Note: Descriptions are shown in the official language in which they were submitted.
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Additional pharmaceutical use
The enzyme cascade of the renin-angiotensin system (RAS) comprises a series of
biochemi-
cal sequences and, as is known, there are different approaches for opening up
possibilities
for the treatment of, for example, hypertension by regulatory intervention.
Angiotensinogen, a a2-macroglycoprotein, is split by the renin enzyme into the
decapitate
angiotensin I, which itself is biologically only very weakly active. The next
step in the cascade
is the removal of a further two amino acids by the action of the angiotensin-
converting
enzyme (ACE), bonded mainly in the endothelium, with formation of angiotensin
II. This
latter is held to be one of the strongest natural vasoconstrictors.
The vasoconstrictive effects of angiotensin II are produced by its action on
the non-striated
muscle cells, the stimulation of the formation of the adrenergenic hormones
epinephrine and
norepinephrine as well as by the increase of the activity of the sympathetic
nervous system
as a result of the formation of norepinephrine. Angiotensin II also has an
influence on the
electrolytic balance, produces e.g. antinatriuretic and antidiuretic effects
in the kidney and
accordingly promotes the release of, on the one hand, the vasopressin peptide
from the
pituitary gland and, on the other hand, of aldosterone from the adrenal
glomerulosa. These
influences all play an, important part in the regulation of blood pressure.
Angiotensin II interacts with specific receptors on the surface of the target
cell. It has been
possible to identify receptor subtypes which are termed e.g. ATE- and AT2-
receptors. Great
efforts have been made lately to identify substances that bind to ATE-
receptors. Such active
ingredients are often termed angiotensin II antagonists or blockers. Because
of the inhibition
of the ATE-receptor such antagonists can be used e.g. as antihypertensives or
for the
treatment of congestive heart failure.
Angiotensin II receptor antagonists are understood to mean those active
ingredients which
bind to the AT1-receptor subtype and inhibit its activity. These include
compounds having
different structural features. Compounds to be mentioned are, for example,
those cited in the
compound claims of EP-443983, fihe subject matter of which is herewith
incorporated by
reference in this application.
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A compound to be highlighted is (S)-N-(1-carboxy-2-methyl-prop-1-yl)-N-
pentanoyl-N-[2'(1 H-
tetrazol-5-yl)biphenyl-4-yl-methyl]amine (hereinafter termed valsartan) of
formula
C \ /CH3
p CH
CH\CFi C\CH C~N~CH
COOH
CHZ ~ ~ ~ L
HN ~ N
N=N
cited in European patent application having the publication no. EP-443983,
Example 16, or a
salt thereof, preferably a pharmaceutically acceptable salt thereof.
Furthermore, the compounds cited in the compound claims of European patent
application
having the publication no. EP-253310 are incorporated by reference in this
application.
A compound to be highlighted is that of the following formula
CI
N I OH
N~
N' NH
\ /
N=N
and the pharmaceutically acceptable salts thereof.
Furthermore, the compounds cited in the compound claims of European patent
application
having the publication no. EP-403159 are incorporated by reference in this
application.
A compound to be highlighted is that of the following formula
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S
N I ~ COOH
N~
COOH
and the pharmaceutically acceptable salts thereof.
Furthermore, the compounds cited in the compound claims of PCT patent
application WO
91/14679 are, with reference to this literature, herewith also included in
this application.
A compound to be highlighted is that of the following formula
N
( O
N
N ' NH
N=N
and the pharmaceutica((y acceptable salts thereof.
Furthermore, the compounds cited in the compound claims of European patent
application
having the publication no. EP-420 237 are incorporated by reference in this
application.
A compound to be highlighted is that of the following formula
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Ni i
N N
COOH
and the pharmaceutically acceptable salts thereof.
Furthermore, the compounds cited in the compound claims of European patent
application
having the publication no. EP-502314 are incorporated by reference in this
application.
A compound to be highlighted is that of the following formula
N
N \ N
COOH
and the pharmaceutically acceptable salts thereof.
Furthermore, the compounds cited in the compound claims of European patent
application
having the publication no. EP-459136 are incorporated by reference in this
application.
A compound to be highlighted is that of the following formula
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N~ ~ ~ o
,~ ~ N ~
O
GO O O
/N\
N
~N_HN
and the pharmaceutically acceptable salts thereof.
Furthermore, the compounds cited in the compound claims of European patent
application
having the publication no. EP-504888 are incorporated by reference in this
application.
A compound to be highlighted is that of the following formula
N I
I ,N
V
and the pharmaceutically acceptable salts thereof.
Furthermore, the compounds cited in the compound claims of European patent
application
having the publication no. EP-514198 are incorporated by reference in this
application.
A compound to be highlighted is that of the following formula
N ' NH
N=N
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N Br
~~N J~ ---CONH
~~ O
NH-SOZ CF3
and the pharmaceutically acceptable salts thereof.
Furthermore, the compounds cited in the compound claims of European patent
application
having the publication no. EP-475206 are incorporated by reference in this
application.
A compound to be highlighted is that of the following formula
COOH
N VN
N ~\NH
N=N
and the pharmaceutically acceptable salts thereof.
Furthermore, the compounds cited in the compound claims of PCT patent
application WO
93/20816 are incorporated by reference included in this application.
A compound to be highlighted is that of the following formula
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N NH
\ /
N=N
-7-
O
/w
and the pharmaceutically acceptable salts thereof.
Pharmaceutically acceptable salts of valsartan, for example, are typically
acid addition salts.
