The present invention relates to solid dosage form comprising valsartan and amlodipine, and process of preparation thereof.
Valsartan is a non-peptide, orally active and specific angiotensin II antagonist on AT1 receptor subtype. Chemically it is N-(1-oxopentyl)-N-{[2'—(1H-tetrazole-5-yl)[1,1'-biphenyl]-4-yl] methyl]-L-valine. Amlodipine is a dihydropyridine calcium channel blocker (CCB). Chemically it is 3-Ethyl-5-methyl (4RS)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3, 5 dicarboxylate benzenesulphonate. Amlodipine and valsartan in combination is marketed by Novartis in the strength of 10 mg: 160 mg, 10 mg: 320 mg, 5 mg : 160 mg, 5 mg : 320 mg, under the trade name of Exforge®, which is a fixed dose combination of amlodipine besylate and valsartan.
Use of angiotensin II receptor antagonists and calcium channel blockers composition as separate compositions is well known in the art from more than a decade. However US patent no 6,395,728 discloses a fixed dose combination pharmaceutical composition comprising AT1 antagonist valsartan and the calcium channel blocker amlodipine comprising specific grades of excipients such as Avicel PH 102, PVPP-XL, along with other excipients. Further US patent no. 6,294,197 discloses compressed solid dosage form comprising a) an active agent containing an effective amount of valsartan or a pharmaceutically acceptable salt thereof; and, b) at least one pharmaceutically acceptable additive wherein the active agents are present in an amount of more than 35% by weight based on the total weight of the compressed solid dosage form.
There has always been a need to develop an alternative compressed solid dosage form comprising valsartan and amlodipine, wherein the active agents are present in an amount of less than 35% by weight based on the total weight of the solid dosage form, which is bioequivalent to the commercially available product, Exforge®.
Hence in one general aspect there is provided a solid dosage form comprising valsartan and amlodipine, wherein the active agents are present in an amount of less than 35% by weight based on the total weight of the solid dosage form.
In another general aspect there is provided a solid dosage form comprising valsartan and amlodipine, microcrystalline cellulose, and crospovidone along with one or more other pharmaceutically acceptable excipients, wherein the active agents are present in an amount of less than 35% by weight based on the total weight of the solid dosage form.
In another general aspect there is provided a solid dosage form comprising valsartan and amlodipine, microcrystalline cellulose in an amount from about 5% to about 60% w/w, and crospovidone in an amount from about 2 % to about 40 % w/w along with one or more other pharmaceutically acceptable excipients, wherein the active agents are present in an amount of less than 35% by weight based on the total weight of the solid dosage form.
In another general aspect there is provided a solid dosage form comprising valsartan and optionally amlodipine in the intragranular portion wherein the active agents are present in an amount of less than 35% by weight based on the total weight of the solid dosage form.
In another general aspect there is provided a process for the preparation of solid dosage form of amlodipine and valsartan comprising:
1. Blending valsartan, amlodipine, a part of microcrystalline cellulose and
crospovidone along with one or more other pharmaceutically acceptable
excipients,
2. Compacting the blend, milling and sifting through proper sieve to
achieve the granules of desired particle size,
3. Blending rest of microcrystalline cellulose and crospovidone along with
one or more other pharmaceutically acceptable excipients with granules of
step 2, and
4. Processing to form suitable solid dosage form,
Wherein the active agent is present in an amount of less than 35% by weight based on the total weight of the solid dosage form.
In another general aspect there is provided a process for the preparation of solid dosage forms of amlodipine and valsartan comprising:
1. Blending valsartan and optionally amlodipine, microcrystalline cellulose,
crospovidone and one or more other pharmaceutically acceptable
excipients,
2. compacting the blend milling and sifting through proper sieve to achieve
the desired particle size granules (compact A),
3. Blending, microcrystalline cellulose and optionally amlodipine along with
one or more other pharmaceutically acceptable excipients.
4. Compacting the blend milling and sifting through proper sieve to
achieve the desired particle size granules (compact B),
5. Blending compact A compact B and one or more other pharmaceutically
acceptable excipients and processing to form suitable solid dosage form,
Wherein the active agents are present in an amount of less than 35% by weight based on the total weight of the compressed solid dosage form, and wherein amlodipine is present atleast in one of the compact A or B.
