U.S. patent application number 10/514682 was filed with the patent office on 2005-10-06 for combination of organic compounds.
Invention is credited to Shetty, Suraj Shivappa, Webb, Randy Lee.
Application Number | 20050222137 10/514682 |
Document ID | / |
Family ID | 29550142 |
Filed Date | 2005-10-06 |
United States Patent
Application |
20050222137 |
Kind Code |
A1 |
Shetty, Suraj Shivappa ; et
al. |
October 6, 2005 |
Combination of organic compounds
Abstract
The present invention relates to a combination of organic
compounds, a pharmaceutical composition and a kit of parts
comprising said combination of organic compounds and to a method of
treatment or prevention of certain conditions or diseases.
Inventors: |
Shetty, Suraj Shivappa; (Far
Hills, NJ) ; Webb, Randy Lee; (Flemington,
NJ) |
Correspondence
Address: |
NOVARTIS
CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 104/3
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
29550142 |
Appl. No.: |
10/514682 |
Filed: |
January 7, 2005 |
PCT Filed: |
May 16, 2003 |
PCT NO: |
PCT/EP03/05180 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60381547 |
May 17, 2002 |
|
|
|
Current U.S.
Class: |
514/223.5 ;
514/355; 514/381 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 9/00 20180101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61P 27/06 20180101; A61P 9/10 20180101;
A61P 3/10 20180101; A61P 25/00 20180101; A61P 9/06 20180101; A61K
31/4184 20130101; A61K 31/196 20130101; A61K 31/19 20130101; A61K
31/44 20130101; A61P 25/28 20180101; A61P 27/02 20180101; A61P
13/12 20180101; A61P 5/42 20180101; A61P 5/00 20180101; A61P 9/04
20180101; A61P 9/14 20180101; A61K 31/44 20130101; A61K 31/196
20130101; A61P 7/10 20180101; A61P 9/12 20180101; A61P 17/00
20180101; A61P 7/00 20180101; A61K 31/19 20130101; A61P 25/06
20180101; A61P 13/02 20180101; A61K 31/4184 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/223.5 ;
514/355; 514/381 |
International
Class: |
A61K 031/549; A61K
031/455; A61K 031/4184 |
Claims
1. A pharmaceutical composition comprising (i) an angiotensin
receptor blocker (ARB) or a pharmaceutically acceptable salt
thereof, (ii) a calcium channel blocker (CCB) or a pharmaceutically
acceptable salt thereof, and (iii) a diuretic or a pharmaceutically
acceptable salt thereof.
2. A pharmaceutical composition according to claim 1, wherein (i)
the angiotensin receptor blocker (ARB) is selected from the group
consisting of candesartan, eprosartan, irbesartan, losartan,
olmesartan, saprisartan, tasosartan, telmisartan, valsartan, E4177,
SC-52458, and ZD8731; (ii) the calcium channel blocker (CCB) is
selected from the group consisting of amlodipine, felodipine,
isradipine, lacidipine, nicardipine, nifedipine, niguldipine,
niludipine, nimodipine, nisoldipine, nitrendipine, nivaldipine,
ryosidine, anipamil, diltiazem, fendiline, flunarizine, gallopamil,
mibefradil, prenylamine, tiapamil, and verapamil; and (iii) the
diuretic is selected from the group consisting of bumetanide,
ethacrynic acid, furosemide, torsemide, amiloride, spironolactone,
triamterene, chlorothalidone, chlorothiazide, hydrochlorothiazide,
hydroflumethiazide, methylchlorothiazide, metolazone, and
dichlorphenamide.
3. A pharmaceutical composition according to claim 2, wherein (i)
the angiotensin receptor blocker (ARB) is valsartan; (ii) the
calcium channel blocker (CCB) is amlodipine; and (iii) the diuretic
is hydrochlorothiazide.
4. A pharmaceutical composition according to claim 3, wherein
valsartan is contained in an amount from about 20 to about 640 mg,
amlodipine is contained in an amount from about 1 mg to about 60
mg, and hydrochlorothiazide is contained in an amount from about 5
mg to about 200 mg.
5. A pharmaceutical composition according to claim 4, wherein
valsartan is contained in an amount from about 40 to about 320 mg,
amlodipine is contained in an amount from about 2.5 mg to about 10
mg, and hydrochlorothiazide is contained in an amount from about 5
mg to about 25 mg.
6. A kit of parts comprising (i) a pharmaceutical composition of an
angiotensin receptor blocker (ARB), (ii) a pharmaceutical
composition of a calcium channel blocker (CCB), and (iii) a
pharmaceutical composition of a diuretic in the form of two or
three separate units of the components (i) to (iii).
7. A kit of parts according to claim 6, wherein (i) the angiotensin
recepror blocker (ARB) is selected from the group consisting of
candesartan, eprosartan, irbesartan, losartan, olmesartan,
saprisartan, tasosartan, telmisartan, valsartan, E-4177, SC-52458,
and ZD8731; (ii) the calcium channel blocker (CCB) is selected from
the group consisting of amlodipine, felodipine, isradipine,
lacidipine, nicardipine, nifedipine, niguldipine, niludipine,
nimodipine, nisoldipine, nitrendipine, nivaldipine, ryosidine,
anipamil, diltiazem, fendiline, flunarizine, gallopamil,
mibefradil, prenylamine, tiapamil, and verapamil; and (iii) the
diuretic is selected from the group consisting of bumetanide,
ethacrynic acid, furosemide, torsemide, amiloride, spironolactone,
triamterene, chlorothalidone, chlorothiazide, hydrochlorothiazide,
hydroflumethiazide, methylchlorothiazide, metolazone, and
dichlorphenamide.
8. A kit of parts according to claim 7, wherein (i) the angiotensin
receptor blocker (ARB) is valsartan; (ii) the calcium channel
blocker (CCB) is amlodipine; and (iii) the diuretic is
hydrochlorothiazide.
9. A kit of parts according to claim 8, wherein valsartan is
contained in an amount from about 20 to about 640 mg, amlodipine
ins contained in an amount from about 1 mg to about 60 mg, and
hydrochlorothiazide is contained in an amount from about 5 mg to
about 200 mg.
