U.S. patent application number 11/915096 was filed with the patent office on 2010-01-07 for solid dosage forms of valsartan, amlodipine and hydrochlorothiazide and method of making the same.
Invention is credited to Yu Cao, Yatindra Joshi, Ping Li, Madhusudhan Pudipeddi, Alan E. Royce, Robert F. Wagner, Jiahao Zhu.
Application Number | 20100003321 11/915096 |
Document ID | / |
Family ID | 38662673 |
Filed Date | 2010-01-07 |
United States Patent
Application |
20100003321 |
Kind Code |
A1 |
Cao; Yu ; et al. |
January 7, 2010 |
SOLID DOSAGE FORMS OF VALSARTAN, AMLODIPINE AND HYDROCHLOROTHIAZIDE
AND METHOD OF MAKING THE SAME
Abstract
Monolayer, bilayer and trilayer solid dosage forms of a
combination of valsartan, amlodipine and hydrochlorothiazide are
made.
Inventors: |
Cao; Yu; (Parsippany,
NJ) ; Joshi; Yatindra; (Princeton, NJ) ; Li;
Ping; (Basking Ridge, NJ) ; Pudipeddi;
Madhusudhan; (Mumbai, IN) ; Royce; Alan E.;
(Saylorsburg, PA) ; Wagner; Robert F.;
(Hillsborough, NJ) ; Zhu; Jiahao; (Whippany,
NJ) |
Correspondence
Address: |
NOVARTIS;CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 104/3
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
38662673 |
Appl. No.: |
11/915096 |
Filed: |
June 26, 2007 |
PCT Filed: |
June 26, 2007 |
PCT NO: |
PCT/US07/72097 |
371 Date: |
November 20, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60805883 |
Jun 27, 2006 |
|
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|
Current U.S.
Class: |
424/474 ;
424/464; 514/223.5 |
Current CPC
Class: |
A61K 31/549 20130101;
A61P 7/00 20180101; A61K 9/209 20130101; A61P 25/28 20180101; A61P
9/12 20180101; A61P 25/00 20180101; A61K 31/41 20130101; A61P 1/16
20180101; A61P 9/00 20180101; A61P 9/10 20180101; A61K 9/2054
20130101; A61P 9/04 20180101; A61P 25/06 20180101; A61P 13/12
20180101; A61P 43/00 20180101; A61P 3/10 20180101; A61K 31/4422
20130101; A61K 31/41 20130101; A61K 2300/00 20130101; A61K 31/4422
20130101; A61K 2300/00 20130101; A61K 31/549 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
424/474 ;
514/223.5; 424/464 |
International
Class: |
A61K 31/549 20060101
A61K031/549; A61K 9/20 20060101 A61K009/20; A61P 9/00 20060101
A61P009/00; A61P 25/00 20060101 A61P025/00 |
Claims
1. A solid dosage form comprising: valsartan; amlodipine;
hydrochlorothiazide; and pharmaceutically acceptable additives
suitable for the preparation of solid dosage forms of
valsartan.
2. The solid dosage form of claim 1, wherein the amlodipine is
provided in the form of amlodipine besylate.
3. The solid dosage form of claim 1, wherein the solid dosage form
takes the form of a monolayer tablet.
4. The solid dosage form of claim 1, wherein the solid dosage form
takes the form of a bilayer tablet.
5. The solid dosage form of claim 4, wherein the bilayer tablet has
the valsartan and the hydrochlorothiazide in a first layer and the
amlodipine in a second layer.
6. The solid dosage form of claim 4, wherein the bilayer tablet has
the valsartan in a first layer and the amlodipine and the
hydrochlorothiazide in a second layer.
7. The solid dosage form of claim 1, wherein the valsartan is
employed in an amount ranging from about 80 mg to about 640 mg.
8. The solid dosage form of claim 7, wherein the valsartan is
employed in an amount selected from 160 mg and 320 mg.
9. The solid dosage form of claim 1, wherein the amlodipine is
employed in an amount ranging from about 2.5 mg to about 20 mg.
10. The solid dosage form of claim 9, wherein the amlodipine is
employed in an amount selected from 5 mg and 10 mg.
11. The solid dosage form of claim 1, wherein the
hydrochlorothiazide is employed in an amount ranging from about
6.25 mg to about 50 mg.
12. The solid dosage form of claim 11, wherein the
hydrochlorothiazide is employed in an amount selected from 12.5 mg
and 25 mg.
13. The solid dosage form of claim 1, wherein the pharmaceutically
acceptable additives are selected from the group consisting of
diluents, disintegrants, glidants, lubricants, binders, colorants
and combinations thereof.
14. A method of making a solid dosage form comprising the steps of:
(a) blending valsartan, amlodipine, hydrochlorothiazide and
pharmaceutically acceptable additives to form a blended material;
(b) sieving the blended material to form a sieved material; (c)
blending the sieved material to form a blended/sieved material; (d)
compacting the blended/sieved material to form a compacted
material; (e) milling the compacted material to form a milled
material; (f) blending the milled material to form blended/milled
material; and (g) compressing the blended/milled material to form a
monolayer solid dosage form.
15. The method of claim 14 further comprising the step of: (h) film
coating the monolayer solid dosage form.
16. A method of making a solid dosage form comprising the steps of:
(a) granulating valsartan, pharmaceutically acceptable additives
and optionally hydrochlorothiazide to form a valsartan granulation;
(b) blending amlodipine, pharmaceutically acceptable additives and
optionally hydrochlorothiazide to form an amlodipine blend; and (c)
compressing the valsartan granulation and the amlodipine blend
together to form a bilayer solid dosage form, wherein
hydrochlorothiazide is present in the valsartan granulation and/or
the amlodipine blend.
17. The method of claim 16, wherein step (a) comprises the steps
of: (a1) blending valsartan, pharmaceutically acceptable additives
and hydrochlorothiazide to form a blended material; (a2) sieving
the blended material to form a sieved material; (a3) blending the
sieved material to form a blended/sieved material; (a4) compacting
the blended/sieved material to form a compacted material; (a5)
milling the compacted material to form a milled material; and (a6)
blending the milled material to form the valsartan granulation.
18. The method of claim 16, wherein step (a) comprises the steps
of: (a1) blending valsartan and pharmaceutically acceptable
additives to form a blended material; (a2) sieving the blended
material to form a sieved material; (a3) blending the sieved
material to form a blended/sieved material; (a4) compacting the
blended/sieved material to form a compacted material; (a5) milling
the compacted material to form a milled material; and (a6) blending
the milled material and hydrochlorothiazide to form the valsartan
granulation.
19. The method of claim 16, wherein step (b) comprises a
granulation process comprising the steps of: (b1) blending
amlodipine, pharmaceutically acceptable additives and
hydrochlorothiazide to form a blended material; (b2) sieving the
blended material to form a sieved material; (b3) blending the
sieved material to form a blended/sieved material; (b4) compacting
the blended/sieved material to form a compacted material; (b5)
milling the compacted material to form a milled material; and (b6)
blending the milled material to form an amlodipine granulation.
20. The method of claim 16, wherein step (b) comprises a
granulation process comprising the steps of: (b1) blending
amlodipine and pharmaceutically acceptable additives to form a
blended material; (b2) sieving the blended material to form a
sieved material; (b3) blending the sieved material to form a
blended/sieved material; (b4) compacting the blended/sieved
material to form a compacted material; (b5) milling the compacted
material to form a milled material; and (b6) blending the milled
material and hydrochlorothiazide to form an amlodipine
granulation.
21. The method of claim 16 further comprising the step of: (d) film
coating the bilayer solid dosage form.
22. A method of making a solid dosage form comprising the steps of:
(a) granulating valsartan, pharmaceutically acceptable additives
and amlodipine to form a valsartan granulation; (b) blending
hydrochlorothiazide, pharmaceutically acceptable additives to form
a hydrochlorothiazide blend; and (c) compressing the valsartan
granulation and the hydrochlorothiazide blend together to form a
bilayer solid dosage form.
23. The method of claim 22, wherein step (a) comprises the steps
of: (a1) blending valsartan, pharmaceutically acceptable additives
and amlodipine to form a blended material; (a2) sieving the blended
material to form a sieved material; (a3) blending the sieved
material to form a blended/sieved material; (a4) compacting the
blended/sieved material to form a compacted material; (a5) milling
the compacted material to form a milled material; and (a6) blending
the milled material to form the valsartan granulation.
24. The method of claim 22, wherein step (a) comprises the steps
of: (a1) blending valsartan and pharmaceutically acceptable
additives to form a blended material; (a2) sieving the blended
material to form a sieved material; (a3) blending the sieved
material to form a blended/sieved material; (a4) compacting the
blended/sieved material to form a compacted material; (a5) milling
the compacted material to form a milled material; and (a6) blending
the milled material and amlodipine to form the valsartan
granulation.