In another general aspect there is provided a method of prevention or treatment of hypertension in a mammal by administering a solid dosage form comprising amlodipine and valsartan wherein the active agent is present in an amount of less than 35% by weight based on the total weight of the compressed solid dosage form.
The term "solid dosage form" as used herein may include tablet, capsule, granules filled in sachets and the like.
The term "amlodipine" as used herein includes free amlodipine base as well as its pharmaceutically acceptable salts with acids such as benzene sulfonic acid, acetic acid, phosphoric acid, sulphuric acid, tartaric acid, hydrochloric acid, citric acid, and the like. The term "valsartan" as used herein includes valsartan acids its pharmaceutically acceptable salts such as valsartan sodium, valsartan potassium, valsartan calcium, valsartan magnesium and the like. The term "Amlodipine" and "valsartan" also include their isomers, enantiomers, stereoisomers solvates, hydrates, and the like. Valsartan and amlodipine may be used in the solid dosage forms in amounts effective to prevent or treat hypertension partly or completely. Amount of valsartan may vary from about 10 to about 350 mg, and that of amlodipine may vary from about 6 mg to about 60 mg.
Microcrystalline cellulose is a purified, partially depolymerised cellulose, prepared by treating alpha-cellulose, obtained as a pulp from fibrous plant material, with mineral acids; used as a tablet diluent. Microcrystalline Cellulose has unique compressibility and carrying capacity. It exhibits excellent properties as an excipient for solid dosage forms. It compacts well under minimum compression pressures, has high binding capability, and creates tablets that are extremely hard, stable, yet disintegrate rapidly. Other advantages include low friability, inherent lubricity, and the highest dilution potential of all binders. Microcrystalline cellulose is available in various grades e.g. Avicel PH 101, 102, 301, 302 etc. Avicel PH-101 is the logical choice for intragranular incorporation as it ensures faster and more trouble-free processing. Avicel PH promotes rapid, even wetting; speeds drying; reduces screen blockage; minimized case hardening; controls dye migration; and promotes disintegration. On the other hand high density Avicel PH-301 or PH-302 as well as Avicel PH-102 may be used as additions to the running mix to improve flow and compatibility during
compression. Microcrystalline cellulose may be incorporated in range of about 5% to about 60% of total weight of solid dosage form.
Crospovidone is a synthetic, insoluble but rapidly swellable, crosslinked homopolymer of N-vinyl-2-pyrrolidone. It is a white, free flowing, and compressible powder that is completely insoluble in water, acids, alkalis, and all organic solvents. It is hygroscopic swells rapidly in water but does not gel even after prolonged exposure. It is useful as dissolution aid for tablets, capsules and pellets. Crospovidone may be incorporated in the range of about 2 % to about 40 % of total weight of solid dosage form.
The term "other pharmaceutically acceptable excipient" as used herein may include all physiologically inert additives used in the pharmaceutical art of dispensing. Examples may include binders, diluents, disintegrants, lubricants/glidants, plasticizer, opacifiers, film-forming polymers, and the like.
Examples of binders may include, methyl cellulose, hydropropylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethylcellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, and the like.
Examples of disintegrant may include, sodium starch glycolate, croscarmellose sodium, Crospovidone, low substituted hydroxypropyl cellulose, and the like.
Examples of diluents may include cellulose powdered, dextrates, dextrins, dextrose excipients fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like.
Examples of lubricants and glidants may include, magnesium stearate, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc,
hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like.
Examples of plasticizers may include, polyethylene glycol, triethyl citrate, triacetin, diethyl phthalate, dibutyl sebacate, and the like.
Examples of opacifiers may include, titanium dioxide, and the like.
Examples of film forming polymers may include, ethylcellulose, hydroxypropyl
methylcellulose, hydroxypropylcellulose, methylcellulose,
carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, or cellulose acetate trimellitate' waxes such polyethylene glycol; methacrylic acid polymers such as Eudragit® RL and RS; and the like. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used for coating.The term "intragranular pharmaceutically acceptable excipient," as used herein, refers to those excipients which are present in granules.
The term "extragranular pharmaceutically acceptable excipient," as used herein, refers to those excipients with which granules may be blended before being processed into suitable solid dosage form.
The solid dosage form of amlodipine and valsartan may be prepared using conventional methods of granulation such as dry/wet granulation, extrusion spheronization, and the like. The granules may be further processed into solid dosage forms using conventional techniques, such as tablet compression, capsule filling, and the like.