These acid addition salts are formed, for example, with strong inorganic
acids, typically
mineral acids, such as sulfuric acid, a phosphoric acid or a hydrohalic acid,
with strong
organic carboxylic acids, typically with C~-C4alkanecarboxylic acids which may
be
substituted, e.g. by halogen, typically acetic acid, for example with
dicarboxylic acids which
may be unsaturated, such as oxalic acid, malonic acid, succinic acid, malefic
acid, fumaric
acid, phthalic acid or terephthalic acid, for example with hydroxycarboxylic
acids, such as
ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric
acid, for example with
amino acids, such as aspartic acid or glutaminic acid, or e.g. benzoic acid,
or with organic
sulfonic acids, for example with C~-C4alkanesulfonic acids or arylsulfonic
acids which may be
substituted, e.g. by halogen, for example with methane- or p-toluenesulfonic
acid. Suitable
salts with bases are typically metal salts, such as alkali metal salts or
alkaline earth metal
salts, typically sodium, potassium or magnesium salts, or salts with ammonia
or an organic
amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-,
di- or tri-lower
alkylamine, typically ethylamine, tert-butylamine, diethylamine,
diisoopropylamine,
triethylamine, tributylamine or dimethylpropylamine, or a mono-, di- or
trihydroxy-lower
alkylamine, typically mono-, di- or triethanolamine. Corresponding internal
salts can also be
used.
Nephrotic syndrome
Nephrotic syndrome is a clinical complex characterized by a number of renal
and extrarenal
features, the most prominent of which are proteinuria of >3.5 g per 1.73 m2
per 24. h (in
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practice, >3.0 to 3.5 g per 24 h), hypoalbuminemia, edema, hyperlipidemia,
lipiduria, and
hypercoagulability. It should be stressed that the key component is
proteinuria, which results
from altered permeability of the glomerular filtration barrier for protein,
namely the glomerular
basement membrane (GBM) and the podocytes and their slit diaphragms. The other
components of the nephrotic syndrome and the ensuing metabolic complications
are all
secondary to urine protein loss and can occur with lesser degrees of
proteinuria or may be
absent even in patients with massive proteinuria.
In general, the greater the proteinuria, the lower the serum albumin level.
Hypoalbuminemia is compounded further by increased renal catabolism and
inadequate,
albeit usually increased, hepatic synthesis of albumin.
Edema is defined as a swelling from excessive accumulation of serous fluid in
tissue.
The pathophysiology of edema formation in nephrotic syndrome is poorly
understood. The
hypothesis is that hypoalbuminemia results in decreased intravascular oncotic
pressure,
leading to leakage of extracellular fluid from blood to the interstitium.
Intravascular volume
falls, thereby stimulating activation of the renin-angiotensin-aldosterone
axis and the
sympathetic nervous system and release of vasopressin (antidiuretic hormone),
and
suppressing atria) natriuretic peptide release. These neural and hormonal
responses
promote renal salt and water retention, thereby restoring intravascular volume
and triggering
further leakage of fluid to the interstitium.
Hyperlipidemia is believed to be a consequence of increased hepatic
lipoprotein synthesis
that is triggered by reduced oncotic pressure and may be compounded by
increased urinary
loss of proteins that regulate lipid homeostasis. Low-density lipoproteins and
cholesterol are
increased in the majority of patients, whereas very low density lipoproteins
and triglycerides
tend to rise in patients with severe disease.
Lipiduria is caused by the filtration of lipoproteins across the damaged
glomerular barrier. On
urine microscopy lipiduria might appear as free fat, or as fat droplets in
tubular cells or casts
where they are referred to as oval fat bodies or fatty casts respectively.
Hypercoagulability is probably multifactorial in origin and is caused, at
least in part, by
increased urinary loss of antithrombin III, altered levels and/or activity of
proteins C and S,
hyperfibrinogenemia due to increased hepatic synthesis, impaired fibrinolysis,
and increased
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platelet aggregability. As a consequence of these perturbations, patients can
develop
spontaneous peripheral arterial or venous thrombosis, renal vein thrombosis,
and pulmonary
embolism. Clinical features that suggest acute renal vein thrombosis include
sudden onset of
flank or abdominal pain, gross hematuria, a left-sided varicocele (the left
testicular vein
drains into the renal vein), increased proteinuria, and an acute decline in
glomerular filtration
rate(GFR). Chronic renal vein thrombosis is usually asymptomatic. Renal vein
thrombosis is
particularly common (up to 40%) in patients with nephrotic syndrome due to
membranous
glomerulopathy, membranoproliferative glomerulonephritis, and amyloidosis.
Other metabolic complications of nephrotic syndrome include protein
malnutrition and iron-
resistant microcytic hypochromic anemia due to transferrin loss. Hypocalcemia
and
secondary hyperparathyroidism can occur as a consequence of vitamin D
deficiency due to
enhanced urinary excretion of cholecalciferol-binding protein, whereas loss of
thyroxine-
binding globulin can result in depressed thyroxine levels. An increased
susceptibility to
infection may reflect low levels of IgG that result from urinary loss and
increased catabolism.
In addition, patients are prone to unpredictable changes in the
pharmacokinetics of
therapeutic agents that are normally bound to plasma proteins.
Nephrotic syndrome can complicate any disease that perturbs the negative
electrostatic
charge or architecture of the glomerular basement membrane and the podocytes
and their
slit diaphragms. Six entities account for greater than 90% of cases of
nephrotic syndrome in
adults: minimal change disease (MCD), focal and segmental glomerulosclerosis
(FSGS),
membranous glomerulopathy, membranoproliferative glomerulonephritis (MPGN),
diabetic
nephropathy, and amyloidosis.
Renal biopsy is a valuable tool in adults with nephrotic syndrome for
establishing a definitive
diagnosis, guiding therapy, and estimating prognosis.
Minimal Change Disease
This glomerulopathy accounts for about 80% of nephrotic syndrome in children
of younger
than 16 years and 20% in adults .The peak incidence is between 6 and 8 years.