25. The method of claim 22, wherein step (b) comprises a
granulation process comprising the steps of: (b1) blending
hydrochlorothiazide and pharmaceutically acceptable additives to
form a blended material; (b2) sieving the blended material to form
a sieved material; (b3) blending the sieved material to form a
blended/sieved material; (b4) compacting the blended/sieved
material to form a compacted material; (b5) milling the compacted
material to form a milled material; and (b6) blending the milled
material to form a hydrochlorothiazide granulation.
26. The method of claim 22 further comprising the step of: (d) film
coating the bilayer solid dosage form.
27. A method of treating hypertension, congestive heart failure,
angina, myocardial infarction, arteriosclerosis, diabetic
nephropathy, diabetic cardiac myopathy, renal insufficiency,
peripheral vascular disease, stroke, left ventricular hypertrophy,
cognitive dysfunction, headache, or chronic heart failure, wherein
the method comprises administering a solid dosage form as defined
in claim 1 to a subject in need of such treatment.
28. The method of treating according to claim 27, wherein the solid
dosage form is orally administered to the subject.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention is directed to solid dosage
formulations containing a combination of valsartan, amlodipine and
a diuretic such as hydrochlorothiazide, as well as to methods of
making such solid dosage forms and a method of treating a subject
with such solid dosage forms.
[0003] 2. Related Background Art
[0004] The development of fixed-combination solid dosage
formulations of certain active ingredients is challenging. As used
herein, "fixed-combination" refers to a combination of two or more
drugs or active ingredients presented in a single dosage unit such
as a tablet or a capsule; further as used herein,
"free-combination" refers to a combination of two or more drugs or
active ingredients dosed simultaneously but as two or more dosage
units. When formulating fixed-combination solid dosage
formulations, the objective is to provide a patient-convenient
combination dosage form of active ingredients that is bioequivalent
to the corresponding free-combination of the same active
ingredients and/or delivers a superior pharmacodynamic effect than
the individual components. Development of fixed-combination dosage
formulations that are bioequivalent to the free-combination is
challenging due to the multiplicity of challenges arising from
pharmacokinetic and pharmaceutical properties of the drugs sought
to be combined.
[0005] For example, valsartan has an absolute oral bioavailability
of only about 25% with a wide range of 10-35%. Valsartan also has
pH dependent solubility whereby it ranges from very slightly
soluble in an acidic environment to soluble in a neutral
environment of the gastrointestinal tract. Further, development of
a patient-convenient oral dosage form of valsartan is challenging
due to its low bulk density. Amlodipine besylate is slightly
soluble in water and has an absolute bioavailability of 64-90%.
Hydrochlorothiazide is slightly soluble in water and has an oral
bioavailability 60-80%. As a result of these complex
biopharmaceutical properties, development of a fixed-combination
dosage form of valsartan, amlodipine and hydrochlorothiazide that
is bioequivalent to a free-combination thereof is challenging.
[0006] Accordingly, a fixed-combination solid dosage formulation of
valsartan, amlodipine and hydrochlorothiazide that is bioequivalent
to the corresponding free-combination would be desirable.
SUMMARY OF THE INVENTION
[0007] In a first embodiment, the present invention is directed to
a solid dosage form comprising a combination of valsartan,
amlodipine and hydrochlorothiazide, and pharmaceutically acceptable
additives suitable for the preparation of solid dosage forms. In
preferred embodiments of this invention, amlodipine free base is
provided in the form of amlodipine besylate, and the
pharmaceutically acceptable additives are selected from diluents,
disintegrants, glidants, lubricants, binders, colorants and
combinations thereof.
[0008] In certain preferred embodiments of this invention, the
solid dosage form is a monolayer tablet. In other preferred
embodiments of this invention, the solid dosage form is a bilayer
tablet, e.g., having the valsartan and the hydrochlorothiazide in
one layer and the amlodipine in another layer or having the
valsartan in one layer and the amlodipine and the
hydrochlorothiazide in another layer or having the valsartan and
the amlodipine in one layer and the hydrochlorothiazide in another
layer. In other preferred embodiments of this invention, the solid
dosage form is a trilayer tablet, e.g., having all three actives in
separate layers. The amount of valsartan employed in such solid
dosage forms, monolayer or bilayer, preferably ranges from about 40
mg to about 640 mg, preferably 80 mg to 640 mg, and more preferably
is 160 mg or 320 mg. The amount of amlodipine employed in such
solid dosage forms, monolayer or bilayer, preferably ranges from
about 2.5 mg to about 20 mg, and more preferably is 5 mg or 10 mg.
The amount of hydrochlorothiazide employed in such solid dosage
forms, monolayer or bilayer, preferably ranges from about 6.25 mg
to about 50 mg, and more preferably is 12.5 mg or 25 mg.
[0009] In a second embodiment, the present invention is directed to
a method of making a solid dosage form of valsartan, amlodipine and
HCTZ comprising the steps of (a) blending valsartan, amlodipine,
hydrochlorothiazide and pharmaceutically acceptable additives to
form a blended material; (b) sieving the blended material to form a
sieved material; (c) blending the sieved material to form a
blended/sieved material; (d) compacting the blended/sieved material
to form a compacted material; (e) milling the compacted material to
form a milled material; (f) blending the milled material to form
blended/milled material; and (g) compressing the blended/milled
material to form a monolayer solid dosage form. A preferred
embodiment of this invention also includes an optional step, step
(h) film coating the monolayer solid dosage form.
[0010] In a third embodiment, this invention is directed to solid
dosage forms of valsartan, amlodipine and HCTZ made according to
the method of the second embodiment.
[0011] In a fourth embodiment, the present invention is directed to
a method of making a solid dosage form of valsartan, amlodipine and
HCTZ comprising the steps of a) blending valsartan and
pharmaceutically acceptable additives to form a blended material;
(b) sieving the blended material to form a sieved material; (c)
blending the sieved material to form a blended/sieved material; (d)
compacting the blended/sieved material to form a compacted
material; (e) milling the compacted material to form a milled
material; (f) blending the milled material with amlodipine and
hydrochlorothiazide to form blended/milled material; and (g)
compressing the blended/milled material to form a monolayer solid
dosage form. A preferred embodiment of this invention also includes
an optional step, step (h) film coating the monolayer solid dosage
form.
[0012] In a fifth embodiment, this invention is directed to solid
dosage forms of valsartan, amlodipine and HCTZ made according to
the method of the fourth embodiment.
[0013] In a sixth embodiment, the present invention is directed to
a method of making a solid dosage form of valsartan, amlodipine and
HCTZ comprising the steps of a) blending valsartan, amlodipine, and
pharmaceutically acceptable additives to form a blended material;
(b) sieving the blended material to form a sieved material; (c)
blending the sieved material to form a blended/sieved material; (d)
compacting the blended/sieved material to form a compacted
material; (e) milling the compacted material to form a milled
material; (f) blending the milled material with hydrochlorothiazide
to form blended/milled material; and (g) compressing the
blended/milled material to form a monolayer solid dosage form. A
preferred embodiment of this invention also includes an optional
step, step (h) film coating the monolayer solid dosage form.
[0014] In a seventh embodiment, this invention is directed to solid
dosage forms of valsartan, amlodipine and HCTZ made according to
the method of the sixth embodiment.
[0015] In an eighth embodiment, the present invention is directed
to a method of making a solid dosage form of valsartan, amlodipine
and HCTZ comprising the steps of a) blending valsartan,
hydrochlorothiazide, and pharmaceutically acceptable additives to
form a blended material; (b) sieving the blended material to form a
sieved material; (c) blending the sieved material to form a
blended/sieved material; (d) compacting the blended/sieved material
to form a compacted material; (e) milling the compacted material to
form a milled material; (f) blending the milled material with
amlodipine to form blended/milled material; and (g) compressing the
blended/milled material to form a monolayer solid dosage form. A
preferred embodiment of this invention also includes an optional
step, step (h) film coating the monolayer solid dosage form.
[0016] In a ninth embodiment, this invention is directed to solid
dosage forms of valsartan, amlodipine and HCTZ made according to
the method of the eighth embodiment.