In one of the embodiment a solid dosage form comprising amlodipine and valsartan may be prepared by a process comprising:
1. Sifting valsartan, amlodipine besylate, intragranular portion of
crospovidone, microcrystalline cellulose and other pharmaceutically
acceptable excipients separately,
2. Blending the material of step 1 and compacting in horizontal feed roller
compactor,
3. Milling the compacts of step 2 in oscillating granulator to achieve granules
of desired particles size,
4. Sifting of extragranular microcrystalline cellulose, crospovidone, and
lubricants/glidants, and blending with granules of step-3, and
5. Compressing the blend into tablets using suitable toolings.
In another embodiment a solid dosage form comprising amlodipine and valsartan may be prepared by a process comprising:
1. Sifting valsartan, microcrystalline cellulose, crospovidone, colloidal
silicon dioxide and amlodipine besylate separately,
2. Transferring the material of step- 1 into a non-shear blender and
blending to form a uniform blend,

3. Sifting magnesium stearate and blending with the blend of step-2,
4. Compacting the blend of step-3 in horizontal feed roller compactor, and
5. Milling the compacts in oscillating granulator to achieve desired sized
granules (compact A),
6. Sifting of pregelatinized starch, microcrystalline cellulose, and
lubricants/glidants,
7. Compacting the material of step-6 in horizontal feed roller compactor,
and
8. Milling the compacts in oscillating granulator to achieve desired sized
granules (compact B),
9. Mixing compact A and compact B granules, and lubricants/glidants in
non-shear blender, and compressing into tablets using suitable toolings.
Solid dosage forms prepared in any of the above embodiments may be coated with one or more nonfunctional coating layers comprising one or more film forming polymers, using the conventional coating technique such as pan coating, dip coating, fluidized bed coating, and the like. Alternatively melt coating technique may also be used.
In another embodiment a solid dosage form comprising amlodipine and valsartan may be prepared by a process comprising:
1. Sifting valsartan, microcrystalline cellulose, crospovidone, and colloidal
silicon dioxide separately,
2. Transferring the material of step- 1 into a non-shear blender and
blending to form a uniform blend,
3. Sifting magnesium stearate and blending with the blend of step-2,
4. Compacting the blend of step-3 in horizontal feed roller compactor, and
5. Milling the compacts in oscillating granulator to achieve desired sized
granules (compact A),
6. Sifting of pregelatinized starch, microcrystalline cellulose,
lubricants/glidants, and amlodipine besylate,
7. Compacting the material of step-6 in horizontal feed roller compactor,
and
8. Milling the compacts in oscillating granulator to achieve desired sized
granules (compact B),
9. Mixing compact A and compact B granules, and lubricants/glidants in
non-shear blender, and compressing into tablets using suitable toolings.
Solid dosage forms prepared in any of the above embodiments may be coated with one or more nonfunctional coating layers comprising one or more film forming polymers, using the conventional coating technique such as pan coating, dip coating, fluidized bed coating, and the like. Alternatively melt coating technique may also be used.
The invention is further illustrated by the following examples but they should not be construed as limiting the scope of the invention any way.
Example 1: Tablet composition
(Table Removed)
Procedure
1. Valsartan, Amlodipine besylate, and intragranular microcrystalline
cellulose (Avicel PH 101), colloidal silicon dioxide, and Crospovidone were
sifted separately.
2. The material of step 1 was blended, compacted in horizontal feed roller
compactor and the compacts were milled in oscillating granulator,
3. The material of step-2 was sifted through #22 BSS (710µ), the oversized
retentions were further milled and sifted through 22# BSS (710µ,), and
collected in a double polythene bag.
4. The material of step-3 were Sifted through #60 BSS (250µ) and fine
portions were collected and compacted to maintain 70 to 30 ratio by
weight of + #60 BSS to - #60 BSS granules and both the materials were
transferred to a low shear blender.
5. Extragranular microcrystalline cellulose (Avicel PH302), crospovidone and
colloidal silicon dioxide were sifted and transferred to the blender of step-4
and blended.
6. Talc and magnesium stearate were sifted through #36 BSS (420µ) and
blended with material of step-5.
7. The blend of step 6 was compressed into tablets using approved oval
shaped punches.