Patients
typically present with nephrotic syndrome and benign urinary sediment.
Microscopic
hematuria is present in 20 to 30%. Hypertension and renal insufficiency are
very rare.
MCD (also called nil disease, lipoid nephrosis, or foot process disease) is so
named because
glomerular size and architecture are normal by light microscopy.
Immunofluorescence
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studies are typically negative for immunoglobulin and C3. Mild mesangial
hypercellularity and
sparse deposits of C3 and IgM may be detected. Occasionally, mesangial
proliferation is
associated with scanty IgA deposits, similar to those found in IgA
nephropathy. However, the
natural history of this variant and response to therapy resemble classic MCD.
Electron
microscopy reveals characteristic diffuse effacement of the foot processes of
visceral
epithelial cells .
Focal and Segmental Glomerulosclerosis with Hyalinosis
The pathognomonic morphologic lesion in FSGS is sclerosis with hyalinosis
involving
portions (segmental) of fewer than 50% (focal) of glomeruli on a tissue
section. The
incidence of idiopathic (primary) FSGS has increased over the past two decades
so that it
now accounts for about one-third of cases of nephrotic syndrome in adults and
as many as
one-half of cases of nephrotic syndrome in blacks. FSGS can complicate a
number of
systemic diseases and sustained glomerular capillary hypertension following
nephron loss
from any cause.
Idiopathic FSGS Typically presents as nephrotic syndrome (-66%) or
subnephrotic
proteinuria (~33%) in association with hypertension, mild renal insufficiency,
and an
abnormal urine sediment that contains red blood cells and leukocytes.
Proteinuria is
nonselective in most cases.
Membranous Glomerulopathy
This lesion is a leading cause of idiopathic nephrotic syndrome in adults (30
to 40%) and a
rare cause in children (<5%). It has a peak incidence between the ages of 30
to 50 years
and a male-female ratio of 2:1. Membranous glomerulopathy derives its name
from the
characteristic light-microscopic appearance on renal biopsy, namely diffuse
thickening of the
glomerular basement membrane which is most apparent upon staining with
periodic acid-
Schiff (PAS). Most patients (>80%) present with nephrotic syndrome,
proteinuria usually
being nonselective. Microscopic hematuria is present in up to 50% of cases,
but red blood
cells casts, macroscopic hematuria, and leukocytes are extremely rare.
Hypertension is
documented in only 10 to 30% of patients at the outset but is common later in
patients with
progressive renal failure. Serologic tests such as antinuclear antibody,
antineutrophil
cytoplasmic antibody, anti-GBM antibody, cryoglobulin titers, and complement
levels are
normal in the idiopathic form.
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Membranoproliferative Glomerulonephritis
This morphologic entity, also known as mesangiocapillary glomerulonephritis,
is
characterized by thickening of the glomerular basement membrane (GBM) and
proliferative
changes on light microscopy. Two major types are identified; both are
characterized by a
diffuse increase in mesangial cellularity and matrix, and by thickening and
reduplication of
the GBM such that the lobular pattern of the glomerular tuft is exaggerated.
The hallmark of
type Imembranoproliferative glomerulonephritis (MPGN) is the presence of
subendothelial
and mesangial deposits on electron microscopy that contain C3 and IgG or IgM;
rarely, IgA
deposits are demonstrated by immunofluorescence microscopy. The hallmark of
type II
MPGN (dense deposit disease) is the presence of electron-dense deposits within
the GBM
and other renal basement membranes (shown by electron microscopy) that stain
for C3, but
little or no immunoglobulin.
Most patients with type I MPGN present with heavy proteinuria or nephrotic
syndrome, active
urinary sediment, and normal or mildly impaired glomerular filtration rate
(GFR). C3 levels
are usually depressed, and C1q and C4 levels are borderline or low. Type I
MPGN is an
immune-complex glomerulonephritis and can be associated with a variety of
chronic
infections (e.g., bacterial endocarditis, HIV, hepatitis B and C), systemic
immune-complex
diseases (e.g., SLE, cryoglobulinemia), and malignancies (e.g., leukemias,
lymphomas).
Type I MPGN is a relatively benign disease, and 70 to 85% of patients survive
without
clinically significant impairment of GFR.
Type II MPGN can also present with proteinuria and nephrotic syndrome;
however, some
patients present with nephritic syndrome,rapidly progressive
glomerulonrphritis (RPGN), or
recurrent macroscopic hematuria. Type II MPGN is an autoimmune disease in
which patients
have an IgG autoantibody, termed C3 nephritic factor that binds to C3
convertase, the
enzyme that metabolizes C3, and renders it resistant to inactivation .
It has been surprisingly found that AT1-receptor antagonist, especially
valsartan, can be
used in therapeutically effective amount for the prevention, delay of
progression or treatment
of nephrotic syndrome and complications of metabolic syndrome.
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In the present description the terms "treatment" or "treat" refer to both
prophylactic or
preventative treatment as well as curative or disease modifying treatment,
including
treatment of patients at risk of contracting the disease or suspected to have
contracted the
disease as well as patients who are ill or have been diagnosed as suffering
from a disease
or medical condition.
Complications of nephrotic syndrome that may require treatment include edema,
hyperlipidemia, thromboembolism, malnutrition, and vitamin D deficiency. Edema
should be
managed cautiously by moderate salt restriction, usually 1 to 2 g/day, and the
judicious use
of loop diuretics. It is unwise to remove >1.0 kg of edema per day as more
aggressive
diuresis may precipitate intravascular volume depletion and prerenal azotemia.
Thromboembolism is defined as an occlusion of a blood vessel by an embolus
that has
broken away from a thrombus.