10. A kit of parts according to claim 9, wherein valsartan is
contained in an amount from about 40 to about 320 mg, amlodipine
ins contained in an amount from about 2.5 mg to about 10 mg, and
hydrochlorothiazide is contained in an amount from about 5 mg to
about 25 mg.
11. A method of treatment or prevention of a condition or disease
selected from the group consisting of hypertension, heart failure
such as (acute and chronic) congestive heart failure, left
ventricular dysfunction and hypertrophic cardiomyopathy, diabetic
cardiac myopathy, supraventricular and ventricular arrhythmias,
atrial fibrillation, atrial flutter, detrimental vascular
remodeling, myocardial infarction and its sequelae,
atherosclerosis, angina (whether unstable or stable), renal
insufficiency (diabetic and non-diabetic), heart failure, angina
pectoris, diabetes, secondary aldosteronism, primary and secondary
pulmonary hypertension, renal failure conditions, such as diabetic
nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis,
proteinuria of primary renal disease, and also renal vascular
hypertension, diabetic retinopathy, the management of other
vascular disorders, such as migraine, peripheral vascular disease,
Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such
as Alzheimer's), glaucoma and stroke, comprising administering a
therapeutically effective amount of combination of (i) an ARB
selected from the group consisting of candesartan, eprosartan,
irbesartan, losartan, olmesartan, saprisartan, tasosartan,
telmisartan, valsartan, E-4177, SC-52458, and ZD8731, or a
pharmaceutically acceptable salt thereof; and (ii) a CCB selected
from the group consisting of amlodipine, felodipine, isradipine,
lacidipine, nicardipine, nifedipine, niguldipine, niludipine,
nimodipine, nisoldipine, nitrendipine, nivaldipine, and ryosidine,
which all belong to the group of dihydropyridines (DHPs) and the
non-DHP CCBs anipamil, diltiazem, fendiline, flunarizine,
gallopamil, mibefradil, prenylamine, tiapamil, and verapamil, or a
pharmaceutically acceptable salt thereof; and (iii) a diuretic
selected from the group consisting of bumetanide, ethacrynic acid,
furosemide, torsemide, amiloride, spironolactone, triamterene,
chlorothalidone, chlorothiazide, hydrochlorothiazide,
hydroflumethiazide, methylchlorothiazide, metolazone, and
dichlorphenamide, or, where appropriate, a pharmaceutically
acceptable salt thereof and a pharmaceutically acceptable carrier
to a mammal in need of such treatment.
12. A commercial package comprising (i) a pharmaceutical
composition of an angiotensin receptor blocker (ARB), (ii) a
pharmaceutical composition of a calcium channel blocker (CCB), and
(iii) a pharmaceutical composition of a diuretic, in the form of
two or three separate units of the components (i) to (iii),
together with instructions for simultaneous, separate or sequential
use thereof for the treatment or prevention of a condition or
disease selected from the group consisting of hypertension, heart
failure such as (acute and chronic) congestive heart failure, left
ventricular dysfunction and hypertrophic cardiomyopathy, diabetic
cardiac myopathy, supraventricular and ventricular arrhythmias,
atrial fibrillation, atrial flutter, detrimental vascular
remodeling, myocardial infarction and its sequelae,
atherosclerosis, angina (whether unstable or stable), renal
insufficiency (diabetic and non-diabetic), heart failure, angina
pectoris, diabetes, secondary aldosteronism, primary and secondary
pulmonary hypertension, renal failure conditions, such as diabetic
nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis,
proteinuria of primary renal disease, and also renal vascular
hypertension, diabetic retinopathy, the management of other
vascular disorders, such as migraine, peripheral vascular disease,
Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such
as Alzheimer's), glaucoma and stroke
13. A commercial package according to claim 12, wherein (i) the
angiotensin receptor blocker (ARB) is valsartan; (ii) the calcium
channel blocker (CCB) is amlodipine; and (iii) the diuretic is
hydrochlorothiazide.
14. A commercial package according to claim 13, wherein the
angiotensin receptor blocker (ARB) (i) and the diuretic (iii) are
present in the form of CO-DIOVAN.RTM. or wherein the angiotensin
receptor blocker (ARB) (i), the CCB (ii) and the diuretic (iii) are
present in the form of CO-DIOVAN.RTM. and Norvasc.RTM..
15. (canceled)
16. A method for the treatment or prevention of a condition or
disease selected from the group consisting of hypertension, heart
failure such as (acute and chronic) congestive heart failure, left
ventricular dysfunction and hypertrophic cardiomyopathy, diabetic
cardiac myopathy, supraventricular and ventricular arrhythmias,
atrial fibrillation, atrial flutter, detrimental vascular
remodeling, myocardial infarction and its sequelae,
atherosclerosis, angina (whether unstable or stable), renal
insufficiency (diabetic and non-diabetic), heart failure, angina
pectoris, diabetes, secondary aldosteronism, primary and secondary
pulmonary hypertension, renal failure conditions, such as diabetic
nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis,
proteinuria of primary renal disease, and also renal vascular
hypertension, diabetic retinopathy, the management of other
vascular disorders, such as migraine, peripheral vascular disease,
Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such
as Alzheimer's), glaucoma and stroke comprising administering a
composition according to claim 1.
17. A method for the treatment or prevention of a condition or
disease selected from the group consisting of hypertension, heart
failure such as (acute and chronic) congestive heart failure, left
ventricular dysfunction and hypertrophic cardiomyopathy, diabetic
cardiac myopathy, supraventricular and ventricular arrhythmias,
atrial fibrillation, atrial flutter, detrimental vascular
remodeling, myocardial infarction and its sequelae,
atherosclerosis, angina (whether unstable or stable), renal
insufficiency (diabetic and non-diabetic), heart failure, angina
pectoris, diabetes, secondary aldosteronism, primary and secondary
pulmonary hypertension, renal failure conditions, such as diabetic
nephropathy, glomerulonephritis, scieroderma, glomerular sclerosis,
proteinuria of primary renal disease, and also renal vascular
hypertension, diabetic retinopathy, the management of other
vascular disorders, such as migraine, peripheral vascular disease,
Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such
as Alzheimer's), glaucoma and stroke comprising administering a
composition according to claim 2.
