hypertension [0128] Type 2 diabetes treated
with agents other than the secretagogues (these include, insulin
thiazolidinediones, alpha-glucosidase inhibitors, exenatide,
pramlintide). Metformin will be allowed provided dose is stable
science last 6 months. [0129] Evidence of poorly-controlled
diabetes [glycosylated hemoglobin (HbA1c)>9%]. [0130] Type I
diabetes mellitus. [0131] Abnormal PT/INR (Prothrombin
Time/International normalized ratio) [0132] Patient on fibrates
(Other antidyslipidemic drugs will be allowed provided dose is
stable in last 6 months) [0133] Use of drugs associated with a
clinical or histological picture consistent with fatty liver
disease or NASH for more than 12 consecutive weeks in the 1 year
prior to start of the study; (these include amiodarone, tamoxifen,
methotrexate, glucocorticoids, anabolic steroids, tetracyclines,
estrogens, valproate/valproic acid, chloroquine, anti-HIV drugs
etc.) [0134] History of thyroid disease poorly controlled on
prescribed medications [0135] History of, or current cardiac
dysrhythmias and/or a history of cardiovascular disease, including
myocardial infarction, except patients with only well controlled
hypertension. [0136] History of bariatric surgery, or undergoing
evaluation for bariatric surgery. [0137] History or other evidence
of severe illness or any other conditions that would make the
patient, in the opinion of the investigator, unsuitable for the
study (such as poorly controlled psychiatric disease, coronary
artery disease, or active gastrointestinal conditions that might
interfere with drug absorption) [0138] Subject on any treatment
with other drugs claimed for treatment of NASH (Pentoxyphyllin,
Ursodeoxycholic acid, acetyl cholinesterase enzyme (ACE) inhibitors
antioxidants such as vitamin E, vitamin C, glutathione,
alpha-tocopherol, or non-prescribed complementary alternative
medications (including dietary supplements, megadose vitamins,
herbal preparations, and special teas).) or any medicine in
clinical trials for NASH. [0139] Other cause of chronic liver
disease [autoimmune, primary biliary cirrhosis, hepatitis B virus
(HBV), Wilson, alpha-1-antitrypsin deficit, hemochromatosis etc.]
i.e. Antinuclear antibodies (ANA)>1:160, Anti-smooth muscle Ab
positive >1:160, Serum hepatitis B surface antigen (HepBsAg)
positive, Serum hepatitis C antibody (HepC Ab) positive,
transferrin saturation >45%
Results
[0140] Subjects were screened for inclusion in the study after
obtaining informed consent, out of which 32 subjects were enrolled
into the study. Out of these 32 subjects, 29 subjects completed the
study.
The effect of Saroglitazar at week 12 on various parameters of
liver function is as below. [0141] There was statistically
significant reduction in the ALT levels from baseline in
Saroglitazar 4 mg treatment group in the PP population at visit 3
and visit 4. (FIG. 1) [0142] There was sustained reduction in ALT
levels 63.16% and 78.95% of patients at visit 3 and visit 4
respectively as per PP. [0143] Saroglitazar showed a statistical
significant decrease in the Aspartate Transaminase, gamma-glutamyl
transpeptidase and alkaline phosphatase at Week 3 and at Week 4 in
the Safety Population. (FIG. 2) [0144] There was a non-significant
change in the C peptide levels in Saroglitazar 4 mg at 6 and 12
weeks as per PP analysis and non-statistically significant
reduction in HOMA--Beta cell function, HOMA--Insulin Resistance.
(FIG. 3) [0145] Baseline TG.ltoreq.150 mg/dl--There was decrease in
triglyceride in Saroglitazar 4 mg at week 12 as compared to
baseline but it was not statistically significant in the PP
population. (FIG. 4) [0146] Baseline TG.gtoreq.150 mg/dl--While
decrease was observed in serum triglycerides at week 6 and 12 as
compared to baseline but it was not statistically significant in
Saroglitazar 4 mg in PP population. (FIG. 4)
[0147] Safety Conclusion:
Overall, Saroglitazar 4 mg was safe and well tolerated. [0148]
There were no deaths or SAEs reported in the Saroglitazar 4 mg
treatment arm. [0149] The overall incidence of AEs was Nil. [0150]
There were no persistent changes from baseline in various
laboratory parameters. Few events of raised creatinine and five
events of raised CPK value were reported during the study. These
events were mild and none of these events were considered
clinically significant by the investigator. [0151] There was no
significant change in weight in Saroglitazar 4 mg group in NASH
patients at visit 2, 3 and 4 visits compared to baseline.
[0152] Thus, the compounds of the present invention and the
pharmaceutical composition as described in the specification are
suitable for reduction and removal of lipid accumulated in the
liver cells (hepatocytes) for the treatment of Nonalcoholic fatty
liver disease (NAFLD) which refers to a wide spectrum of liver
diseases ranging from simple fatty liver (steatosis) to
nonalcoholic steatohepatitis (NASH).
* * * * *