Anticoagulation is indicated for patients with deep venous thrombosis,
arterial thrombosis,
and pulmonary embolism. Patients may be relatively resistant to heparin as a
consequence
of antithrombin III deficiency. Renal vein and vena caval angiography are
indicated only
when embolization occurs on anticoagulation and insertion of a caval filter is
contemplated.
Malnutrition which is defined as a state of poor nutrition can result from
insufficient or
excessive or unbalanced diet or from inability to absorb foods.
Vitamin D deficiency exists when the concentration of 25-hydroxy-vitamin D (25-
OH-D) in the
blood serum occurs at 12 ng/ml (nanograms/milliliter), or less. The normal
concentration of
25-hydroxy-vitamin D in the blood serum is 25-50 ng/ml. When vitamin D
deficiency
continues for many months in growing children, the disease commonly referred
to as rickets
will occur. A prolonged deficiency of the vitamin in adults results in
osteomalacia. Both
diseases involve defects in bones.
A vitamin D deficiency disease of infancy or childhood with a disturbance of
the normal
process of ossification and bone growth. Often manifests with bone deformity.
Vitamin D supplementation is advisable in patients with clinical or
biochemical evidence of
vitamin D deficiency.
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The favourable effect of AT1-receptor antagonists on nephrotic syndrome , e.g.
by the use
of valsartan, can be manifested, for example, by the following experimental
procedure:
Administration of puromycin to rats induces progressive renal disease
characterized by
proteinuria, edema, sodium retention and hyperlipidemia. Thus, this
experimental model of
nephrotic syndrome is often used to study the potential beneficial effects of
pharmacological
interventions in the disease condition (Arevalo et al. Clin Chim Acta,
191:175, 1990;
Diamond and Anderson, Am J Pathol, 137:1323, 1990).
Male Sprague-Dawley rats weighing about 200 g are housed in a temperature- and
light-
controlled room with 12 h light and dark cycles. The rats are allowed free
access to food and
water. Animals are randomized into the following groups: normal vehicle
controls, drug-
treated (monotherapy or combination therapy) normal (non-nephrotic) groups,
nephrotic
untreated controls, and drug-treated (monotherapy or combination therapy)
nephrotic
groups. The rats assigned to the nephrotic group receive sequential
intraperitoneal injections
(i.p.) of puromycin aminonucleoside (PAN) on day 1 (130 mg/kg) and day 14 (60
mg/kg).
The rats assigned to the control group receive intraperitoneal injections of
equivalent
amounts of water. Animals are then placed in individual metabolic cages for
daily 24-h urine
collections. Drugs are administered by oral gavage, subcutaneous osmotic
pumps, inclusion
in drinking water, or admixed with food, as appropriate. Typical dosages for
valsartan in
drinking water range from 3 to 30 mg/kg/day and those of the HMG-CoA reductase
inhibitor
is highly dependent upon the specific agent used. For example, with
lovastatin, a dose of 15
mg/kg/day (oral gavage) is used. Urinary sodium concentration, serum and
urinary
creatinine concentrations, as well as urinary protein concentrations are
measured. Blood
pressure is measured by tail plethysmography. Blood samples are obtained from
the tail
vein for additional blood chemistry. All parameters are evaluated at baseline
and periodically
during the subsequent twelve weeks. At the end of the experiment, rats are
sacrificed
(pentobarbital 40mg/kg, i.p.) and kidneys are excised for histological
studies.
It can be shown that urinary protein concentration is significantly lower in
valsartan-treated
nephrotic animals relative to that in untreated nephrotic animals. Consistent
with this
observation, it can also be shown that renal structure and function is better
preserved in
valsartan-treated nephrotic animals relative to that in untreated nephrotic
animals. It can be
further shown that combination therapy of PAN-treated animals with valsartan
and an HMG-
CoA reductase inhibitor elicits further improvement in renal structure and
function relative to
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monotherapy with valsartan. This is manifested as further significant
reductions in urinary
protein excretion and concomitant amelioration of tubulointerstitial
morphologic
derangements relative to monotherapy with valsartan.
The person skilled in the pertinent art is fully enabled to select a relevant
test model to prove
the efficacy of a combination of the present invention in the hereinbefore and
hereinafter
indicated therapeutic indications.
It is the object of this invention to provide pharmaceutical compositions for
the prevention ,
delay of progression or treatment of nephrotic syndrome and its complications,
which
composition comprises an AT1-receptor antagonist, in particular valsartan, or
a
pharmaceutically acceptable salt thereof.
It has been surprisingly found that compositions of valsartan and
antihyperlipidemia agent
show a particular potentiation, synergism, in the prevention, delay of
progression or
treatment of nephrotic syndrome and its complications.
In a preferred embodiment of the invention, the antihyperlipidemia agent are
statins.
HMG-CoA reductase inhibitors, also called ~i-hydroxy-(3-methylglutaryl-co-
enzyme-A
reductase inhibitors and also called statins) are understood to be those
active agents which
may be preferably used to lower the lipid levels including cholesterol in
blood and can be
used e.g. for the prevention or treatment of hyperlipidemia and
artheriosclerosis.
The class of HMG-Co-A reductase inhibitors comprises compounds having
differing
structural features
HMG-CoA reductase inhibitor compounds are disclosed, e.g., in the following
commonly
assigned patents, published patent applications and publications which are all
hereby
incorporated herein by reference:
Preferred are compounds which are selected from the group consisting of
atorvastatin,
cerivastatin, fluvastatin, lovastatin, pitavastatin (formerly itavastatin),
pravastatin,
rosuvastatin, and simvastatin, or, in each case, a pharmaceutically acceptable
salt thereof.
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Especially preferred HMG-Co-A reductase inhibitors are those agents which have
been
marketed. Most preferred are atorvastatin, fluvastatin, pitavastatin,
rosuvastatin or
simvastatin or a pharmaceutically acceptable salt thereof, in the first line
pitavastatin or a
pharmaceutically acceptable salt thereof.
