FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
J. Title of the invention - STABLE PHARMACEUTICAL COMPOSITIONS OF VALSARTAN AND AMLODIPINE OR SALTS THEREOF


2. Applicant(s)
(a) NAME:
(b) NATIONALITY (C) ADDRESS:

ALEMBIC LIMITED
An Indian Company
Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India

3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.


STABLE PHARMACEUTICAL COMPOSITIONS OF VALSARTAN AND AMLODIPINE OR SALTS THEREOF
FIELD OF THE INVENTION
The present invention relates to stable pharmaceutical composition comprising granules of valsartan or pharmaceutically acceptable salts thereof and granules of amlodipine or pharmaceutically acceptable salts thereof optionally with other pharmaceutically acceptable excipients. The invention also relates to process of preparing such compositions.
BACKGROUND OF THE INVENTION
Valsartan, an orally active angiotensin II antagonist in combination with a calcium channel blocker like amlodipine is prescribed for the treatment of hypertension and heart failure and is available under the brand name of EXFORGE* (Novartis).
Combination compositions of angiotensin II antagonist and calcium channel blockers shows a synergistic therapeutic effect exhibiting better efficacy and also the lower doses of individual drugs leading to less side effects. Compositions comprising valsartan or its pharmaceutically acceptable salts and amlodipine or its pharmaceutically acceptable salts and their process of preparation have been disclosed in prior art.
US 6,395,728 and US 2008/0171086 describe a fixed combination solid dosage formulation of valsartan and amlodipine.
US 2008/0279942 discloses a combination composition of angiotensin II receptor antagonist and a calcium channel blocker together with a hydrophilic polymer, an acidic substance and a fluidizing agent.
WO 2004/062552 discloses a combination composition comprising enteric coated tablets /pellets of two different active ingredients filled in a HPMC capsule. The active ingredients are coated differently to ensure the therapeutical compatibility.

WO 2007/001067 discloses a solid dosage form comprising an angiotensin II receptor antagonist and calcium channel blocker, wherein the active ingredients are formulated with out intimate mixing in the said dosage form.
The development of fixed combination dosage formulations of certain active ingredients is challenging. When formulating fixed combination solid dosage forms, the objective is to provide a stable product. Convenient combination dosage form of active ingredients that is stable and bioequivalent to free combination is challenging due to multiplicity of factors arising from pharmacokinetic and pharmaceutical properties of drugs sought to be combined.
The most important factor which should be considered in formulating combination products is the physico-chemical compatibility between the active ingredients. Some of the above prior arts involve mixing of valsartan and amlodipine in which there are chances of interaction between both the active ingredients leading to degradation of active ingredients forming impurities and resulting in less stable compositions.
Further, many inventions have been disclosed relating to bilayer and multilayer compositions for which specialized equipments are needed and involves complex technology. The process of preparing layered tablets is less economical and the tablets produced are susceptible to layer separation. Some of the inventions have described coating of different active ingredients separately and then combinely formulating them in capsule or tablet form to avoid contact between active ingredients which is time consuming and expensive.
To overcome the said problems in the development of combination compositions, the applicants of present invention have developed a stable pharmaceutical composition of valsartan and amlodipine or their pharmaceutically acceptable salts which can be prepared by simple, less expensive and less time consuming processes.

SUMMARY OF THE INVENTION
In one aspect of the invention there is provided a stable pharmaceutical composition comprising granules of valsartan or pharmaceutically acceptable salts thereof and amlodipine or pharmaceutically acceptable salts thereof.
In another aspect, the invention relates to stable pharmaceutical composition comprising granules of valsartan or pharmaceutically acceptable salts thereof and granules of amlodipine or pharmaceutically acceptable salts thereof, optionally with other pharmaceutically acceptable excipients wherein, at least 25% of said granules have a size greater than 250um.
In another aspect, the invention relates to stable pharmaceutical composition comprising granules of valsartan or pharmaceutically acceptable salts thereof and granules of amlodipine or pharmaceutically acceptable salts thereof, optionally with other pharmaceutically acceptable excipients wherein, at least 30% of said granules have a size ranging from about 250um to about 1.5mm.
In another aspect, the invention relates to stable pharmaceutical composition comprising granules of valsartan or pharmaceutically acceptable salts thereof and granules of amlodipine or pharmaceutically acceptable salts thereof, optionally with other pharmaceutically acceptable excipients wherein, at least 40% of said granules have a size ranging from about 250um to about 1.5mm.
In another aspect, the invention relates to stable pharmaceutical composition comprising granules of valsartan or pharmaceutically acceptable salts thereof and granules of amlodipine or pharmaceutically acceptable salts thereof, optionally with other pharmaceutically acceptable excipients, wherein at least 60% of said granules have a size greater than 75 urn.