[0017] In a tenth embodiment, the present invention is directed to
a method of making a solid dosage form of valsartan, amlodipine and
HCTZ comprising the steps of (a) granulating valsartan,
pharmaceutically acceptable additives and optionally
hydrochlorothiazide to form a valsartan granulation; (b)
granulating amlodipine, pharmaceutically acceptable additives and
optionally hydrochlorothiazide to form an amlodipine granulation;
and (c) compressing the valsartan granulation and the amlodipine
granulation together to form a bilayer solid dosage form, wherein
hydrochlorothiazide is present in the valsartan granulation and/or
the amlodipine blend. In a preferred embodiment of the invention,
step (a) comprises the steps of (a1) blending valsartan,
pharmaceutically acceptable additives and optionally
hydrochlorothiazide to form a blended material; (a2) sieving the
blended material to form a sieved material; (a3) blending the
sieved material to form a blended/sieved material; (a4) compacting
the blended/sieved material to form a compacted material; (a5)
milling the compacted material to form a milled material; and (a6)
blending the milled material to form the valsartan granulation. In
another preferred embodiment, step (b) comprises a granulation
process with the steps of (b1) blending amlodipine,
pharmaceutically acceptable additives and optionally
hydrochlorothiazide to form a blended material; (b2) sieving the
blended material to form a sieved material; (b3) blending the
sieved material to form a blended/sieved material; (b4) compacting
the blended/sieved material to form a compacted material; (b5)
milling the compacted material to form a milled material; and (b6)
blending the milled material to form an amlodipine granulation.
Another preferred embodiment of this invention also includes an
optional step, step (d) film coating the bilayer solid dosage form.
Hydrochlorothiazide can be incorporated at step a1 and/or a6, and
at step b1 and/or b6.
[0018] In a eleventh embodiment, this invention is directed to
solid dosage forms of valsartan, amlodipine and HCTZ made according
to the method of the tenth embodiment.
[0019] In another embodiment, this invention is directed to a
method of making a solid dosage form of valsartan, amlodipine and
HCTZ comprising the steps of (a) granulating valsartan,
pharmaceutically acceptable additives and optionally amlodipine to
form a valsartan granulation; (b) granulating hydrochlorothiazide,
pharmaceutically acceptable additives and optionally amlodipine to
form a hydrochlorothiazide granulation; and (c) compressing the
valsartan granulation and the hydrochlorothiazide granulation
together to form a bilayer solid dosage form, wherein amlodipine is
present in the valsartan granulation and/or the hydrochlorothiazide
blend. In a preferred embodiment of the invention, step (a)
comprises the steps of (a1) blending valsartan, pharmaceutically
acceptable additives and optionally amlodipine to form a blended
material; (a2) sieving the blended material to form a sieved
material; (a3) blending the sieved material to form a
blended/sieved material; (a4) compacting the blended/sieved
material to form a compacted material; (a5) milling the compacted
material to form a milled material; and (a6) blending the milled
material to form the valsartan granulation. In another preferred
embodiment, step (b) comprises a granulation process with the steps
of (b1) blending hydrochlorothiazide, pharmaceutically acceptable
additives and optionally amlodipine to form a blended material;
(b2) sieving the blended material to form a sieved material; (b3)
blending the sieved material to form a blended/sieved material;
(b4) compacting the blended/sieved material to form a compacted
material; (b5) milling the compacted material to form a milled
material; and (b6) blending the milled material to form a
hydrochlorothiazide granulation. Another preferred embodiment of
this invention also includes an optional step, step (d) film
coating the bilayer solid dosage form. Amlodipine can be
incorporated at step a1 and/or a6, and at step b1 and/or b6.
[0020] Yet another embodiment of the invention is directed to a
method of treating hypertension, congestive heart failure, angina,
myocardial infarction, arteriosclerosis, diabetic nephropathy,
diabetic cardiac myopathy, renal insufficiency, peripheral vascular
disease, stroke, left ventricular hypertrophy, cognitive
dysfunction, headache, or chronic heart failure comprising
administering a solid dosage form of valsartan, amlodipine and
hydrochlorothiazide to a subject in need of such treatment. In a
preferred embodiment, the solid dosage form is orally administered
to the subject.
DETAILED DESCRIPTION
[0021] The present invention relates to solid dosage forms which
contain a combination of valsartan, amlodipine and
hydrochlorothiazide.
[0022] The first embodiment of the invention is directed to a solid
dosage form comprising a combination of valsartan, amlodipine and
hydrochlorothiazide, and pharmaceutically acceptable additives
suitable for the preparation of solid dosage forms. The solid
dosage forms of the present invention can take the form of
monolayer tablets (having the valsartan, the amlodipine and the
hydrochlorothiazide in one layer) or bilayer tablets (e.g., having
the valsartan in one layer and the amlodipine and the
hydrochlorothiazide in another layer or having the valsartan and
the hydrochlorothiazide in one layer and the amlodipine in another
layer or having the valsartan and the amlodipine in one layer and
the hydrochlorothiazide in another layer) or trilayer tablets
(e.g., having the valsartan, amlodipine and hydrochlorothiazide all
in separate layers.) or a trilayer tablet of two active layers
(amlodipine+HCTZ, amlodipine+valsartan) separated by a non-active
layer and a third layer of valsartan or HCTZ or amlodipine.
[0023] Valsartan
((S)--N-valeryl-N-{[2'-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine)
suitable for use in the present invention can be purchased from
commercial sources or can be prepared according to known methods.
For example, the preparation of valsartan is described in U.S. Pat.
No. 5,399,578, the entire disclosure of which is incorporated by
reference herein. Valsartan may be used for purposes of this
invention in its free form as well as in any suitable salt
form.
[0024] Valsartan is employed in an amount typically ranging from
about 40 mg to about 640 mg, preferably from about 80 mg to about
320 mg, and more preferably is about 160 mg or about 320 mg in a
monolayer tablet or a bilayer tablet or a trilayer tablet. The
amount of valsartan noted above refers to the amount of free
valsartan or salt thereof present in a given solid dosage form.
[0025] Amlodipine
(3-ethyl-5-methyl-2(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-
-methyl-3,5-pyridinedicarboxylate benzenesulphonate) suitable for
use in the present invention can be purchased from commercial
sources or can be prepared according to known methods. Amlodipine
may be used for purposes of this invention in its free form as well
as in any suitable salt form; in a preferred embodiment of this
invention, amlodipine free base is supplied to the solid dosage
forms through the use of amlodipine besylate.
[0026] Amlodipine is employed in an amount ranging from 2.5 mg to
about 20 mg, preferably from about 5 mg to about 10 mg, and more
preferably is about 5 mg or about 10 mg in a monolayer tablet or a
bilayer tablet or a trilayer tablet. The amount of amlodipine noted
above refers to the amount of free amlodipine present in a given
solid dosage form.
[0027] Hydrochlorothiazide suitable for use in the present
invention can be purchased from commercial sources or can be
prepared according to known methods. Hydrochlorothiazide may be
used for purposes of this invention in its free form as well as in
any suitable salt form.
[0028] Hydrochlorothiazide is employed in an amount ranging from
6.25 mg to about 50 mg, preferably from about 12.5 mg to about 25
mg, and more preferably is about 12.5 mg or about 25 mg in a
monolayer tablet or a bilayer tablet or a trilayer tablet. The
amount of hydrochlorothiazide noted above refers to the amount of
free hydrochlorothiazide present in a given solid dosage form.
[0029] Pharmaceutically acceptable additives suitable for use in
the present invention include, without limitation, diluents or
fillers, disintegrants, glidants, lubricants, binders, colorants
and combinations thereof. The amount of each additive in a solid
dosage formulation may vary within ranges conventional in the
art.
[0030] Suitable diluents include, without limitation,
microcrystalline cellulose (e.g., cellulose MK GR), mannitol,
sucrose or other sugars or sugar derivatives, low-substituted
hydroxypropyl cellulose, di-calcium phosphate, lactose, and
combinations thereof. When present, a diluent may be employed in an
amount ranging from about 10% to about 80%, preferably from about
32% to about 51% by weight of the solid dosage form (prior to any
optional film coating). For monolayer tablets, a diluent is
preferably employed in an amount ranging from about 10% to about
80%, more preferably in an amount ranging from about 32% to about
39% by weight of the solid dosage form. For bilayer tablets, a
diluent is preferably employed in an amount ranging from about 10%
to about 80%, more preferably in an amount ranging from about 47%
to about 51% by weight of the solid dosage form.
[0031] Suitable disintegrants include, without limitation,
crospovidone, sodium starch glycolate, L-hydroxy propyl cellulose,
croscarmellose sodium, and combinations thereof. When present, a
disintegrant may be employed in an amount ranging from about 0.5%
to about 50%, preferably from about 5% to about 14% by weight of
the solid dosage form (prior to any optional film coating). For
monolayer tablets, a disintegrant is preferably employed in an
amount ranging from about 0.5% to about 50%, more preferably in an
amount ranging from about 5% to about 14% by weight of the solid
dosage form. For bilayer tablets, a disintegrant is preferably
employed in an amount ranging from about 0.5% to about 50%, more
preferably in an amount ranging from about 7% to about 10% by
weight of the solid dosage form.
[0032] Suitable glidants include, without limitation, colloidal
silicon dioxide (e.g., Aerosil 200), magnesium trisilicate,
powdered cellulose, starch, talc and combinations thereof. When
present, a glidant may be employed in an amount ranging from about
0.1% to about 10%, preferably from about 0.6% to about 0.8% by
weight of the solid dosage form (prior to any optional film
coating). For monolayer tablets, a glidant is preferably employed
in an amount ranging from about 0.1% to about 10%, more preferably
in an amount of about 0.75% by weight of the solid dosage form. For
bilayer tablets, a glidant is employed in an amount ranging from
about 0.1% to about 10%, more preferably in an amount of about
0.65% by weight of the solid dosage form.