Only salts that are pharmaceutically acceptable and non-toxic are used
therapeutically and
those salts are therefore preferred.
The corresponding active ingredient or a pharmaceutically acceptable salts
thereof may also
be used in form of a solvate, such as a hydrate or including other solvents,
used for
crystallization.
The structure of the active agents identified hereinbefore or hereinafter by
generic or trade
names may be taken from the actual edition of the standard compendium "The
Merck Index"
or from databases, e.g. Patents International (e.g. IMS World Publications).
The
corresponding content thereof is hereby incorporated by reference. Any person
skilled in the
art is fully enabled to identify the active agent and, based on these
references, likewise
enabled to manufacture and test the pharmaceutical indications and properties
in standard
test models, both in vitro and in vivo.
The term "potentiation" shall mean an increase of a corresponding
pharmacological activity
or therapeutical effect, respectively. Potentiation of one component of the
combination
according to the present invention by co-administration of an other component
according to
the present invention means that an effect is being achieved that is greater
than that
achieved with one component alone or that is greater than the sum of effects
of each
component.
The term "synergistic" shall mean that the drugs, when taken together, produce
a total joint
effect that is greater than the sum of the effects of each drug when taken
alone.
Further benefits are that lower doses of the individual drugs to be combined
according to the
present invention can be used to reduce the dosage, for example, that the
dosages need not
only often be smaller but are also applied less frequently, thereby
diminishing the incidence
of side effects. This is in accordance with the desires and requirements of
the patients to be
treated.
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It is another object of this invention to provide pharmaceutical compositions
for the
prevention, delay of progression or treatment of nephrotic syndrome and its
complications,
which composition comprises an AT1-receptor antagonist, in particular
valsartan, or a
pharmaceutically acceptable salt thereof in combination with an
antihyperlipidemia agent,
especially a statin .
It is another object of this invention to provide pharmaceutical compositions
for the
prevention, delay of progression or treatment of nephrotic syndrome and its
complications,
which composition comprises an AT1-receptor antagonist, in particular
valsartan, or a
pharmaceutically acceptable salt thereof in combination with a statin selected
from the group
consisting of atorvastatin, fluvastatin, pitavastatin, simvastatin and
rosuvastatin or a
pharmaceutically acceptable salt thereof .
In another embodiment, the invention provides a combination, such as a
combined
preparation or pharmaceutical composition for the prevention, delay of
progression or
treatment of nephrotic syndrome and its complications, wherein the combination
comprises
an AT1-receptor antagonist, in particular valsartan, or a pharmaceutically
acceptable salt
thereof in combination with atorvastatin or a pharmaceutically acceptable salt
thereof .
In another embodiment, the invention provides a combination, such as a
combined
preparation or pharmaceutical composition for the prevention, delay of
progression or
treatment of nephrotic syndrome and its complications, wherein the combination
comprises
an AT1-receptor antagonist, in particular valsartan, or a pharmaceutically
acceptable salt
thereof in combination with simvastatin or a pharmaceutically acceptable salt
thereof .
In another embodiment, the invention provides a combination, such as a
combined
preparation or pharmaceutical composition for the prevention, delay of
progression or
treatment of nephrotic syndrome and its complications, wherein the combination
comprises
an AT1-receptor antagonist, in particular valsartan, or a pharmaceutically
acceptable salt
thereof in combination with rosuvastatin or a pharmaceutically acceptable salt
thereof .
In a preferred embodiment, the invention provides a combination, such as a
combined
preparation or pharmaceutical composition for the prevention, delay of
progression or
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treatment of nephrotic syndrome and its complications, wherein the combination
comprises
an AT1-receptor antagonist, in particular valsartan, or a pharmaceutically
acceptable salt
thereof in combination with fluvastatin or a pharmaceutically acceptable salt
thereof .
In a preferred embodiment, the invention provides a combination, such as a
combined
preparation or pharmaceutical composition for the prevention, delay of
progression or
treatment of nephrotic syndrome and its complications, wherein the combination
comprises
an AT1-receptor antagonist, in particular valsartan, or a pharmaceutically
acceptable salt
thereof in combination with pitavastatin or a pharmaceutically acceptable salt
thereof .
The invention also relates to the use of an AT1-receptor antagonist, in
particular valsartan,
or a pharmaceutical salt thereof for the preparation of a pharmaceutical
composition for the
prevention, delay of progression or treatment of nephrotic syndrome and its
complications.
The invention also relates to the use of an AT1-receptor antagonist, in
particular valsartan,
or a pharmaceutical salt thereof for the preparation of a pharmaceutical
composition for the
prevention, delay of progression or treatment of nephrotic syndrome and its
complications by
administering to a mammal in need thereof a therapeutically effective amount
of valsartan or
a pharmaceutically acceptable salt thereof in combination with an
antihyperlipidemia agent,
especially a statin.
The invention also relates to the use of an AT1-receptor antagonist, in
particular valsartan,
or a pharmaceutical salt thereof for the preparation of a pharmaceutical
composition for the
prevention, delay of progression or treatment of nephrotic syndrome and its
complications by
administering to a mammal in need thereof a therapeutically effective amount
of valsartan or
a pharmaceutically acceptable salt thereof in combination with a statin
selected from the
group consisting of atorvastatin, fluvastatin, pitavastatin, rosuvastatin and
simvastatin, or a
pharmaceutically acceptable salt thereof.
In a preferred embodiment the invention relates to the use of an AT1-receptor
antagonist, in
particular valsartan, or a pharmaceutical salt thereof for the preparation of
a pharmaceutical
composition for the prevention, delay of progression or treatment of nephrotic
syndrome and
its complications by administering to a mammal in need thereof a
therapeutically effective
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amount of valsartan or a pharmaceutically acceptable salt thereof in
combination with
fluvastatin or a pharmaceutically acceptable salt thereof.