In another aspect, the invention relates to stable pharmaceutical composition comprising granules of valsartan or pharmaceutically acceptable salts thereof and granules of amlodipine or pharmaceutically acceptable salts thereof, optionally with other pharmaceutically acceptable excipients wherein, at least 70% of said granules have a size ranging from about 75um to about 1,5mm.
In another aspect, the invention relates to stable pharmaceutical composition comprising granules of valsartan or pharmaceutically acceptable salts thereof and granules of amlodipine or pharmaceutically acceptable salts thereof, optionally with other pharmaceutically acceptable excipients wherein, at least 80% of said granules have a size ranging from about 75|im to about 1.5mm.
In another aspect, the invention relates to stable pharmaceutical compositions comprising granules of valsartan or pharmaceutically acceptable salts thereof and granules of amlodipine or pharmaceutically acceptable salts thereof, optionally with other pharmaceutically acceptable excipients, wherein at least 90% of granules have a size less than 1.5mm.
In another aspect of the invention, there is provided a process for preparing stable pharmaceutical composition comprising granules of valsartan or pharmaceutically acceptable salts thereof and granules of amlodipine or pharmaceutically acceptable salts thereof wherein, at least 25% of granules have a size greater than 250um or at least 60% of said granules have a size greater than 75um and which process comprises (i) mixing of valsartan or its pharmaceutically acceptable salts with pharmaceutically acceptable excipients to form premix (ii) converting the premix of step (i) to get the granules of valsartan (iii) mixing of amlodipine or its pharmaceutically acceptable salts with pharmaceutically acceptable excipients to form premix (iv) converting the premix of step (iii) to get the granules of amlodipine (v) mixing the granules of step (ii) and (iv) to form granule mix, (vi) converting the granule mix of step (v) in to suitable dosage form.

In another aspect of the invention, there is provided a stable pharmaceutical composition comprising granules of valsartan or pharmaceutically acceptable salts thereof and granules of amlodipine or pharmaceutically acceptable salts thereof optionally with other pharmaceutically acceptable excipients wherein, at least 25% of granules have a size greater than 250um or at least 60% of granules of amlodipine or valsartan have a size greater than 75um and said composition contains degradation product which is impurity D in an amount less than 0.1 %.
In another aspect of the invention, there is provided a stable pharmaceutical composition comprising granules of valsartan or pharmaceutically acceptable salts thereof and granules of amlodipine or pharmaceutically acceptable salts thereof optionally with other pharmaceutically acceptable excipients wherein, at least 25% of granules have a size greater than 250um or at least 60% of granules of amlodipine or valsartan have a size greater than 75 um and said composition contains degradation product which is impurity D in an amount less than 0.07%.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a stable pharmaceutical composition comprising granules of valsartan or pharmaceutically acceptable salts thereof and granules of amlodipine or pharmaceutically acceptable salts thereof wherein, at least 25% of granules have a size greater than 250um. Preferably, at least 25%) of granules have a size ranging from about 250um to about 1.5mm.
The present invention also relates to a stable pharmaceutical composition comprising granules of valsartan or pharmaceutically acceptable salts thereof and amlodipine or pharmaceutically acceptable salts thereof wherein, at least 60% of granules have a size greater than 75 um. Preferably, at least 60% of granules have a size ranging from about 75um to about 1.5mm.

Inventors of the present invention have surprisingly discovered that when size of granules of amlodipine and valsartan is controlled in such a way that at least 25% of granules have size greater than 250um or at least 60% of granules have a size greater than 75um so that, the surface area of contact between amlodipine and valsartan is minimized, it leads to minimum interaction between the two ingredients even when mixed together resulting in a stable pharmaceutical composition.
As a result, both ingredients can be effectively formulated in to fixed combination dosage form without need of physical separation from each other by using cost effective, less time consuming manufacturing techniques.
The dosage form of the invention comprises one or more of tablet, capsule, tablet in tablet, tablet in capsule, pellets, granules, powder, pellets in capsule, granules in capsule, spheroids, beads or other dosage form suitable for administration.
Applicants of the present invention have further found when amlodipine and valsartan are mixed together as such and wet granulated without controlling the size of granules, it leads to an unstable product as is depicted in Table -5, wherein Example A gives an impurity D in an amount 0.696%. When both the active ingredients are wet granulated separately as in Example B, the impurity obtained is 0.540%. When both amlodipine and valsartan are mixed together as such and dry granulated as in Example C, the impurity D is found to be 0.372% but when both the active ingredients are dry granulated separately with control in granule size as in Example D, the amount of impurity D found is 0.060% i.e. most stable formulation.
The compositions according to the invention may further comprise any of the typical excipients useful in preparing solid dosage forms. Such excipients include but are not limited to diluents, lubricants, binders, glidants. stabilizing agents, fillers and surfactants.
Diluents may include but are not limited to microcrystalline cellulose, powdered cellulose, compressible sugar, fructose, dextrans, other sugars such as mannitol, sorbitol.