[0033] Suitable lubricants include, without limitation, magnesium
stearate, calcium stearate, aluminum or calcium silicate, stearic
acid, cutina, PEG 4000-8000, talc and combinations thereof. When
present, a lubricant may be employed in an amount ranging from
about 0.1% to about 10%, preferably from about 2% to about 3% by
weight of the solid dosage form (prior to any optional film
coating). For monolayer tablets, a lubricant is preferably employed
in an amount ranging from about 0.1% to about 10%, more preferably
in an amount of about 2% by weight of the solid dosage form. For
bilayer tablets, a lubricant is preferably employed in an amount
ranging from about 0.1% to about 10%, more preferably in an amount
of about 2% by weight of the solid dosage form.
[0034] Suitable binders include, without limitation,
polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl
cellulose, pregelatinized starch, microcrystalline cellulose (e.g.,
cellulose MK GR), and combinations thereof. When present, a binder
may be employed in an amount ranging from about 0.5% to about 40%,
preferably in an amount of about 10% by weight of the solid dosage
form (prior to any optional film coating). For monolayer tablets, a
binder is preferably employed in an amount ranging from about 0.5%
to about 40%, more preferably in an amount of about 10% by weight
of the solid dosage form. For bilayer tablets, a binder is
preferably employed in an amount ranging from about 0.5% to about
40%, more preferably in an amount of about 10% by weight of the
solid dosage form.
[0035] Suitable colorants include, without limitation, iron oxides
such as yellow, red, and black iron oxide, and titanium dioxide and
combinations thereof. When present, a colorant may be employed in
an amount ranging from about 0.01% to about 0.1% by weight of the
solid dosage form (prior to any optional film coating). In a
preferred embodiment, monolayer tablets contain no colorant. Film
coating for monolayer tablets are given in the example Tables
[0036] The solid dosage forms of the first embodiment of the
invention are monolayer or bilayer tablet dosage forms of suitable
hardness, e.g., an average hardness ranging from about 60 N to
about 350 N for monolayer forms and an average hardness ranging
from about 100 N to about 350 N for bilayer forms. Such an average
hardness is determined prior to the application of any film coating
on the solid dosage forms. In that regard, a preferred embodiment
of this invention is directed to solid dosage forms which are
film-coated. Suitable film coatings are known and commercially
available or can be made according to known methods. Typically the
film coating material is a polymeric film coating material
comprising materials such as hydroxypropylmethyl cellulose,
polyethylene glycol, talc and colorant. Generally, a film coating
material is applied in such an amount as to provide a film coating
that ranges from about 1% to about 7% by weight of the film-coated
tablet.
[0037] The second embodiment of the present invention is directed
to a method of making a solid dosage form of valsartan, amlodipine
and HCTZ comprising the steps of (a) blending valsartan,
amlodipine, hydrochlorothiazide and pharmaceutically acceptable
additives to form a blended material; (b) sieving the blended
material to form a sieved material; (c) blending the sieved
material to form a blended/sieved material; (d) compacting the
blended/sieved material to form a compacted material; (e) milling
the compacted material to form a milled material; (f) blending the
milled material to form blended/milled material; and (g)
compressing the blended/milled material to form a monolayer solid
dosage form. The details regarding the valsartan, amlodipine,
hydrochlorothiazide and pharmaceutically acceptable additives,
i.e., source, amount, etc., are as set forth above with regard to
the first embodiment of the invention. This embodiment can be in
the form of all possible permutations, e.g., valsartan may be
blended alone and amlodipine and hydrochlorothiazide may be added
in the final blending step.
[0038] In the first step of the method of the second embodiment,
valsartan, amlodipine, hydrochlorothiazide and pharmaceutically
acceptable additives are blended to form a blended material.
Blending can be accomplished using any suitable means such as a
diffusion blender or diffusion mixer. In the second step, the
blended material is sieved to form a sieved material. Sieving can
be accomplished using any suitable means. In the third step of the
method of the second embodiment, the sieved material is blended to
form a blended/sieved material. Again blending can be accomplished
using any suitable means.
[0039] In the fourth step, the blended/sieved material is compacted
to form a compacted material. Compacting can be accomplished using
any suitable means. Typically compacting is accomplished using a
roller compactor with a compaction force ranging from about 0.5 kN
to about 90 kN, preferably about 20 kN to about 60 kN. Compaction
may also be carried out by slugging the blended powders into large
tablets that are then size-reduced.
[0040] In the fifth step of the method of the second embodiment,
the compacted material is milled to form a milled material. Milling
can be accomplished using any suitable means. In the sixth step,
the milled material is blended to form blended/milled material.
Here again blending can be accomplished using any suitable means.
In the final step of the method of the second embodiment, the
blended/milled material is compressed to form a monolayer solid
dosage form. Compression can be accomplished using any suitable
means. Typically compression is accomplished using a rotary tablet
press. Compression force for such a rotary tablet press typically
ranges from about 5 kN to about 40 kN.
[0041] Optionally, the method of the second embodiment comprises
the step of (h) film coating the monolayer solid dosage form. The
details regarding the film coating material, i.e., components,
amounts, etc., are as described above with regard to the first
embodiment of the invention. Film coating can be accomplished using
any suitable means.
[0042] In a third embodiment, this invention is directed to solid
dosage forms of valsartan made according to the method of the
second embodiment.
[0043] In a fourth embodiment, the present invention is directed to
a method of making a solid dosage form of valsartan amlodipine and
HCTZ comprising the steps of a) blending valsartan and
pharmaceutically acceptable additives to form a blended material;
(b) sieving the blended material to form a sieved material; (c)
blending the sieved material to form a blended/sieved material; (d)
compacting the blended/sieved material to form a compacted
material; (e) milling the compacted material to form a milled
material; (f) blending the milled material with amlodipine and
hydrochlorothiazide to form blended/milled material; and (g)
compressing the blended/milled material to form a monolayer solid
dosage form. A preferred embodiment of this invention also includes
an optional step, step (h) film coating the monolayer solid dosage
form.
[0044] In a fifth embodiment, this invention is directed to solid
dosage forms of valsartan, amlodipine and HCTZ made according to
the method of the fourth embodiment.
[0045] In a sixth embodiment, the present invention is directed to
a method of making a solid dosage form of valsartan, amlodipine and
HCTZ comprising the steps of a) blending valsartan, amlodipine, and
pharmaceutically acceptable additives to form a blended material;
(b) sieving the blended material to form a sieved material; (c)
blending the sieved material to form a blended/sieved material; (d)
compacting the blended/sieved material to form a compacted
material; (e) milling the compacted material to form a milled
material; (f) blending the milled material with hydrochlorothiazide
to form blended/milled material; and (g) compressing the
blended/milled material to form a monolayer solid dosage form. A
preferred embodiment of this invention also includes an optional
step, step (h) film coating the monolayer solid dosage form.
[0046] In a seventh embodiment, this invention is directed to solid
dosage forms of valsartan, amlodipine and HCTZ made according to
the method of the sixth embodiment.
[0047] In an eighth embodiment, the present invention is directed
to a method of making a solid dosage form of valsartan, amlodipine
and HCTZ comprising the steps of a) blending valsartan,
hydrochlorothiazide, and pharmaceutically acceptable additives to
form a blended material; (b) sieving the blended material to form a
sieved material; (c) blending the sieved material to form a
blended/sieved material; (d) compacting the blended/sieved material
to form a compacted material; (e) milling the compacted material to
form a milled material; (f) blending the milled material with
amlodipine to form blended/milled material; and (g) compressing the
blended/milled material to form a monolayer solid dosage form. A
preferred embodiment of this invention also includes an optional
step, step (h) film coating the monolayer solid dosage form.
[0048] In a ninth embodiment, this invention is directed to solid
dosage forms of valsartan, amlodipine and HCTZ made according to
the method of the eighth embodiment.
[0049] The tenth embodiment of the present invention is directed to
a method of making a solid dosage form of valsartan, amlodipine and
HCTZ comprising the steps of (a) granulating valsartan,
pharmaceutically acceptable additives and optionally
hydrochlorothiazide to form a valsartan granulation; (b) blending
amlodipine, pharmaceutically acceptable additives and optionally
hydrochlorothiazide to form an amlodipine blend; and (c)
compressing the valsartan granulation and the amlodipine blend
together to form a bilayer solid dosage form, wherein
hydrochlorothiazide is present in the valsartan granulation and/or
the amlodipine blend. The details regarding the valsartan,
amlodipine, hydrochlorothiazide and pharmaceutically acceptable
additives, i.e., source, amount, etc., are as set forth above with
regard to the first embodiment of the invention.