In a preferred embodiment the invention relates to the use of an AT1-receptor
antagonist, in
particular valsartan, or a pharmaceutical salt thereof for the preparation of
a pharmaceutical
composition for the prevention, delay of progression or treatment of nephrotic
syndrome and
its complications by administering to a mammal in need thereof a
therapeutically effective
amount of valsartan or a pharmaceutically acceptable salt thereof in
combination with
pitavastatin or a pharmaceutically acceptable salt thereof.
The invention also relates to a method for the prevention, delay of
progression or treatment
of nephrotic syndrome and its complications, which method comprises
administering to a
mammal in need thereof a therapeutically effective amount of valsartan or a
pharmaceutical
salt thereof.
The invention also relates to a method for the prevention, delay of
progression or treatment
of nephrotic syndrome and its complications, which method comprises
administering to a
mammal in need thereof a therapeutically effective amount of valsartan or a
pharmaceutical
salt thereof in combination with an antihyperlipidemia agent, especially a
statin .
The invention also relates to a method for the prevention, delay of
progression or treatment
of nephrotic syndrome and its complications, which method comprises
administering to a
mammal in need thereof a therapeutically effective amount of valsartan or a
pharmaceutical
salt thereof in combination with a statin selected from the group consisting
of atorvastatin,
fluvastatin, pitavastatin, rosuvastatin and simvastatin, or a pharmaceutically
acceptable salt
thereof .
In a preferred embodiment the invention relates to a method for the
prevention, delay of
progression or treatment of nephrotic syndrome and its complications, which
method
comprises administering to a mammal in need thereof a therapeutically
effective amount of
valsartan or a pharmaceutical salt thereof in combination fluvastatin or a
pharmaceutically
acceptable salt thereof .
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In a preferred embodiment the invention relates to a method for the
prevention, delay of
progression or treatment of nephrotic syndrome and its complications, which
method
comprises administering to a mammal in need thereof a therapeutically
effective amount of
valsartan or a pharmaceutical salt thereof in combination pitavastatin or a
pharmaceutically
acceptable salt thereof .
The present invention relates to a package comprising an AT 1- receptor
blocker, especially
valsartan together with instructions for use for the prevention, delay of
progression or
treatment of nephrotic syndrome and its complications.
The present invention relates to a package comprising an AT 1- receptor
blocker together
with instructions for use in combination with an antihyperlipidemia agent for
the prevention ,
delay of progression or treatment of nephrotic syndrome and its complications
.
The invention also relates to a "kit of parts" in the sense that the
components can be dosed
independently or by use of different fixed combinations with distinguished
amounts of the
components at different time points. The parts of the "kit of parts" can then,
e.g., be
administered simultaneously or chronologically staggered, that is at different
time points and
with equal or different time intervals for any part of the "kit of parts".
Preferably, the time
intervals are chosen such that the effect on the treated disease or condition
in the combined
use of the parts is larger than the effect that would be obtained by use of
only any one of the
components. Preferably, there is at least one beneficial effect, e.g., a
mutual enhancing of
the effect of at least two therapeutic agents selected from the group
consisting of
(i) an AT 1- receptor blocker, specially valsartan and
(ii) an antihyperlipiemia agent, especially a statin.
The present invention provides a kit comprising in separate containers in a
single package
pharmaceutical compositions comprising in one container a pharmaceutical
composition
comprising the AT 1- receptor blocker valsartan and in a second container a
pharmaceutical
composition comprising an antihyperlipidemia agent especially a statin.
In a preferred embodiment the present invention provides a kit comprising in
separate
containers in a single package pharmaceutical compositions comprising in one
container a
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pharmaceutical composition comprising the AT 1- receptor blocker valsartan and
in a second
container a pharmaceutical composition comprising the antihyperlipidemia agent
fluvastatin.
In another preferred embodiment the present invention provides a kit
comprising in separate
containers in a single package pharmaceutical compositions comprising in one
container a
pharmaceutical composition comprising the AT 1- receptor blocker valsartan and
in a second
container a pharmaceutical composition comprising the antihyperlipidemia agent
pitavastatin .
Said pharmaceutical compositions are those for enteral, such as oral, and also
rectal or
parenteral administration to mammals (warm-blooded animals), including man,
the
pharmacological active ingredient being present on its own or together with
the usual
pharmaceutical excipients. The pharmaceutical compositions contain, for
example, from
about 0.1 % to 100 %, preferably from about 1 % to about 80 %, of the active
ingredient.
Pharmaceutical compositions for enteral or parenteral and also for ocular
administration are
typically those in unit dose forms, such as dragees, tablets, capsules or
suppositories and
also ampoules. These are prepared in a manner known per se, for example by
means of
conventional mixing, granulating, sugar-coating, dissolving or lyophilising
methods.
Accordingly, pharmaceutical compositions for oral use can be obtained by
combining the
active ingredient with solid carriers, if desired granulating a mixture
obtained, and processing
the mixture or granules, if desired or necessary after the addition of
suitable excipients, to
give tablets or dragee cores.
Suitable carriers are preferably fillers, typically sugars, such as lactose,
saccharose,
mannitol or sorbitol, cellulose compositions and/or calcium phosphates, e.g.
tricalcium
phosphate or calciumhydrogen phosphate, furthermore binders, such as starch
paste,
typically using e.g. corn starch, wheat starch, rice starch or potato starch,
gelatin, traga-
canth gum, methylcellulose and/or polyvinylpyrrolidone and, if desired,
disintegrants, such as
the above-mentioned starches, furthermore carboxymethyl starch, crosslinked
polyvinyl-
pyrrolidone, agar, alginic acid or a salt thereof, typically sodium alginate.