18. A method for the treatment or prevention of hypertension, heart
failure such as (acute and chronic) congestive heart failure, left
ventricular dysfunction and hypertrophic cardiomyopathy, diabetic
cardiac myopathy, supraventricular and ventricular arrhythmias,
atrial fibrillation, atrial flutter, detrimental vascular
remodeling, myocardial infarction and its sequelae,
atherosclerosis, angina (whether unstable or stable), renal
insufficiency (diabetic and non-diabetic), heart failure, angina
pectoris, diabetes, secondary aldosteronism, primary and secondary
pulmonary hypertension, renal failure conditions, such as diabetic
nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis,
proteinuria of primary renal disease, and also renal vascular
hypertension, diabetic retinopathy, the management of other
vascular disorders, such as migraine, peripheral vascular disease,
Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such
as Alzheimer's), glaucoma and stroke, comprising administering the
kit of parts of claim 6.
Description
[0001] The present invention relates to a combination of organic
compounds that are antihypertensive agents with complementary modes
of action for eliciting blood pressure-lowering, and also for
attenuating the varied pathological sequelae of hypertension and
several other cardiovascular disorders. Furthermore, this invention
addresses the disparate responsiveness of humans to
antihypertensive monotherapy, based on age and/or ethnicity (Campo
C, Segura J, Ruilope L M, J Clin Hypertens (Greenwich) 2002
January, 4(1):35-40). Finally, the choice of agents and their
respective dosages in the combination regimen are designed to
enhance tolerability by minimizing the risk of dose-dependent
adverse effects associated with individual agents.
[0002] Numerous clinical studies have shown that lowering blood
pressure in hypertensive patients reduces mortality and morbidity
(Collins R, Peto R, MacMahon S, Hebert P, Fiebach N H, Eberlein K
A, Godwin J, Qizilbash N, Taylor J O, Hennekens C H, Lancet 1990,
335(8693):827-38). Despite the availability and use of various
classes of agents in the treatment of this medical condition,
adequate control of blood pressure is not always achieved (Waeber
B, Brunner H R, Am J Hypertens 1997,10(7 Pt 2):131 S-i 37S). Using
a combination of agents is one way to achieve the desired
therapeutic end-point. An arbitrary selection of antihypertensive
agents of different classes for inclusion in a combination therapy
regimen does not necessarily help achieve target levels of blood
pressure in hypertensive mammals including humans (MacGregor G A,
Markandu N D, Banks R A, Bayliss J, Roulston J E, Jones J C, Br Med
J (Clin Res Ed), 284(631 7):693-6). Therefore, a need for further
development of methods of treatment, combinations, and
pharmaceutical compositions clearly exists.
[0003] Specifically, the present invention relates to
pharmaceutical compositions comprising (i) an angiotensin receptor
(Type 1, AT.sub.1) blocker (ARB) selected from the group consisting
of candesartan, eprosartan, irbesartan, losartan, olmesartan,
saprisartan, tasosartan, telmisartan, valsartan, E-4177, SC-52458,
and ZD8731, and pharmaceutically acceptable salts thereof; (ii) a
calcium channel blocker (CCB) selected from the group consisting of
amlodipine, felodipine, isradipine, lacidipine, nicardipine,
nifedipine, niguldipine, niludipine, nimodipine, nisoldipine,
nitrendipine, nivaldipine, ryosidine, anipamil, diltiazem,
fendiline, flunarizine, gallopamil, mibefradil, prenylamine,
tiapamil, and verapamil, and pharmaceutically acceptable salts
thereof; and, (iii) a diuretic selected from the group consisting
of bumetanide, ethacrynic acid, furosemide, torsemide, amiloride,
spironolactone, triamterene, chlorothalidone, chlorothiazide,
hydrochlorothiazide, hydroflumethiazide, methylchlorothiazide,
metolazone, and dichlorphenamide, and pharmaceutically acceptable
salts thereof where appropriate, i.e. if the diuretic compound is
not already present as a pharmaceutically acceptable salt as e.g.
In the case of hydrochlorothiazide; optionally in the presence of a
pharmaceutically acceptable carrier. The invention further provides
methods for treating hypertension and a variety of cardiovascular
disorders enumerated below and their sequelae by administration of
the pharmaceutical composition comprising (i) an angiotensin
receptor blocker (ARB), (ii) a calcium channel blocker (CCB), (iii)
and a diuretic to a mammal including humans.