[0050] In the first step of the method of the tenth embodiment,
valsartan is granulated with pharmaceutically acceptable additives
and optionally hydrochlorothiazide to form a valsartan granulation.
Valsartan granulation can be accomplished by any suitable means. In
a preferred embodiment of this invention, valsartan granulation is
accomplished by (a1) blending valsartan, pharmaceutically
acceptable additives and optionally hydrochlorothiazide to form a
blended material; (a2) sieving the blended material to form a
sieved material; (a3) blending the sieved material to form a
blended/sieved material; (a4) compacting the blended/sieved
material to form a compacted material; (a5) milling the compacted
material to form a milled material; and (a6) blending the milled
material to form the valsartan granulation. Hydrochlorothiazide can
be incorporated at step a1 and/or a6.
[0051] The blending of step (a1) can be accomplished using any
suitable means. Typically the valsartan, pharmaceutically
acceptable additives and optionally the hydrochlorothiazide are
dispatched to a suitable vessel such as a diffusion blender or
diffusion mixer. The sieving of step (a2) can be accomplished using
any suitable means. The blending of step (a3) can be accomplished
using any suitable means. The compacting of step (a4) can be
accomplished using any suitable means. Typically compacting is
accomplished using a roller compactor with a compaction force
ranging from about 0.5 kN to about 90 kN, preferably about 20-60
kN. Compaction may also be carried out by slugging the blended
powders into large tablets that are then size-reduced. The milling
of step (a5) can be accomplished using any suitable means.
Typically the compacted material is milled through a screening
mill. The blending of step (a6) can be accomplished using any
suitable means. Preferably the milled material is blended, often
with a pharmaceutically acceptable additive such as a lubricant, in
a diffusion blender.
[0052] In the second step of the method of the tenth embodiment,
amlodipine is blended with pharmaceutically acceptable additives
and optionally hydrochlorothiazide to form an amlodipine blend.
Amlodipine granulation can be accomplished by any suitable means.
In a preferred embodiment, blending step (b) comprises the process
of granulating amlodipine. Amlodipine granulation can be
accomplished by any suitable means including but not limited wet
granulation, dry granulation, melt granulation or dry blend. In a
more preferred embodiment of this invention, amlodipine granulation
is accomplished by (b1) blending amlodipine, pharmaceutically
acceptable additives and optionally hydrochlorothiazide to form a
blended material; (b2) sieving the blended material to form a
sieved material; (b3) blending the sieved material to form a
blended/sieved material; (b4) compacting the blended/sieved
material to form a compacted material; (b5) milling the compacted
material to form a milled material; and (b6) blending the milled
material to form an amlodipine granulation. Hydrochlorothiazide can
be incorporated at step b1 and/or b6. Hydrochlorothiazide can be
incorporated by any suitable means including but not limited wet
granulation, dry granulation, melt granulation or dry blend.
[0053] The blending of step (b1) can be accomplished using any
suitable means. The sieving of step (b2) can be accomplished using
any suitable means. The blending of step (b3) can be accomplished
using any suitable means. The compacting of step (b4) can be
accomplished using any suitable means. Typically compacting is
accomplished using a roller compactor with a compaction force
ranging from about 0.5 kN to about 90 kN, preferably about 20 kN to
about 60 kN. The milling of step (b5) can be accomplished using any
suitable means. Typically the compacted material is milled through
a screening mill. The blending of step (b6) can be accomplished
using any suitable means.
[0054] In the final step of the method of the tenth embodiment, the
valsartan granulation and the amlodipine blend are compressed
together to form a bilayer solid dosage form. Compression can be
accomplished using any suitable means. Typically compression is
accomplished using a bilayer rotary tablet press. Typical
compression force ranges from about 5 kN to about 40 kN.
[0055] In this embodiment, hydrochlorothiazide is present in one of
the valsartan granulation and the amlodipine blend. In other words,
the inclusion of hydrochlorothiazide in the bilayer solid dosage
form is not optional; only its placement in the same, i.e., in the
valsartan layer or in the amlodipine layer, is variable. However,
in other embodiments hydrochlorothiazide may be present alone in a
separate layer.
[0056] Optionally, the method of the tenth embodiment comprises the
step of (d) film coating the bilayer solid dosage form. The details
regarding the film coating material, i.e., components, amounts,
etc., are as described above with regard to the first embodiment of
the invention. Film coating can be accomplished using any suitable
means.
[0057] An eleventh embodiment of the present invention is directed
to a bilayer solid dosage form of valsartan, amlodipine and HCTZ
made according to the method of the tenth embodiment.
[0058] In another embodiment, this invention is directed to a
method of making a solid dosage form of valsartan, amlodipine and
HCTZ comprising the steps of (a) granulating valsartan,
pharmaceutically acceptable additives and optionally amlodipine to
form a valsartan granulation; (b) granulating hydrochlorothiazide,
pharmaceutically acceptable additives and optionally amlodipine to
form a hydrochlorothiazide granulation; and (c) compressing the
valsartan granulation and the hydrochlorothiazide granulation
together to form a bilayer solid dosage form, wherein amlodipine is
present in the valsartan granulation and/or the hydrochlorothiazide
blend. In a preferred embodiment of the invention, step (a)
comprises the steps of (a1) blending valsartan, pharmaceutically
acceptable additives and optionally amlodipine to form a blended
material; (a2) sieving the blended material to form a sieved
material; (a3) blending the sieved material to form a
blended/sieved material; (a4) compacting the blended/sieved
material to form a compacted material; (a5) milling the compacted
material to form a milled material; and (a6) blending the milled
material to form the valsartan granulation. In another preferred
embodiment, step (b) comprises a granulation process with the steps
of (b1) blending hydrochlorothiazide, pharmaceutically acceptable
additives and optionally amlodipine to form a blended material;
(b2) sieving the blended material to form a sieved material; (b3)
blending the sieved material to form a blended/sieved material;
(b4) compacting the blended/sieved material to form a compacted
material; (b5) milling the compacted material to form a milled
material; and (b6) blending the milled material to form a
hydrochlorothiazide granulation. Another preferred embodiment of
this invention also includes an optional step, step (d) film
coating the bilayer solid dosage form. Amlodipine can be
incorporated at step a1 and/or a6, and at step b1 and/or b6.
[0059] Yet another embodiment of the invention is directed to a
method of treating hypertension, congestive heart failure, angina,
myocardial infarction, arteriosclerosis, diabetic nephropathy,
diabetic cardiac myopathy, renal insufficiency, peripheral vascular
disease, stroke, left ventricular hypertrophy, cognitive
dysfunction, headache, or chronic heart failure. The method
comprises administering a solid dosage form of valsartan,
amlodipine and hydrochlorothiazide to a subject in need of such
treatment. In a preferred embodiment, the solid dosage form is
orally administered to the subject.
[0060] Specific embodiments of the invention will now be
demonstrated by reference to the following examples. It should be
understood that these examples are disclosed solely by way of
illustrating the invention and should not be taken in any way to
limit the scope of the present invention.
Example 1
160/12.5/5 mg Tablet
[0061] A monolayer solid dosage form of valsartan, amlodipine and
HCTZ was made using the ingredients set forth in Table 1 below.
TABLE-US-00001 TABLE 1 Ingredient (mg) % A valsartan 160.00 40.00 B
hydrochlorothiazide 12.50 3.13 C amlodipine besylate 6.94* 1.74 D
microcrystalline cellulose 154.56 38.64 E crospovidone 54.00 13.50
F colloidal silicon dioxide 3.00 0.75 G magnesium stearate (I) 6.00
1.50 H magnesium stearate (II) 3.00 0.75 total 400.00 *corresponds
to 5 mg amlodipine free base
[0062] Ingredients A-G are placed into a diffusion blender and
blended. Then, the blended material is sieved. Next, the sieved
material is blended again in a diffusion blender. The
blended/sieved material is then compacted using a roller compactor.
The compacted material is milled through a screen and then blended
with ingredient H in a diffusion blender. (This second blending
step achieves the desired level of lubricant for the granulation
and, in certain cases, combines sub-divided batches of ingredients
A-G.) Next, the blended/milled material is compressed into
monolayer solid dosage forms using a rotary tablet press, and the
monolayer solid dosage forms are optionally film coated.
[0063] Ingredients A, C, D, E, F, and G are placed into a diffusion
blender and blended. Then, the blended material is sieved. Next,
the sieved material is blended again in a diffusion blender. The
blended/sieved material is then compacted using a roller compactor.
The compacted material is milled through a screen and then blended
with ingredient B and H in a diffusion blender. (This second
blending step achieves the desired level of B and H for the
granulation and, in certain cases, combines sub-divided batches of
ingredients A, C, D, E, F, and G.) Next, the blended/milled
material is compressed into monolayer solid dosage forms using a
rotary tablet press, and the monolayer solid dosage forms are
optionally film coated.