Excipients are
primarily flow regulators and lubricants, typically silica gel, talcum,
stearic acid or salts
thereof, typically magnesium stearate or calcium stearate, andlor polyethylene
glycol.
Dragee cores are provided with suitable coatings which, if desired, are
resistant to gastric
juice, using, inter alia, concentrated sugar solutions which optionally
contain gum arabic,
talcum, polyvinylpyrrolidone, polyethylene glycol andlor titanium dioxide,
coating solutions in
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suitable organic solvents or solvent mixtures or, for the preparation of
gastric juice-resistant
coatings, solutions of suitable cellulose compositions, typically
acetylcellulose phthalate or
hydroxypropylmethylcellulose phthalate. Colorants or pigments may be added to
the tablets
or dragee coatings, for example to identify or indicate different doses of
active ingredient.
Other pharmaceutical compositions for oral administration are dry-filled
gelatin capsules as
well as soft closed capsules made of gelatin and a plasticizer, such as
glycerol or sorbitol.
The dry-filled capsules may contain the active ingredient in the form of
granules, typically in
admixture with fillers, such as lactose, binders, such as starches, and/or
lubricants, such as
talcum or magnesium stearate. In soft capsules, the active ingredient is
preferably dissolved
or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid
polyethylene glycols,
and stabilisers can also be added.
Suitable pharmaceutical compositions for rectal administration are typically
suppositories
consisting of a combination of the active ingredient with a suppository base.
Suitable
suppository bases are, for example, natural or synthetic triglycerides,
paraffin hydrocarbons
and higher alkanols. Furthermore, gelatin rectal capsules containing a
combination of the
active ingredient with a base substance may also be used. Suitable base
substances are, for
example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.
Suitable compositions for parenteral administration are primarily aqueous
solutions of an
active ingredient in water-soluble form, typically a water-soluble salt, and
also suspensions
of the active ingredient, such as appropriate oily injection suspensions,
using suitable
lipophilic solvents or vehicles, typically fatty oils, e.g. sesame oil, or
synthetic fatty acid
esters, typically ethyl oleate or triglycerides, or aqueous injection
suspensions containing
viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol
and/or dextran
and, optionally, also stabilisers.
For preventive treatments, unit dosage forms for oral administration are
preferred, typically
tablets or capsules and, in acute treatments, i.v. application forms.
The dose of the active ingredient can depend of various factors, e.g. mode of
application,
species of warm-blooded animal, age and/or individual state. The estimated
normal dose for
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oral administration to a patient weighing about 75 kg is an approximate dose
of about 10 mg
to about 640 mg of AT1-receptor antagonist.
In a preferred embodiment of this invention, pharmaceutically acceptable
compositions
comprising valsartan are used. The daily dose for oral administration of AT1-
antagonist
valsartan in a unit dose form is preferably about 20 mg to about 320 mg, more
preferably
about 40 mg or about 80 mg.
The following Example illustrates the above invention without, however,
limiting it in its scope
in any way.
Formulation Example 1:
Film-Coated Tablets:
Components Compostion Per UnitStandards
(mg)
Granulation - .
Valsartan [= active ingredient]80.00
Microcrystalline cellulose/ 54.00 NF, Ph.
Avicel PH 102 Eur
Crospovidone 20.00 NF, Ph.
Eur
Colloidal anhydrous silica 0.75 Ph. Eur/
l NF
colloidal silicon dioxide /
Aerosil 200
Magnesium stearate 2.5 NF, Ph.
Eur
Blending
Colloidal anhydrous silica 0.75 Ph. Eur/
/ NF
colloidal silicon dioxide /
Aerosil 200
Magnesium stearate 2.00 NF, Ph.
Eur
Coating
Purified water
DIOLACK pale red OOF34899 7.00
Total tablet mass 167:00
*~ Removed during processing.
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The film-coated tablet is manufactured e.g. as follows:
A mixture of valsartan, microcrystalline cellulose, crospovidone, part of the
colloidal
anhydrous silica/colloidal silicon dioxide/Aerosile 200, silicon dioxide and
magnesium
stearate is premixed in a diffusion mixer and then sieve through a screnning
mill. The
resulting mixture is again pre-mixed in a diffusion mixer, compacted in a
roller compacter
and then sieve through a screening mill. To the resulting mixture, the rest of
the colloidal
anhydrous silica/colloidal silicon dioxidelAerosile 200 are added and the
final blend is made
in a diffusion mixer. The whole mixture is compressed in a rotary tabletting
machine and the
tablets are coated with a film by using Diolack pale red in a perforated pan.
Formulation Example 2:
Film-coated tablets:
Components Compostion Per Unit Standards
(mg)
Granulation
Valsartan [= active ingredient]160.00
Microcrystalline cellulose/ 108.00 NF, Ph.
Avicel PH 102 Eur
Crospovidone 40.00 NF, Ph.
Eur
Colloidal anhydrous silica 1.50 Ph. Eur/
/ NF
colloidal silicon dioxide /
Aerosil 200
Magnesium stearate 5.00 NF, Ph.
Eur
Blending
Colloidal anhydrous silica 1.50 Ph. Eur/
/ NF
colloidal silicon dioxide l
Aerosil 200
Magnesium stearate 4.00 NF, Ph.
Eur
Coating
Opadry Light Brown OOF33172 10.00
Total tablet mass 330.00
The film-coated tablet is manufactured e.g. as described in Formulation
Example 1.