[0004] Thus, the invention further relates to a pharmaceutical
composition or a kit of parts, e.g. for the treatment or prevention
of a condition or disease selected from the group consisting of
hypertension, heart failure such as (acute and chronic) congestive
heart failure, left ventricular dysfunction and hypertrophic
cardiomyopathy, diabetic cardiac myopathy, supraventricular and
ventricular arrhythmias, atrial fibrillation, atrial flutter,
detrimental vascular remodeling, myocardial infarction and its
sequelae, atherosclerosis, angina (whether unstable or stable),
renal insufficiency (diabetic and non-diabetic), heart failure,
angina pectoris, diabetes, secondary aldosteronism, primary and
secondary pulmonary hypertension, renal failure conditions, such as
diabetic nephropathy, glomerulonephritis, scleroderma, glomerular
sclerosis, proteinuria of primary renal disease, and also renal
vascular hypertension, diabetic retinopathy, the management of
other vascular disorders, such as migraine, peripheral vascular
disease, Raynaud's disease, luminal hyperplasia, cognitive
dysfunction (such as Alzheimer's), glaucoma and stroke which
composition (or kit of part) comprises (i) an ARB selected from the
group consisting of candesartan, eprosartan, irbesartan, losartan,
olmesartan, saprisartan, tasosartan, telmisartan, valsartan,
E-4177, SC-52458, and ZD8731, or a pharmaceutically acceptable salt
thereof; and (ii) a CCB selected from the group consisting of
amlodipine, felodipine, isradipine, lacidipine, nicardipine,
nifedipine, niguldipine, niludipine, nimodipine, nisoldipine,
nitrendipine, nivaldipine, and ryosidine, which all belong to the
group of dihydropyridines (DHPs) and the non-DHP CCBs anipamil,
diltiazem, fendiline, flunarizine, gallopamil, mibefradil,
prenylamine, tiapamil, and verapamil, or a pharmaceutically
acceptable salt thereof; and (iii) a diuretic selected from the
group consisting of bumetanide, ethacrynic acid, furosemide,
torsemide, amiloride, spironolactone, triamterene, chlorothalidone,
chloroethiazide, hydrochlorothiazide, hydroflumethiazide,
methylchlorothiazide, metolazone, and dichlorphenamide, or, where
appropriate, a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
[0005] A further aspect of the present invention is a method for
the treatment or prevention of a condition or disease selected from
the group consisting of hypertension, heart failure such as (acute
and chronic) congestive heart failure, left ventricular dysfunction
and hypertrophic cardiomyopathy, diabetic cardiac myopathy,
supraventricular and ventricular arrhythmias, atrial fibrillation,
atrial flutter, detrimental vascular remodeling, myocardial
infarction and its sequelae, atherosclerosis, angina (whether
unstable or stable), renal insufficiency (diabetic and non-
diabetic), heart failure, angina pectoris, diabetes, secondary
aldosteronism, primary and secondary pulmonary hypertension, renal
failure conditions, such as diabetic nephropathy,
glomerulonephritis, scieroderma, glomerular sclerosis, proteinuria
of primary renal disease, and also renal vascular hypertension,
diabetic retinopathy, the management of other vascular disorders,
such as migraine, peripheral vascular disease, Raynaud's disease,
luminal hyperplasia, cognitive dysfunction (such as Alzheimer's),
glaucoma and stroke, comprising administering a therapeutically
effective amount of combination of (i) an ARB selected from the
group consisting of candesartan, eprosartan, irbesartan, losartan,
olmesartan, saprisartan, tasosartan, telmisartan, valsartan,
E-4177, SC-52458, and ZD8731, or a pharmaceutically acceptable salt
thereof; and (ii) a CCB selected from the group consisting of
amlodipine, felodipine, isradipine, lacidipine, nicardipine,
nifedipine, niguldipine, niludipine, nimodipine, nisoldipine,
nitrendipine, nivaldipine, and ryosidine, which all belong to the
group of dihydropyridines (DHPs) and the non-DHP CCBs anipamil,
diltiazem, fendiline, flunarizine, gallopamil, mibefradil,
prenylamine, tiapamil, and verapamil, or a pharmaceutically
acceptable salt thereof; and (iii) a diuretic selected from the
group consisting of bumetanide, ethacrynic acid, furosemide,
torsemide, amiloride, spironolactone, triamterene, chlorothalidone,
chlorothiazide, hydrochlorothiazide, hydroflumethiazide,
methylchlorothiazide, metolazone, and dichlorphenamide, or, where
appropriate, a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier to a mammal In need of such
treatment.
[0006] The invention also relates to combining separate
pharmaceutical compositions in kit form. That is a kit combining
two or three separate units: e.g. a pharmaceutical composition
comprising an ARB, an pharmaceutical composition comprising a CCB,
and a pharmaceutical composition comprising a diuretic; or a
pharmaceutical composition comprising an ARB and a diuretic, and a
pharmaceutical composition comprising a CCB; or a pharmaceutical
composition comprising a CCB and a diuretic, and a pharmaceutical
composition comprising an ARB. Although the kit form is
particularly advantageous when the separate components must be
administered In different dosage forms (e.g. parenteral valsartan
formulation and oral amlodipine or hydrochlorothiazide
formulations) or are administered at different dosage intervals,
the administration of the single components of such a kit of parts
may, without any restriction be effected simultaneously,
sequentially or staggered with time.
[0007] In a preferred embodiment, the (commercial) product is a
commercial package comprising as active ingredients the combination
according to the present invention (in the form of two or three
separate units of the components (i) to (iii)), together with
instructions for its simultaneous, separate or sequential use, or
any combination thereof, in the delay of progression or treatment
of the diseases mentioned herein. A preferred commercial package,
is where the ARB (i) and the diuretic (iii) are present in the form
of Co-DIOVAN .RTM., or where the ACE inhibitor (i), the CCB (ii)
and the diuretic (iii) are present in the form of Co-DIOVAN .RTM.
and NORVASC.RTM..
[0008] The pharmaceutical preparations of the present invention are
for enteral, such as oral, and also rectal or parenteral,
administration to homeotherms, with the preparations comprising the
pharmacological active compound either alone or together with
customary pharmaceutical auxiliary substances. For example, the
pharmaceutical preparations consist of from about 0.1% to 90%,
preferably of from about 1% to about 80%, of the active compounds.
Pharmaceutical preparations for enteral or parenteral
administration are, for example, in unit dose forms, such as coated
tablets, tablets, capsules or suppositories and also ampoules.
These are prepared in a manner, which is known per se, for example
using conventional mixing, granulation, coating, solubulizing or
lyophilizing processes. Thus, pharmaceutical preparations for oral
use can be obtained by combining the active compounds with solid
excipients, if desired granulating a mixture which has been
obtained, and, if required or necessary, processing the mixture or
granulate into tablets or coated tablet cores after having added
suitable auxiliary substances.
[0009] The dosage of the active compound can depend on a variety of
factors, such as mode of administration, homeothermic species, age
and/or individual condition. Preferred dosages for the active
ingredients of the pharmaceutical combination according to the
present invention are therapeutically effective dosages, especially
those that are commercially available. Normally, in the case of
oral administration, an approximate daily dose of from about 20 mg
to about 900 mg of active agents, i.e. ARB plus CCB plus diuretic,
is to be estimated e.g. for a patient of approximately 75 kg in
weight.
[0010] In the present invention preferred ARBs are those agents
that have been marketed, as e.g. valsartan and losartan. The same
applies to the CCBs employed In the present invention, of which
amlodipine and felodipine are preferred. The most preferred
diuretic Is hydrochlorothiazide (HCTZ).