[0064] Ingredients A, B, D, E, F, and G are placed into a diffusion
blender and blended. Then, the blended material is sieved. Next,
the sieved material is blended again in a diffusion blender. The
blended/sieved material is then compacted using a roller compactor.
The compacted material is milled through a screen and then blended
with ingredient C and H in a diffusion blender. (This second
blending step achieves the desired level of B and H for the
granulation and, in certain cases, combines sub-divided batches of
ingredients A, B, D, E, F, and G.). Next, the blended/milled
material is compressed into monolayer solid dosage forms using a
rotary tablet press, and the monolayer solid dosage forms are
optionally film coated.
[0065] Ingredients A, D, E, F, and G are placed into a diffusion
blender and blended. Then, the blended material is sieved. Next,
the sieved material is blended again in a diffusion blender. The
blended/sieved material is then compacted using a roller compactor.
The compacted material is milled through a screen and then blended
with ingredient B, C and H in a diffusion blender. (This second
blending step achieves the desired level of B, C, and H for the
granulation and, in certain cases, combines sub-divided batches of
ingredients A, D, E, F, and G.) Next, the blended/milled material
is compressed into monolayer solid dosage forms using a rotary
tablet press, and the monolayer solid dosage forms are optionally
film coated.
Example 2
160/12.5/10 mg Tablet
[0066] A monolayer solid dosage form of valsartan, amlodipine and
HCTZ was made using the ingredients set forth in Table 2 below.
TABLE-US-00002 TABLE 2 Ingredient (mg) % A valsartan 160.00 40.00 B
hydrochlorothiazide 12.50 3.13 C amlodipine besylate 13.87* 3.47 D
microcrystalline cellulose 147.63 36.91 E crospovidone 54.00 13.50
F colloidal silicon dioxide 3.00 0.75 G magnesium stearate (I) 6.00
1.50 H magnesium stearate (II) 3.00 0.75 total 400.00 *corresponds
to 10 mg amlodipine free base
[0067] Ingredients A-G are placed into a diffusion blender and
blended. Then, the blended material is sieved. Next, the sieved
material is blended again in a diffusion blender. The
blended/sieved material is then compacted using a roller compactor.
The compacted material is milled through a screen and then blended
with ingredient H in a diffusion blender. (This second blending
step achieves the desired level of lubricant for the granulation
and, in certain cases, combines sub-divided batches of ingredients
A-G.) Next, the blended/milled material is compressed into
monolayer solid dosage forms using a rotary tablet press, and the
monolayer solid dosage forms are optionally film coated.
[0068] Ingredients A, C, D, E, F, and G are placed into a diffusion
blender and blended. Then, the blended material is sieved. Next,
the sieved material is blended again in a diffusion blender. The
blended/sieved material is then compacted using a roller compactor.
The compacted material is milled through a screen and then blended
with ingredient B and H in a diffusion blender. (This second
blending step achieves the desired level of B and H for the
granulation and, in certain cases, combines sub-divided batches of
ingredients A, C, D, E, F, and G.) Next, the blended/milled
material is compressed into monolayer solid dosage forms using a
rotary tablet press, and the monolayer solid dosage forms are
optionally film coated.
[0069] Ingredients A, B, D, E, F, and G are placed into a diffusion
blender and blended. Then, the blended material is sieved. Next,
the sieved material is blended again in a diffusion blender. The
blended/sieved material is then compacted using a roller compactor.
The compacted material is milled through a screen and then blended
with ingredient C and H in a diffusion blender. (This second
blending step achieves the desired level of B and H for the
granulation and, in certain cases, combines sub-divided batches of
ingredients A, B, D, E, F, and G.) Next, the blended/milled
material is compressed into monolayer solid dosage forms using a
rotary tablet press, and the monolayer solid dosage forms are
optionally film coated.
[0070] Ingredients A, D, E, F, and G are placed into a diffusion
blender and blended. Then, the blended material is sieved. Next,
the sieved material is blended again in a diffusion blender. The
blended/sieved material is then compacted using a roller compactor.
The compacted material is milled through a screen and then blended
with ingredient B, C and H in a diffusion blender. (This second
blending step achieves the desired level of B, C, and H for the
granulation and, in certain cases, combines sub-divided batches of
ingredients A, D, E, F, and G.) Next, the blended/milled material
is compressed into monolayer solid dosage forms using a rotary
tablet press, and the monolayer solid dosage forms are optionally
film coated.
Example 3
160/25/10 mg Tablet
[0071] A monolayer solid dosage form of valsartan, amlodipine and
HCTZ was made using the ingredients set forth in Table 3 below.
TABLE-US-00003 TABLE 3 Ingredient (mg) % A valsartan 160.00 40.00 B
hydrochlorothiazide 25.00 6.25 C amlodipine besylate 13.87* 3.47 D
microcrystalline cellulose 135.13 33.78 E crospovidone 54.00 13.50
F colloidal silicon dioxide 3.00 0.75 G magnesium stearate (I) 6.00
1.50 H magnesium stearate (II) 3.00 0.75 total 400.00 *corresponds
to 10 mg amlodipine free base
[0072] Ingredients A-G are placed into a diffusion blender and
blended. Then, the blended material is sieved. Next, the sieved
material is blended again in a diffusion blender. The
blended/sieved material is then compacted using a roller compactor.
The compacted material is milled through a screen and then blended
with ingredient H in a diffusion blender. (This second blending
step achieves the desired level of lubricant for the granulation
and, in certain cases, combines sub-divided batches of ingredients
A-G.) Next, the blended/milled material is compressed into
monolayer solid dosage forms using a rotary tablet press, and the
monolayer solid dosage forms are optionally film coated.
[0073] Ingredients A, C, D, E, F, and G are placed into a diffusion
blender and blended. Then, the blended material is sieved. Next,
the sieved material is blended again in a diffusion blender. The
blended/sieved material is then compacted using a roller compactor.
The compacted material is milled through a screen and then blended
with ingredient B and H in a diffusion blender. (This second
blending step achieves the desired level of B and H for the
granulation and, in certain cases, combines sub-divided batches of
ingredients A, C, D, E, F, and G.) Next, the blended/milled
material is compressed into monolayer solid dosage forms using a
rotary tablet press, and the monolayer solid dosage forms are
optionally film coated.
[0074] Ingredients A, B, D, E, F, and G are placed into a diffusion
blender and blended. Then, the blended material is sieved. Next,
the sieved material is blended again in a diffusion blender. The
blended/sieved material is then compacted using a roller compactor.
The compacted material is milled through a screen and then blended
with ingredient C and H in a diffusion blender. (This second
blending step achieves the desired level of B and H for the
granulation and, in certain cases, combines sub-divided batches of
ingredients A, B, D, E, F, and G.) Next, the blended/milled
material is compressed into monolayer solid dosage forms using a
rotary tablet press, and the monolayer solid dosage forms are
optionally film coated.
[0075] Ingredients A, D, E, F, and G are placed into a diffusion
blender and blended. Then, the blended material is sieved. Next,
the sieved material is blended again in a diffusion blender. The
blended/sieved material is then compacted using a roller compactor.
The compacted material is milled through a screen and then blended
with ingredient B, C and H in a diffusion blender. (This second
blending step achieves the desired level of B, C, and H for the
granulation and, in certain cases, combines sub-divided batches of
ingredients A, D, E, F, and G.) Next, the blended/milled material
is compressed into monolayer solid dosage forms using a rotary
tablet press, and the monolayer solid dosage forms are optionally
film coated.
Example 4
160/25/5 mg Tablet
[0076] A monolayer solid dosage form of valsartan, amlodipine and
HCTZ was made using the ingredients set forth in Table 4 below.
TABLE-US-00004 TABLE 4 Ingredient (mg) % A valsartan 160.00 40.00 B
hydrochlorothiazide 25.00 6.25 C amlodipine besylate 6.94* 1.74 D
microcrystalline cellulose 142.06 35.51 E crospovidone 54.00 13.50
F colloidal silicon dioxide 3.00 0.75 G magnesium stearate (I) 6.00
1.50 H magnesium stearate (II) 3.00 0.75 total 400.00 *corresponds
to 5 mg amlodipine free base
[0077] Ingredients A-G are placed into a diffusion blender and
blended. Then, the blended material is sieved. Next, the sieved
material is blended again in a diffusion blender. The
blended/sieved material is then compacted using a roller compactor.
The compacted material is milled through a screen and then blended
with ingredient H in a diffusion blender. (This second blending
step achieves the desired level of lubricant for the granulation
and, in certain cases, combines sub-divided batches of ingredients
A-G.) Next, the blended/milled material is compressed into
monolayer solid dosage forms using a rotary tablet press, and the
monolayer solid dosage forms are optionally film coated.