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Formulation Example 3:
Film-Coated Tablets:
Components Compostion Per Unit Standards
(mg)
Core: Internal phase
Valsartan 40.00
[= active ingredient]
Silica, colloidal anhydrous1.00 Ph. Eur, USP/NF
(Colloidal silicon
dioxide)
[= Glidant]
Magnesium stearate 2.00 USP/NF
[= Lubricant]
Crospovidone 20.00 Ph. Eur
[Disintegrant]
Microcrystalline cellulose124.00 USP/NF
[= Binding agent]
External phase
Silica, colloidal anhydrous,1.00 Ph. Eur, USP/NF
(Colloidal silicon
dioxide)
[= Glidant]
Magnesium stearate 2.00 USP/NF
[Lubricant]
Film coating
Opadry brown OOF 16711~~9.40
Purified Water ' -
Total tablet mass 199.44
x~ The composition of the Opadry° brown OOF16711 coloring agent is
tabulated below.
i~~ Removed during processing
Opadry° Composition:
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Ingredient ~ Approximate % Composition
Iron oxide, black (C.1. No. 77499,0.50
E 172)
Iron oxide, brown (C.1. No. 77499,0.50
E 172
Iron oxide, red (C.1. No. 77491, 0.50
E 172)
Iron oxide, yellow (C.1. No. 77492,0.50
E 172)
Macrogolum (Ph. Eur) 4.00
Titanium dioxide (C.1. No. 77891,14.00
E 171)
Hypromellose (Ph. Eur) 80.00
The film-coated tablet is manufactured e.g. as described in Formulation
Example 1.
Formulation Example 4:
Capsules:
Components Compostion Per Unit
(mg)
Valsartan [= active ingredient]80.00
Microcrystalline cellulose 25.10
Crospovidone 13.00
Povidone 12.50
Magnesium stearate 1.30
Sodium lauryl sulphate 0.60
Shell
Iron oxide, red 0.123
(C.1. No. 77491, EC No. E 172)
Iron oxide, yellow 0.123
(C.1. No. 77492, EC No. E 172)
Iron oxide, black 0.245
(C.1. No. 77499, EC No. E 172)
Titanium dioxide 1.540
Gelatin 74.969
Total tablet mass 209.50
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The tablet is manufactured e.g. as follows:
Granulation/Drying
Valsartan and microcrystallin cellulose are spray-granulated in a fluidised
bed granulator with
a granulating solution consisting of povidone and sodium lauryl sulphate
dissolved in purified
water. The granulate obtained is dried in a fluidised bed dryer.
Milling/Blending
The dried granulate is milled together with crospovidone and magnesium
stearate. The
mass is then blended in a conical srew type mixer for approximately 10
minutes.
Encapsulation
The empty hard gelatin capsules are filled with the blended bulk granules
under controlled
temperature and humidity conditions. The filed capsules are dedustee, visually
inspected,
weightchecked and quarantied until by Quality assurance department.
Examples 7 to 11:
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Exam 1e 7 8 9 10 11
COmpOnentS COMPOSITIONCOMPOSITIONCOMPOSITIONCOMPOSITIONCOMPOSITION
PER PER UNITPER UNIT PER UNITPER UNIT
UNIT m m m m m
Granulation
Valsartan Dru Substance80.000 160.000 40.000 320.000 320.000
Microcrystalline 54.000 108.000 27.000 216.000 216.000
Cellulose
NF, Ph.Eur. / Avicel
PH 102
Crospovidone (NF, 15.000 30.000 7.500 80.000 60.000
Ph.Eur.)
Colloidal Anhydrous1.500 3.000 0.750 3.000 6.000
Silica
(Ph. Eur.)/COlloidal
Silicon
Dioxide NF /Aerosil
200
Magnesium Stearate 3.000 6.000 1.500 10.000 12.000
( NF,
Ph.Eur.
Blending
Colloidal Anhydrous--- --- --- 3.000
Silica
(Ph. Eur.)/COlloidal
Silicon
Dioxide NF /Aerosil
200
Magnesium Stearate,1.500 3.000 0.750 8.000 6.000
NF,
Ph.Eur.
Core Weightlmg 155.000 310.000 77.500 640.000 620.000
Coating - - 3.800 15.000 16.000
Formulation Example 5:
Capsules:
Components Composition Per
Unifi (mg)
Valsartan [= active ingredient]160.00
Microcrystalline cellulose 50.20
Crospovidone 26.00
Povidone 25.00
Magnesium stearate 2.60
Sodium lauryl sulphate 1.20
Shell
Iron oxide, red 0.123
(C.1. No. 77491, EC No. E 172)
Iron oxide, yellow 0.123
(C.1. No. 77492, EC No. E 172)
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Iron oxide, black 0.245
(C.1. No. 77499, EC No.
E 172)
Titanium dioxide 1.540
Gelatin 74.969
Total tablet mass 342.00
The formulation is manufactured e.g. as described in Formulation Example 4.
Formulation Example 6:
Hard Gelatine Capsule:
Components Compostion Per Unit
(mg)
Valsartan [= active 80.00
ingredient]
Sodium laurylsulphate 0.60
Magnesium stearate 1.30
Povidone 12.50
Crospovidone 13.00
Microcrystalline cellulose21.10
Total tablet mass 130.00
Formulation Example 6 bis
A hard gelatin capsule, comprising as active ingredient e.g. (S)-N-(1-carboxy-
2-methylprop-
1-yl)-N-pentanoyl-N-[2'(1 H-tetrazol-5-yl)biphenyl-4-yl-methyl]amine, can be
formulated, for
example, as follows:
Composition:
(1 ) valsartan 80.0 mg
(2) microcrystalline 110.0 mg
cellulose
(3) polyvidone K30 45.2 mg
(4) sodium lauryl sulfate1.2 mg
(5) crospovidone 26.0 mg
(6) magnesium stearate 2.6 mg
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Components (1) and (2) are granulated with a solution of components (3) and
(4) in water.
The components (5) and (6) are added to the dry granulate and the mixture is
filled into size
1 hard gelatin capsules.