[0011] Very surprisingly is the finding that, a combination of (i)
an ARB, (ii) a CCB, and (iii) a diuretic and in particular a
combination comprising valsartan, amlodipine and HCTZ achieves
greater therapeutic effect than the administration of valsartan,
amlodipine, or HCTZ alone or in a combination of two of these
agents. Greater efficacy can also be documented as a prolonged
duration of action. The duration of action can be monitored as
either the time to return to baseline prior to the next dose or as
the area under the curve (AUC) and is expressed as the product of
the change in blood pressure in millimeters of mercury (change in
mmHg) and the duration of the effect (minutes, hours or days). The
aforementioned combination treatment also unexpectedly reduces
blood pressure in hypertensive mammals in a smooth and sustained
fashion. The trough:peak blood pressure ratio demonstrated by this
combination is close to unity leading to a more homogenous blood
pressure control during the Inter-dosing period. The combined
regimen is almost completely devoid of either orthostatic
hypotension or first-dose hypotension, and incidences of rebound
hypertension after cessation of treatment are very rare. It can be
shown that combination therapy according to the invention results
in lessening of pulse pressure in hypertensive mammals.
Furthermore, this combination therapy can ameliorate endothelial
dysfunction and improve vascular compliance and distensibility in
hypertensive mammals. It can also slow the progression of cardiac,
renal and cerebral end-organ damage in these mammals. 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, or can be used to
diminish the incidence of side effects. Surprisingly, the
combination of valsartan, amlodipine and HCTZ significantly reduce
the Incidences of peripheral edema relative to those observed in
mammals treated with amlodipine alone. Also, the undesirable
effects of HCTZ on serum lipids, glucose, and uric acid levels are
surprisingly attenuated in mammals treated with the combined
regimens of valsartan, amlodipine and HCTZ.
[0012] In particular the combined administration of valsartan or a
pharmaceutically acceptable salt thereof, amlodipine or a
pharmaceutically acceptable salt thereof, and HCTZ results in a
significant response in a greater percentage of treated patients
compared to monotherapy or combination therapy e.g. valsartan and
HCTZ, that is, a greater responder rate results, regardless of the
underlying etiology of the condition. This is In accordance with
the desires and requirements of the patients to be treated. The
combination treatment effectively lowers blood pressure in
hypertensive patients in all age groups including pre and
postmenopausal women. It can be shown that combination therapy with
valsartan, amlodipine, and HCTZ results in a more effective
antihypertensive therapy (whether for malignant, essential,
renovascular, diabetic, isolated systolic, or other secondary type
of hypertension) and lessening of pulse pressure through improved
efficacy. The combination is also useful in the treatment or
prevention of heart failure such as (acute and chronic) congestive
heart failure, left ventricular dysfunction and hypertrophic
cardiomyopathy, diabetic cardiac myopathy, supraventricular and
ventricular arrhythmias, atrial fibrillation, atrial flutter or
detrimental vascular remodeling. It can further be shown that a
valsartan, amiodipine, and HCTZ combination therapy proves to be
beneficial In the treatment and prevention of myocardial infarction
and its sequelae. A valsartan, amlodipine, and HCTZ combination is
also useful in treating atherosclerosis, angina (whether stable or
unstable), renal Insufficiency (diabetic and non-diabetic),
peripheral vascular disease, cognitive dysfunction, and stroke.
Furthermore, the improvement in endothelial function with the
combination therapy using valsartan, amlodipine, and HCTZ provides
benefit in diseases in which normal endothelial function is
disrupted such as heart failure, angina pectoris and diabetes.
Furthermore, the combination of the present invention may be used
for the treatment or prevention of secondary aldosteronism, primary
and secondary pulmonary hypertension, renal failure conditions,
such as diabetic nephropathy, glomerulonephritis, scleroderma,
glomerular sclerosis, proteinuria of primary renal disease, and
also renal vascular hypertension, diabetic retinopathy, the
management of other vascular disorders, such as migraine,
peripheral vascular disease, Raynaud's disease, luminal
hyperplasia, cognitive dysfunction (such as Alzheimer's), glaucoma
and stroke. The combination regimen also surprisingly reduces the
rate of progression of cardiac, renal and cerebral end-organ
damage. By providing enhanced efficacy, safety and tolerability,
the combination of drugs Indicated in this invention also has the
potential to promote patient compliance, a major consideration in
the pharmacological treatment of hypertension.
[0013] 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 herein before and hereinafter
indicated therapeutic indications.
[0014] The advantages of the present combinations are, for example,
demonstrated in a clinical study or in the test procedure as
essentially described hereinafter. Many clinical study protocols
adapted to test our combinations are known by the person skilled in
the art. An example of a clinical trial useful to demonstrate the
unexpected advantages of our new combinations is described by
Waeber B et al. (J Hypertens. 2001 November;19(1 1):2097-104. The
same protocol is performed with our preferred combinations such as
a combination, preferably fixed-dose combination, of valsartan 80
mg, hydrochlorothiazide 12.5 mg, and amlodipine 5 mg. This protocol
is hereby incorporated into the present application by reference to
this publications.
[0015] Representative studies are carried out with a combination of
valsartan, amlodipine, and HCTZ applying the following methodology.
Drug efficacy is assessed in various animal models including the
deoxycorticosterone acetate--salt rat (DOCA-salt) and the
spontaneously hypertensive rat (SHR), either maintained on a normal
salt diet or with salt loading (4-8% salt In rat chow or 1% NaCl as
drinking water).
[0016] The DOCA-salt test model utilizes either an acute or chronic
study protocol. An acute study procedure involves assessment of the
effects of various test substances over a six-hour experimental
period using rats with indwelling femoral arterial and venous
catheters. The Acute Study Procedure evaluates test substances for
their ability to reduce blood pressure during the established phase
of DOCA-salt hypertension. In contrast, the Chronic Study Procedure
assesses the ability of test substances to prevent or delay the
rise in blood pressure during the development phase of DOCA-salt
hypertension. Therefore, blood pressure will be monitored In the
chronic study procedure by means of a radiotransmitter. The
radiotransmitter is surgically implanted into the abdominal aorta
of rats, prior to the Initiation of DOCA-salt treatment and thus,
prior to the induction of hypertension. Blood pressure is
chronically monitored for periods of up 6 weeks (approximately one
week prior to DOCA-salt administration and for 5 weeks
thereafter).