lactitol, saccharose or a mixture thereof, siliconised microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate, colloidal or fumed silica or mixtures thereof. Preferably, in the present invention the diluent is microcrystalline cellulose.
Lubricants may include but are not limited to Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc. Preferably, in the present invention lubricant is magnesium stearate.
Binders include, but are not limited to polyvinylpyrrolidone (povidone), microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or other cellulose ethers, starch, pregelatinised starch, or polymethacrylate, or mixtures thereof. Preferably, in the present invention the binder is microcrystalline cellulose.
Glidants include, but are not limited to talc, starches, anhydrous colloidal silica, colloidal silicone dioxide, magnesium trisilicate and the like. Preferably, in the present invention glidants is colloidal silicone dioxide.
The composition of the present invention may be prepared by conventional technique well known to those skilled in the art such as wet granulation, dry granulation, direct compression and the like. Amlodipine or a pharmaceutically acceptable salt thereof may be mixed with one or more pharmaceutically acceptable excipients. The mixture may be dry granulated, compacted, milled and sifted to get the granules. In a similar way valsartan or a pharmaceutically acceptable salt thereof may be mixed with one or more pharmaceutically acceptable excipients. The mixture may be dry granulated, compacted, milled and sifted to get the granules. The granules of both the active ingredients may be sifted, mixed, lubricated and compressed to form tablets or filled into capsules. The tablets may be coated with non-functional coat.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention may be further illustrated by the following non-limiting examples.
Example A
Table!

Sr.
No. Name of the Ingredients % w/w
1 Valsartan 27.51
2 Amlodipine Besylate 0.60
3 Microcrystalline cellulose 55.71
4 Pregelatinised starch 2.49
5 Crospovidone 4.73
6 Purified water q.s.
7 Crospovidone 4.73
8 Colloidal silicon dioxide 0.86
9 Magnesium Stearate 0.95
10 Opadry 2.44
11 Purified water q.s.
Procedure:
Valsartan, amlodipine besylate, microcrystalline cellulose, pregelatinised starch and crospovidone are mixed and granulated with water. The wet mass is dried and converted to granules. The granules are lubricated with crospovidone, colloidal silicon dioxide and magnesium stearate followed by compression by using appropriate size oval shaped biconcave punch. The uncoated tablets are coated with aqueous opadry dispersion.

Example B
Table-2

Sr. No. Name of the Ingredients % w/w
1 Valsartan 27.51
2 Amlodipine Besylate 0.60
3 Microcrystalline cellulose 55.71
4 Pregelatinised starch 2.49
5 Crospovidone 4.73
6 Purified water q.s.
7 Crospovidone 4.73
8 Colloidal silicon dioxide 0.86
9 Magnesium Stearate 0.95
10 Opadry 2.44
11 Purified water q.s.
Procedure:
Valsartan, microcrystalline cellulose, pregelatinised starch and crospovidone are mixed and granulated with water. The wet mass is dried and converted to granules. Amlodipine, microcrystalline cellulose, pregelatinised starch and crospovidone are mixed and granulated with water. The wet mass is dried and converted to granules. The blend of valsartan granules and amlodipine granules are lubricated with crospovidone, colloidal silicon dioxide and magnesium stearate followed by compression by using appropriate size oval shaped biconcave punch. The uncoated tablets are coated with aqueous opadry dispersion.