[0078] Ingredients A, C, D, E, F, and G are placed into a diffusion
blender and blended. Then, the blended material is sieved. Next,
the sieved material is blended again in a diffusion blender. The
blended/sieved material is then compacted using a roller compactor.
The compacted material is milled through a screen and then blended
with ingredient B and H in a diffusion blender. (This second
blending step achieves the desired level of B and H for the
granulation and, in certain cases, combines sub-divided batches of
ingredients A, C, D, E, F, and G.) Next, the blended/milled
material is compressed into monolayer solid dosage forms using a
rotary tablet press, and the monolayer solid dosage forms are
optionally film coated.
[0079] Ingredients A, B, D, E, F, and G are placed into a diffusion
blender and blended. Then, the blended material is sieved. Next,
the sieved material is blended again in a diffusion blender. The
blended/sieved material is then compacted using a roller compactor.
The compacted material is milled through a screen and then blended
with ingredient C and H in a diffusion blender. (This second
blending step achieves the desired level of B and H for the
granulation and, in certain cases, combines sub-divided batches of
ingredients A, B, D, E, F, and G.) Next, the blended/milled
material is compressed into monolayer solid dosage forms using a
rotary tablet press, and the monolayer solid dosage forms are
optionally film coated.
[0080] Ingredients A, D, E, F, and G are placed into a diffusion
blender and blended. Then, the blended material is sieved. Next,
the sieved material is blended again in a diffusion blender. The
blended/sieved material is then compacted using a roller compactor.
The compacted material is milled through a screen and then blended
with ingredient B, C and H in a diffusion blender. (This second
blending step achieves the desired level of B, C, and H for the
granulation and, in certain cases, combines sub-divided batches of
ingredients A, D, E, F, and G.) Next, the blended/milled material
is compressed into monolayer solid dosage forms using a rotary
tablet press, and the monolayer solid dosage forms are optionally
film coated.
Example 5
320/25/10 mg Tablet
[0081] A monolayer solid dosage form of valsartan, amlodipine and
HCTZ was made using the ingredients set forth in Table 5 below.
TABLE-US-00005 TABLE 5 Ingredient (mg) % A valsartan 320.00 40.00 B
hydrochlorothiazide 25.00 3.13 C amlodipine besylate 13.87* 1.73 D
microcrystalline cellulose 309.12 38.64 E crospovidone 108.00 13.50
F colloidal silicon dioxide 6.00 0.75 G magnesium stearate (I)
12.00 1.50 H magnesium stearate (II) 6.00 0.75 total 800.00
*corresponds to 10 mg amlodipine free base
[0082] Ingredients A-G are placed into a diffusion blender and
blended. Then, the blended material is sieved. Next, the sieved
material is blended again in a diffusion blender. The
blended/sieved material is then compacted using a roller compactor.
The compacted material is milled through a screen and then blended
with ingredient H in a diffusion blender. (This second blending
step achieves the desired level of lubricant for the granulation
and, in certain cases, combines sub-divided batches of ingredients
A-G.) Next, the blended/milled material is compressed into
monolayer solid dosage forms using a rotary tablet press, and the
monolayer solid dosage forms are optionally film coated.
[0083] Ingredients A, C, D, E, F, and G are placed into a diffusion
blender and blended. Then, the blended material is sieved. Next,
the sieved material is blended again in a diffusion blender. The
blended/sieved material is then compacted using a roller compactor.
The compacted material is milled through a screen and then blended
with ingredient B and H in a diffusion blender. (This second
blending step achieves the desired level of B and H for the
granulation and, in certain cases, combines sub-divided batches of
ingredients A, C, D, E, F, and G.). Next, the blended/milled
material is compressed into monolayer solid dosage forms using a
rotary tablet press, and the monolayer solid dosage forms are
optionally film coated.
[0084] Ingredients A, B, D, E, F, and G are placed into a diffusion
blender and blended. Then, the blended material is sieved. Next,
the sieved material is blended again in a diffusion blender. The
blended/sieved material is then compacted using a roller compactor.
The compacted material is milled through a screen and then blended
with ingredient C and H in a diffusion blender. (This second
blending step achieves the desired level of B and H for the
granulation and, in certain cases, combines sub-divided batches of
ingredients A, B, D, E, F, and G.) Next, the blended/milled
material is compressed into monolayer solid dosage forms using a
rotary tablet press, and the monolayer solid dosage forms are
optionally film coated.
[0085] Ingredients A, D, E, F, and G are placed into a diffusion
blender and blended. Then, the blended material is sieved. Next,
the sieved material is blended again in a diffusion blender. The
blended/sieved material is then compacted using a roller compactor.
The compacted material is milled through a screen and then blended
with ingredient B, C and H in a diffusion blender. (This second
blending step achieves the desired level of B, C, and H for the
granulation and, in certain cases, combines sub-divided batches of
ingredients A, D, E, F, and G.) Next, the blended/milled material
is compressed into monolayer solid dosage forms using a rotary
tablet press, and the monolayer solid dosage forms are optionally
film coated.
Example 6
160/12.5/5; 160/12.5/10; 160/25/5; 160/25/10 and 320/25/10 mg
Tablet
[0086] A bilayer solid dosage form of valsartan, amlodipine and
HCTZ was made using the ingredients set forth in Table 6 below.
TABLE-US-00006 TABLE 6 Ingredient (mg) %
valsartan/hydrochlorothiazide layer A valsartan 320.00 35.56 B
hydrochlorothiazide 25.00 2.78 C microcrystalline cellulose 151.00
16.78 D crospovidone 80.00 8.89 E colloidal silicon dioxide 6.00
0.67 F magnesium stearate (I) 12.00 1.33 G magnesium stearate (II)
6.00 0.67 subtotal 600.00 amlodipine layer H amlodipine besylate
13.87* 1.54 I microcrystalline cellulose 279.03 31.00 J sodium
starch glycolate 6.00 0.67 K colorant 0.20 0.02 L magnesium
stearate (III) 0.30 0.03 M magnesium stearate (IV) 0.60 0.07
subtotal 300.00 total 900.00 -corresponds to 10 mg amlodipine free
base
TABLE-US-00007 TABLE 7 160/25/10 mg 160/25/5 mg 160/12.5/5 mg
160/12.5/10 mg Ingredient mg/unit % mg/unit % mg/unit % mg/unit %
Valsartan and HCTZ layer A Valsartan DS 160.00 26.67 160.00 35.56
160.00 35.56 160.00 26.67 B HCTZ 25.00 4.17 25.00 5.56 12.50 2.78
12.50 2.08 C Avicel 102 63.00 10.50 63.00 14.00 85.50 19.00 85.50
14.25 D Crospovidone 40.00 6.67 40.00 8.89 30.00 6.67 30.00 5.00 E
Cab-O-Sil 3.00 0.50 3.00 0.67 3.00 0.67 3.00 0.50 F Mag. St. (I)
6.00 1.00 6.00 1.33 6.00 1.33 6.00 1.00 G Mag. St. (II) 3.00 0.50
3.00 0.67 3.00 0.67 3.00 0.50 Sub-total 300.00 300.00 300.00 300.00
Amlodipine layer H Amlodipine 13.87.sup.a 2.31 6.94.sup.b 1.54
6.94.sup.b 1.54 13.87.sup.a 2.31 Besylate I Avicel 279.03 46.51
139.51 31.00 139.51 31.00 279.03 46.51 PH102 J Sodium 6.00 1.00
3.00 0.67 3.00 0.67 6.00 1.00 Starch Glycolate K Iron oxide 0.20
0.03 0.10 0.02 0.10 0.02 0.20 0.03 yellow L Mag. St. (III) 0.30
0.05 0.15 0.03 0.15 0.03 0.30 0.05 M Mag. St. (IV) 0.60 0.10 0.30
0.07 0.30 0.07 0.60 0.10 Sub-total 300.00 150.00 150.00 300.00
Total 600.00 100.00 450.00 100.00 450.00 100.00 600.00 100.00
.sup.acorresponds to 10 mg amlodipine free base; .sup.bcorresponds
to 5 mg amlodipine free base
[0087] First, the valsartan is granulated by combining ingredients
A-F in a diffusion blender. Then, the blended material is sieved
through a screen. Next, the sieved material is blended again in a
diffusion blender. The blended/sieved material is then compacted
using a roller compactor. The compacted material is milled through
a screen and then blended with ingredient G in a diffusion blender.
(This second blending step achieves the desired level of lubricant
for the granulation and, in certain cases, combines sub-divided
batches of ingredients A-F.)
[0088] Second, the amlodipine besylate is granulated by combining
ingredients H-L in a diffusion blender. Then, the blended material
is sieved through a screen. Next, the sieved material is blended
again in a diffusion blender. The blended/sieved material is then
compacted using a roller compactor. The compacted material is
milled through a screen and then blended with ingredient M in a
diffusion blender. (This second blending step achieves the desired
level of lubricant for the granulation and, in certain cases,
combines sub-divided batches of ingredients H-L.)