[0017] Rats are anesthetized with 2-3% Isoflurane in oxygen
inhalant followed by Amytal sodium (amobarbital) 100 mg/kg, ip. The
level of anesthesia is assessed by a steady rhythmic breathing
pattern.
[0018] Acute Study Procedure:
[0019] Rats undergo a unilateral nephrectomy at the time of DOCA
implantation. Hair Is clipped on the left flank and the back of the
neck and scrubbed with sterile alcohol swabs and povidone/iodine.
During surgery rats are placed on a heating pad to maintain body
temperature at 37.degree. C.
[0020] A 20 mm incision is made through the skin and underlying
muscle to expose the left kidney. The kidney is freed of
surrounding tissue, exteriorized and two ligatures (3-0 silk) are
tied securely around the renal artery and vein proximal to their
juncture with the aorta. The renal artery and vein are then severed
and the kidney removed. The muscle and skin wounds are closed with
4-0 silk suture and stainless steel wound clips, respectively. At
the same time, a 15 mm incision is made on the back of the neck and
a 3-week-release pellet (Innovative Research of America, Sarasota,
Florida) containing deoxycorticosterone acetate (100 mg/kg) is
implanted subcutaneously. The wound is then closed with
stainless-steel clips and both wounds are treated with
povidone/iodine; the rats are given a post-surgical intramuscular
Injection of procaine penicillin G (100,000 U) and buprenorphine
(0.05-0.1 mg/kg) s.c. The rats are immediately placed on 1%
NaCl+0.2% KCl drinking water; this treatment continues for at least
3 weeks at which time the animals have become hypertensive and
available for experimentation.
[0021] Forty-eight hours prior to experimentation, animals are
anesthetized with isoflurane and catheters are implanted in the
femoral artery and vein for measuring arterial pressure, collection
of blood, and administration of test compounds. Rats are allowed to
recover for 48 hours while tethered In a Plexiglas home cage, which
also serves as the experimental chamber.
[0022] Chronic Study Procedure:
[0023] This procedure is the same as above except that rats are
Implanted with a radiotransmitter, 7-10 days prior to the
unilateral nephrectomy and initiation of DOCA and salt. In
addition, rats do not undergo surgery for placement of femoral
arterial and venous catheters. Radiotransmitters are implanted as
described in M. K. Bazil, C. Krulan and R. L. Webb. Telemetric
monitoring of cardiovascular parameters In conscious spontaneously
hypertensive rats. J.Cardiovasc. Pharmacol. 22: 897-905, 1993.
[0024] Protocols are then set-up on the computer for measurement of
blood pressure, heart rate, etc, at predetermined time points.
Baseline data is collected at various time points and over various
time intervals. For example, baseline or pre-dose values usually
consist of data collection and averaging over 3 consecutive,
24-hour time periods prior to drug administration.
[0025] Blood pressure, heart rate and activity are determined at
various pre-selected time points before, during, and after drug
administration. All measurements are performed in unrestrained and
undisturbed animals. The maximum study time, determined by battery
life, could be as long as nine months. For studies of this
duration, rats are dosed orally (1-3 ml/kg vehicle), no more than
twice daily or drug Is administered via the drinking water or mixed
with food. For studies of a shorter duration, that is, up to 8
weeks, drugs are given via subcutaneously implanted osmotic
minipumps. Osmotic minipumps are selected based on drug delivery
rate and time. Valsartan dosages range from 1 to 100 mg/kg/day,
amlodipine dosages range from 1 to 75 mg/kg/day, and HCTZ dosages
range from 1 to 75 mg/kg/day.
[0026] Additionally, SHR are utilized to study the effects of
valsartan in combination with amlodipine, and HCTZ. The
hypertensive background of the SHR is modified either by chronic
salt loading in an effort to suppress the RMS or chronic salt
depletion to activate the RAAS in the SHR. These manipulations will
be carried out to more extensively evaluate the efficacy of the
various test substances. Experiments are performed in spontaneously
hypertensive rats (SHR) supplied by Taconic Farms, Germantown, N.Y.
(Tac:N(SHR)fBR). A radiotelemetric device (Data Sciences
International, Inc., St. Paul, Minn.) is implanted into the lower
abdominal aorta of all test animals between the ages of 14 to 16
weeks of age. All SHR are allowed to recover from the surgical
implantation procedure for at least 2 weeks prior to the initiation
of the experiments. Cardiovascular parameters are continuously
monitored via the radiotransmitter and transmitted to a receiver
where the digitized signal is then collected and stored using a
computerized data acquisition system. Blood pressure (mean
arterial, systolic and diastolic pressure) and heart rate are
monitored in conscious, freely moving and undisturbed SHR in their
home cages. The arterial blood pressure and heart rate are measured
every 10 minutes for 10 seconds and recorded. Data reported for
each rat represent the mean values averaged over a 24 hour period
and are made up of the 144-10 minute samples collected each day.
The baseline values for blood pressure and heart rate consist of
the average of three consecutive 24 hour readings taken prior to
initiating the drug treatments. All rats are individually housed in
a temperature and humidity controlled room and are maintained on a
12 hour light dark cycle.
[0027] In addition to the cardiovascular parameters, weekly
determinations of body weight also are recorded in all rats.
Treatments are administered in the drinking water, via daily oral
gavage or in osmotic minipumps as stated above. If given in
drinking water, water consumption is measured five times per week.
Valsartan, amlodipine, and HCTZ doses for individual rats are then
calculated based on water consumption for each rat, the
concentration of drug substance in the drinking water, and
individual body weights. All drug solutions in the drinking water
are made up fresh every three to four days. Typical dosages for
valsartan in drinking water range from 1 to 100 mg/kg/day, dosages
of amlodipine range from 1 to 75 mg/kg/day, and dosages of HCTZ
range from 1 to 75 mg/kg/day. In most situations, a daily dose will
not exceed 100 mg/kg/day when administered as the monotherapy. In
combination, lower dosages of each agent are used and
correspondingly, valsartan is given in the range of 1 to 30
mg/kg/day, and amlodipine and HCTZ are give in dosages below 50
mg/kg/day.
[0028] When drugs are administered by oral gavage, the dose of
valsartan ranges from 1 to 50 mg/kg/day and that of amlodipine and
HCTZ does not exceed 75 mg/kg/day, respectively.