Example C
Table-3

Sr. No. Name of the Ingredients % w/w
1 Valsartan 27.51
2 Amlodipine Besylate 0.60
3 Microcrystalline cellulose 60.30
4 Crospovidone 5.16
5 Colloidal silicon dioxide 3.01
6 Magnesium Stearate 0.99
7 Opadry 2.44
8 Purified water q.s.
Procedure:
Valsartan, amlodipine besylate, microcrystalline cellulose, crospovidone and colloidal silicon dioxide are mixed and dry granulated. The granules are lubricated with magnesium stearate followed by compression by using appropriate size oval shaped biconcave punch. The uncoated tablets are coated with aqueous opadry dispersion.

Example D
Table-4

Sr. No. Name of the Ingredients % w/w
1 Valsartan 27.02
2 Amlodipine Besylate 1.17
3 Microcrystalline cellulose 61.42
4 Crospovidone 5.07
5 Colloidal silicon dioxide 1.48
6 Magnesium Stearate 0.93
7 Opadry 2.91
8 Purified water q.s.
Procedure:
Valsartan, microcrystalline cellulose, crospovidone and colloidal silicon dioxide are mixed and dry granulated to get the valsartan granules. In similar way amlodipine besylate, microcrystalline cellulose and crospovidone are mixed and dry granulated to get the amlodipine granules. The granules prepared are in specific size ranges such as 40% of the granules have a size ranging from about 250um to about 1.5mm. The blend of valsartan granules and amlodipine granules are lubricated with crospovidone, colloidal silicon dioxide and magnesium stearate. The lubricated granules are then compressed by using appropriate size oval shaped biconcave punch and the tablets are coated with aqueous opadry dispersion.

Table-5- Comparative Impurity data :

Formulation Example A Example B Example C Example D
Related Substance Under stress condition for 15 days in 50°C, and 40°C/75% RH

Initial 50°C 40°C/
75% Initial 50°C 40°C/
75% Initial 50°C 40°C/
75% Initial 50°C 40°C/
75%
RH RH RH RH
Impurity-D 0.283 0.493 0.696 0.385 0.848 0.540 0.138 0.301 0.372 0.040 0.064 0.060
Highest
Unknown 0.087 0.132 0.274 0.493 2.428 3.764 0.057 0.073 0.109 0.044 0.066 0.057
Impurity
Total
Impurity 0.394 0.625 0.970 0.828 3.276 4.402 0.327 0.374 0.481 0.235 0.351 0.306
(Amlodipine)

We Claim:
1. A stable pharmaceutical composition comprising granules of valsartan or
pharmaceutically acceptable salts thereof and granules of amlodipine or pharmaceutically
acceptable salts thereof, wherein at least 25% of said granules have a size greater than
250um.
2. The composition of claim 1, wherein at least 25% or at least 30% or at least 40% of
said granules have a size ranging from about 250um to about 1.5mm.
3. A stable pharmaceutical composition comprising granules of valsartan or
pharmaceutically acceptable salts thereof and granules of amlodipine or pharmaceutically
acceptable salts thereof, wherein at least 60% of said granules have a size greater than
75um.
4. The composition of claim 3, wherein at least 60% or at least 70% or at least 80% of said granules have a size ranging from about 75|j.ni to about 1.5mm.
5. A process of preparation of stable pharmaceutical composition comprising granules of valsartan or pharmaceutically acceptable salts thereof and amlodipine or pharmaceutically acceptable salts thereof wherein, at least 25% of said granules have a size greater than 250um or at least 60% of said granules have size greater than 75um and the process comprises (i) mixing of valsartan or its pharmaceutically acceptable salts with pharmaceutically acceptable excipients to form premix (ii) converting the premix of step (i) to get the granules of valsartan (iii) mixing of amlodipine or its pharmaceutically acceptable salts with pharmaceutically acceptable excipients to form premix (iv) converting the premix of step (iii) to get the granules amlodipine (v) mixing the granules of step (ii) and (iv) to form granule mix, (vi) converting the granule mix of step (v) in to suitable dosage form.

6. The process of claim 5 wherein, the amlodipine granules are prepared by dry
granulation.
7. A stable pharmaceutical composition comprising granules of valsartan or
pharmaceutically acceptable salts thereof and granules of amlodipine or pharmaceutically
acceptable salts thereof, wherein at least 25% of said granules have a size greater than
250um or at least 60% of said granules have a size greater than 75um and the
composition contains degradation product which is impurity D in an amount less than
0.1%.
8. The composition of claim 7, wherein the composition contains degradation product
which is impurity D in an amount less than 0.07%.
9. The composition of as per any preceding claims comprises one or more of tablet,
capsule, tablet in tablet, tablet in capsule, pellets, granules, powder, pellets in capsule,
granules in capsule, spheroids and beads.