[0089] Finally, the valsartan granulation and the amlodipine
granulation are compressed into bilayer solid dosage forms using a
bilayer rotary tablet press, and the bilayer solid dosage forms are
optionally film coated.
Example 7
160/12.5/5; 160/12.5/10; 160/25/5; 160/25/10 and 160/12.5/5 mg
Tablet
[0090] A bilayer solid dosage form of valsartan, amlodipine and
HCTZ was made using the ingredients set forth in Table 8 and 9
below.
TABLE-US-00008 TABLE 8 Ingredient (mg) % valsartan layer A
valsartan 160.00 34.78 B microcrystalline cellulose 108.00 23.48 C
crospovidone 30.00 6.52 D colloidal silicon dioxide 3.00 0.65 E
magnesium stearate (I) 6.00 1.30 F magnesium stearate (II) 3.00
0.65 subtotal 310.00 amlodipine/hydrochlorothiazide layer G
amlodipine besylate 6.94* 1.51 H hydrochlorothiazide 12.50 2.72 I
microcrystalline cellulose 127.02 27.61 J sodium starch glycolate
3.00 0.65 K colorant 0.10 0.02 L magnesium stearate (III) 0.15 0.03
M magnesium stearate (IV) 0.30 0.07 subtotal 150.00 total 460.00
*corresponds to 5 mg amlodipine free base
TABLE-US-00009 TABLE 9 160/25/10 mg 160/25/5 mg 160/12.5/10 mg
320/25/10 mg Ingredient mg/unit % mg/unit % mg/unit % mg/unit %
Valsartan layer A Valsartan DS 160.00 26.23 160.00 26.23 160.00
26.23 320.00 34.78 B Avicel 102 108.00 17.70 108.00 17.70 108.00
17.70 216.00 23.48 C Crospovidone 30.00 4.92 30.00 4.92 30.00 4.92
60.00 6.52 D Cab-O-Sil 3.00 0.49 3.00 0.49 3.00 0.49 6.00 0.65 E
Mag. St. (I) 6.00 0.98 6.00 0.98 6.00 0.98 12.00 1.30 F Mag. St.
(II) 3.00 0.49 3.00 0.49 3.00 0.49 6.00 0.65 Sub-total 310.00
310.00 310.00 620.00 Amlodipine and HCTZ layer G Amlodipine 13.87
2.27 6.94 1.14 13.87 2.27 13.87 1.51 Besylate H HCTZ 25.00 4.10
25.00 4.10 12.50 2.05 25.00 2.72 I Avicel 254.03 41.64 260.96 42.78
266.53 43.69 254.03 27.61 PH102 J Sodium 6.00 0.98 6.00 0.98 6.00
0.98 6.00 0.65 Starch Glycolate K Iron oxide 0.20 0.03 0.20 0.03
0.20 0.03 0.20 0.02 yellow L Mag. St. (III) 0.30 0.05 0.30 0.05
0.30 0.05 0.30 0.03 M Mag. St. (IV) 0.60 0.10 0.60 0.10 0.60 0.10
0.60 0.07 Sub-total 300.00 300.00 300.00 300.00 Total 610.00 100.00
610.00 100.00 610.00 100.00 920.00 100.00
[0091] First, the valsartan is granulated by combining ingredients
A-E in a diffusion blender. Then, the blended material is sieved
through a screen. Next, the sieved material is blended again in a
diffusion blender. The blended/sieved material is then compacted
using a roller compactor. The compacted material is milled through
a screen and then blended with ingredient F in a diffusion blender.
(This second blending step achieves the desired level of lubricant
for the granulation and, in certain cases, combines sub-divided
batches of ingredients A-E.)
[0092] Second, the amlodipine besylate is granulated by combining
ingredients G-L in a diffusion blender. Then, the blended material
is sieved through a screen. Next, the sieved material is blended
again in a diffusion blender. The blended/sieved material is then
compacted using a roller compactor. The compacted material is
milled through a screen and then blended with ingredient M in a
diffusion blender. (This second blending step achieves the desired
level of lubricant for the granulation and, in certain cases,
combines sub-divided batches of ingredients G-L.)
[0093] Finally, the valsartan granulation and the amlodipine
granulation are compressed into bilayer solid dosage forms using a
bilayer rotary tablet press, and the bilayer solid dosage forms are
optionally film coated.
Example 8
160/12.5/5; 160/12.5/10; 160/25/5; 160/25/10 and 320/25/10 mg
Tablet
[0094] A bilayer solid dosage form of valsartan, amlodipine and
HCTZ was made using the ingredients set forth in Table 10 and 11
below.
TABLE-US-00010 TABLE 10 160/25/10 mg 160/25/5 mg Ingredient mg/unit
% mg/unit % Valsartan and amlodipine layer A Valsartan DS 160.00
25.24 160.00 25.48 B Amlodipine 13.87 2.19 6.94 1.10 besylate C
Avicel PH102 108.13 17.06 109.07 17.37 D Crospovidone XL 40.00 6.31
40.00 6.37 E Cab-o-sil 3.00 0.47 3.00 0.48 F Mg. Stearate (I) 6.00
0.95 6.00 0.96 G Mg. Stearate (I) 3.00 0.47 3.00 0.48 Sub-total
334.00 328.00 HCTZ layer H HCTZ 25.00 3.94 25.00 3.98 I Avicel
PH102 267.90 42.26 267.90 42.66 J Sodium Starch 6.00 0.95 6.00 0.96
Glycolate K Iron oxide yellow 0.20 0.03 0.20 0.03 L Mag. St. (III)
0.30 0.05 0.30 0.05 M Mag. St. (IV) 0.60 0.09 0.60 0.10 Sub-total
300.00 300.00 Total 634.00 100.00 628.00 100.00
TABLE-US-00011 TABLE 11 160/12.5/5 mg 160/12.5/10 mg 20/25/10 mg
Ingredient mg/unit % mg/unit % mg/unit % Valsartan and amlodipine
layer A Valsartan DS 160.00 33.06 160.00 25.48 320.00 33.47 B
Amlodipine besylate 13.87 2.87 6.94 1.10 13.87 1.45 C Avicel PH102
108.13 22.34 109.07 17.37 218.13 22.82 D Crospovidone XL 40.00 8.26
40.00 6.37 80.00 8.37 E Cab-o-sil 3.00 0.62 3.00 0.48 6.00 0.63 F
Mg. Stearate (I) 6.00 1.24 6.00 0.96 12.00 1.26 G Mg. Stearate (I)
3.00 0.62 3.00 0.48 6.00 0.63 Sub-total 334.00 328.00 656.00 HCTZ
layer H HCTZ 12.50 2.58 12.50 1.99 25.00 2.62 I Avicel PH102 133.95
27.68 280.40 44.65 267.90 28.02 J Sodium Starch Glycolate 3.00 0.62
6.00 0.96 6.00 0.63 K Iron oxide yellow 0.10 0.02 0.20 0.03 0.20
0.02 L Mag. St. (III) 0.15 0.03 0.30 0.05 0.30 0.03 M Mag. St. (IV)
0.30 0.06 0.60 0.10 0.60 0.06 Sub-total 150.00 300.00 300.00 Total
484.00 100.00 628.00 100.00 956.00 100.00
[0095] First, the valsartan is granulated by combining ingredients
A-F in a diffusion blender. Then, the blended material is sieved
through a screen. Next, the sieved material is blended again in a
diffusion blender. The blended/sieved material is then compacted
using a roller compactor. The compacted material is milled through
a screen and then blended with ingredient G in a diffusion blender.
(This second blending step achieves the desired level of lubricant
for the granulation and, in certain cases, combines sub-divided
batches of ingredients A-F.)
[0096] Second, the HCTZ is granulated by combining ingredients H-L
in a diffusion blender. Then, the blended material is sieved
through a screen. Next, the sieved material is blended again in a
diffusion blender. The blended/sieved material is then compacted
using a roller compactor. The compacted material is milled through
a screen and then blended with ingredient M in a diffusion blender.
(This second blending step achieves the desired level of lubricant
for the granulation and, in certain cases, combines sub-divided
batches of ingredients H-L.)
[0097] Finally, the valsartan granulation and the amlodipine
granulation are compressed into bilayer solid dosage forms using a
bilayer rotary tablet press, and the bilayer solid dosage forms are
optionally film coated.
[0098] While the invention has been described above with reference
to specific embodiments thereof, it is apparent that many changes,
modifications, and variations can be made without departing from
the inventive concept disclosed herein. Accordingly, it is intended
to embrace all such changes, modifications, and variations that
fall within the spirit and broad scope of the appended claims. All
patent applications, patents, and other publications cited herein
are incorporated by reference in their entirety.
* * * * *