[0029] Upon completion of the chronic studies, SHR or DOCA-salt
rats are anesthetized, blood samples obtained for biochemical
analysis and the heart rapidly removed. After separation and
removal of the atrial appendages, left ventricle and left plus
right ventricle (total) are weighed and recorded. Left ventricular
and total ventricular mass are then normalized to body weight and
reported.
[0030] Vascular function and structure are evaluated after
treatment to assess the beneficial effects of the combination. SHR
are studied according to the methods described by intengan HD,
Thibault G, Li J S, Schiffrin E L, Circulation 1999, 100 (22):
2267-2275. Similarly, the methodology for assessing vascular
function in DOCA-salt rats is described in Intengan HD, Park J B,
Schiffrin, E L, Hypertension, 1999, 34(4 Part 2): 907-913.
Assessment of vascular compliance and distensibility following
treatment with the combination regimen is performed according to
the methods described by Ceiler D L, Nelissen-Vrancken H J, De Mey
J G, Smits J F, J Cardiovasc Pharmacol 1998, 31(4):630-7.
Amelioration of cardiac, renal, and cerebral injury secondary to
hypertension is assessed after treatment with the combination
regimen in salt-loaded stroke-prone spontaneously hypertensive rats
according to the methods described by Nagura J, Yamamoto M, Hui C,
Yasuda S, Hachisu M, Konno F, Clin Exp Pharmacol Physiol 1996,
23(3):229-35. Propensity of the combination therapy to elicit
postural or orthostatic hypotension is assessed in SHRs by the
methods described by Nabata H, Aono J, Ishizuka N, Sakai K, Arch
Int Pharmacodyn Ther 1985, 277(1):104-18. Tendency to produce
peripheral edema by the combination regimen was assessed by the
methods described by Lacolley P, Poitevin P, Koen R, Levy BI, J
Hypertens 1998, 16(3):349-55.
[0031] Valsartan is supplied in the form of suitable dosage unit
form, for example, a capsule or tablet, and comprising a
therapeutically effective amount, e.g. from about 20 to about 320
or 640 mg, of valsartan which may be applied to patients. The
application of the active ingredient may occur up to three times a
day, starting e.g. with a daily dose of 20 mg or 40 mg of
valsartan, increasing via 80 mg daily and further to 160 mg daily
up to 320 or 640 mg daily. Preferably, valsartan is applied once a
day or twice a day in heart failure patients with a dose of 80 mg
or 160 mg, respectively, each. Corresponding doses may be taken,
for example, in the morning, at mid-day or in the evening.
Preferred is q.d. or b.i.d. administration in heart failure.
[0032] In case of amlodipine, preferred dosage unit forms are, for
example, tablets or capsules comprising e.g. from about 1 mg to
about 60 mg, preferably 2.5 to 20 mg, more preferably between 2.5
and 10 mg daily when administered orally.
[0033] In case of HCTZ, preferred dosage unit forms are, for
example, tablets or capsules comprising e.g. from about 5 mg to
about 200 mg preferably from about 50 mg to about 150 mg, even more
preferably from about 25 mg to about 100 mg and even more
preferably from about 5 mg to about 25 mg, administered orally once
a day.
[0034] An example of a preferred composition, comprises an amount
of Valsartan between 60 and 100 mg e.g. 80 mg, an amount of
amlodipine between 2 and 12 mg e.g. 2.5 or 5 mg and an amount of
HCTZ between 8 and 16 mg e.g. 12.5 mg.
[0035] Another example of a preferred composition, comprises an
amount of Valsartan between 140 and 180 mg e.g. 160 mg, an amount
of amlodipine between 2 and 12 mg e.g. 2.5 or 5 or 10 mg and an
amount of HCTZ between 8 and 16 mg e.g. 12.5 mg.
[0036] Another example of a preferred composition comprises an
amount of Valsartan between 140 and 180 mg e.g. 160 mg, an amount
of amlodipine between 4 and 12 mg e.g. 5 mg or 10 mg, and an amount
of HCTZ between 20 and 30 mg e.g. 25 mg.
[0037] The combination of (i) an ARB, (ii) a CCB, and (iii) a
diuretic may, according to the present invention be manufactured
and administered in free or fixed dose combinations of the
respective pharmaceutically active agents. It may be advantageous
to begin the treatment with free combinations that allow an easy
adjustment of the administered dose of each individual agent. When
the ideal dose regimen, which generally is dependent on the
specific condition of the individual to be treated, the individuals
weight, other medication administered to the individual and the
like, is reached, a fixed dose combination may be administered in
case where an administration once a day or e.g. twice or three
times daily is possible and a sufficient control of blood pressure
is achieved.
[0038] Presently it is preferred to combine two of the components
(i) to (iii) and administer the third separately at the same or at
a different time.
[0039] Valsartan is being marketed under the trade name
Diovan.RTM.. A combination of valsartan and HCTZ is being marketed
under the trade name Co-Diovan.RTM. and amlodipine is being
marketed under the trade name Norvasc.RTM.. All of these marketed
products may be utilized in as such for combination therapy
according to the present invention.
[0040] The following examples illustrate the invention described
above and are not Intended to restrict the scope of this Invention
in any way.
FORMULATION EXAMPLE 1
[0041] Composition and Batch Quantities for Diovan.RTM. Tablets
1 COMPOSITION QUANTITY Components PER UNIT (mg) PER BATCH.sup.1
(kg) Granulation 40 mg 80 mg 160 mg 320 mg 40 mg 80 mg 160 mg 320
mg Diovan Drug Substance 40.000 80.000 160.000 320.000 144.000
144.000 144.000 144.000 Microcrystalline 27.000 54.000 108.000
216.000 97.200 97.200 97.200 97.200 Cellulose(NF, Ph.Eur.) Avicel
PH102 Crospovidone (NF, Ph.Eur.) 7.500 15.000 30.000 60.000 27.000
27.000 27.000 27.000 Colloidal Anhydrous Silica 0.750 1.500 3.000
6.000 2.700 2.700 2.700 2.700 (Ph.Eur.)/Colloidal silicon Dioxide
(NF)/Aerosil 200 Magnesium Stearate 1.500 3.000 6.000 12.000 5.400
5.400 5.400 5.400 (NF, Ph.Eur.) Blending Magnesium Stearate 0.750
1.500 3.000 6.000 2.700 2.700 2.700 2.700 (NF, Ph.Eur.) Coating
DIOLACK Gelb F32892 2.800 11.090.sup.2 DIOLACK Blassrot F34899
6.000 12.420.sup.3 DIOLACK Hellbraun 9.000 9.720.sup.4 F33172
DIOLACK Braun F16711 16.000 8.640.sup.4 Purified Water 62.843
70.380 55.080 48.960 Total Tablet/Batch Weight 80.300 161.000
319.000 636.000 289.080 289.800 287.100 286.200 .sup.1A total of 2
subdivisions of granulation per batch .sup.2A 10% excess of coating
solution was manufactured to account for loss during coating.
.sup.3A 15% excess of coating solution was manufactured to account
for loss during coating. .sup.4A 20% excess of coating solution was
manufactured to account for loss during coating.
[0042] Composition of Diolack
2 Iron Oxide Iron Oxide Iron Oxide Titanium (Red) (Yellow) (Brown)
Iron Oxide HPMC Dioxide Ph.Fr./NF/ Ph.Fr./NF/ Mixture of iron
(Black) USP/Ph.Eur PEG 8000 (White) E172/CFR/ E172/CFR/ oxide red
& E172/CFR/ DIOLACK (603) USP/Ph.Eur. USP/Ph.Eur CI 77491 CI
77492 black CI 77499 Gelb 80.00% 4.00% 13.48% 0.01% 2.50% -- 0.01%
F32892 Blassrot 80.00% 4.00% 15.50% 0.40% 0.10% -- -- F34899
Hellbraun 80.00% 4.00% 9.34% 0.25% 6.40% -- 0.01% F33172 Braun
80.00% 4.00% 14.00% 0.50% 0.50% 0.50% 0.50% F16711
[0043] A mixture of Diovan drug substance, 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 sieved
through a screening mill. The resulting mixture is again pre-mixed
in a diffusion mixer, compacted in a roller compacter and then
sieved through a screening mill. To the resulting mixture, the rest
of the colloidal anhydrous silica/colloidal silicon
dioxide/Aerosile 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
the appropriate composition of Diolack in a perforated pan.
FORMULATION EXAMPLE 2
[0044] Composition and Quantities for Co-Diovan.RTM. Tablets
3 COMPO- COMPO- COMPO- SITION SITION SITION PER PER PER Components
UNIT (mg) UNIT (mg) UNIT (mg) Granulation Diovan Drug Substance
80.000 160.000 160.00 Esidrex Drug Substance 12.500 12.500 25.00
(micro) Microcrystalline Cellulose 31.500 75.500 63.00 (NF,
Ph.Eur.)/Avicel PH 102 Crospovidone (NF, 20.000 40.000 40.00
Ph.Eur.) Colloidal Anhydrous Silica 1.500 3.00 3.00
(Ph.Eur.)/Colloidal Silicon Dioxide (NF)/Aerosil 200 Magnesium
Stearate (NF, 3.000 6.000 6.00 Ph.Eur.) Blending Magnesium
Stearate, NF, 1.500 3.000 3.00 Ph.Eur. Coating Opadry Black
OOF17713 -- -- 0.096 Opadry Red OOF15613 -- -- 0.762 Opadry Yellow
OOF12951 -- -- 3.808 Opadry White OOF18296 -- -- 5.334 Hydroxy
propyl 2.76 5.510 -- Methylcellulose Iron Oxide Yellow 0.025 -- --
Iron Oxide Red 0.025 0.750 -- Polyethylene Glycol 8000 0.50 1.000
-- Talc 2.000 3.990 -- Titanium Dioxide 0.70 0.750 -- Total
Tablet/Batch Weight 156.000 312.000 310.00
[0045] Composition of Opadry
4 Iron Oxide Iron Oxide Titanium (Red) (Yellow) IronOxide HPMC
Dioxide Ph.Fr./NF/ Ph.Fr./NF/ (Black) USP/Ph.Eur PEG 4000 Talc
USP/Ph.Eur E172/CFR/ E172/CFR/ E172/CFR/ OPADRY (603) USP/Ph.Eur.
USP/Ph.Eur (White) CI 77491 CI 77492 CI 77499 Opadry White 71.4%
7.15% 7.15% 14.3% -- -- -- OOF18296* Opadry Red 71.4% 7.15% 7.15%
-- 14.3% -- -- OOF15613* Opadry Red 71.4% 7.15% 7.15% -- -- 14.3%
-- OOF15613* Opadry Black 71.4% 7.15% 7.15% -- -- -- 14.3%
OOF17713*
[0046] A mixture of Diovan drug substance, Esidrex drug substance
(micro), microcrystalline cellulose, crospovidone, colloidal
anhydrous silica/Aerosil 200 and part of the magnesium stearate is
premixed in a diffusion mixer and then sieve through a screening
mill. The resulting mixture is again pre-mixed in a diffusion
mixer, compacted in a roller compacter and then sieved through a
screening mill. The final blend is made in a diffusion mixer under
addition of the remaining part of the magnesium stearate, which is
hand screened before. The whole mixture is compressed in a rotary
tabletting machine and the tablets are coated with a film by using
the appropriate composition of Opadry in a perforated pan.
FORMULATION OF EXAMPLE 3
[0047] Composition and Quantities for a Combination of Valsartan
and Amlodipine
5 COMPOSITION PER Components UNIT (mg) COMPOSITION (%) Diovan Drug
Substance 80.00 43.02 Amlodipine Drug 6.94 3.73 Substance Avicel
102 (I) 54.00 29.04 Avicel 102 (II) 20.00 10.76 Crospovidone (I)
15.00 8.07 Crospovidone (II) 4.0 2.15 Cab-O-Sil 1.50 0.81 Magnesium
Stearate (I) 3.00 1.61 Magnesium Stearate (II) 1.50 0.81 185.94
100.00
[0048] The tablet is manufactured e.g essentially as described In
Formulation Example 1.
* * * * *