8. Opadry was dispersed in purified water under mechanical stirring to get
about 12% w/w dispersion.
9. Tablets of step 7 were coated using the dispersion of Step 8 to get a
target weight build up of 3.0% w/w.
Example 2: Tablet composition
(Table Removed)
Procedure
1. Valsartan, Amlodipine besylate (For Example 2B only), microcrystalline
cellulose (Avicel PH 101), colloidal silicon dioxide and crospovidone were
sifted together through # 25 BSS (600µ), and transferred into a non-shear
blender and blended.
2. Magnesium stearate was sifted through # 36 BSS (420µ) and added to the
material of step - 1.
3. The material of step - 2 was compacted in horizontal feed roller
compactor and the compact were milled in oscillating granulator.
4. The material of step - 3 was sifted through # 22 BSS (710µ), the
retentions if any, were further milled and resitted through # 22 BSS (710µ)
and collected in a double polythene bag.
5. The granules of step - 4 were passed through # 60 BSS (250µ), and
undersize and oversize fractions were collected separately. The undersize
fraction was recompacted as per step 3 & 4 till the undersize/fines
collected below # 60 BSS was NMT 30% w/w and the blend was named
as Compact A,
6. Amlodipine besylate (for Example 2A only), pregelatinized starch,
microcrystalline cellulose (Avicel PH 102), talc, colloidal silicon dioxide
and magnesium stearate, were sifted through # 36 BSS (420µ).
7. The material of step - 6 was compacted in horizontal feed roller
compactor and the compact obtained were milled in oscillating granulator.
8. The material of step - 7 was sifted through # 22 BSS (710µ), the
retentions if any, were further milled and resifted through # 22 BSS (710µ)
and collected in a double polythene bag.
9. The material of step - 8 was sifted through # 60 BSS (250µ), and
undersize and oversize fractions were collected separately. The undersize
fraction was recompacted as per step 7 and 8 till the undersize/fines
collected below # 60 BSS was NMT 30% w/w and the blend was named
as Compact B.
10. Compact A and Compact B were weighed and mixed in non-shear blender
after adjusting the weight as per the yield of compact A.
11. Magnesium stearate was sifted through # 44 BSS (355µ).
12. The blend of step 10 was lubricated with magnesium stearate of step 11 in
non-shear blender, and were compressed into tablets using approved oval
shaped punches.
13.Opadry of respective strengths was dispersed in purified water under
mechanical stirring to get about 10% w/w dispersion. 14. Tablets of step 12 were coated using the dispersion of Step 13 to get a
target weight build up of 3.0% w/w.

WE CLAIM:
1. A solid dosage form comprising valsartan and amlodipine, wherein the active
agents are present in an amount of less than 35% by weight based on the
total weight of the solid dosage form.
2. The solid dosage form according to claim 1 wherein the dosage form
comprises microcrystalline cellulose, and crospovidone.
3. The solid dosage form according to claim 2 wherein the dosage form
comprises microcrystalline cellulose in an amount between 5% to 60% w/w,
and crospovidone in an amount between 2 % to 40 % w/w.
4. The solid dosage form according to claim 1 wherein the dosage form
comprises one or more other pharmaceutically acceptable excipients selected
from the group consisting of binders, disintegrants, plasticizers,
lubricants/glidants, opacifiers, and film-forming polymers.
5. The solid dosage form according to claim 1 wherein the dosage form is
selected from the group consisting of tablets, capsule, and granules filled in
sachets.
6. The solid dosage form according to claim 1 wherein the dosage form is
prepared by the process comprising:
A. Blending valsartan, amlodipine, microcrystalline cellulose, crospovidone
along with one or more other pharmaceutically acceptable excipients,
B. Compacting the blend, milling and sifting through proper sieve to achieve
the granules of desired particle size,
C. Blending microcrystalline cellulose and crospovidone along with one or
more other pharmaceutically acceptable excipients with granules of step 2,
and
D. Processing to form suitable solid dosage form.
7. The solid dosage form according to claim 1 wherein the dosage form is
prepared by the process comprising:
A. Blending valsartan and amlodipine, microcrystalline cellulose,
crospovidone and one or more other pharmaceutically acceptable excipients,
B. compacting the blend milling and sifting through proper sieve to achieve
the desired particle size granules (compact A),
C. Blending, microcrystalline cellulose along with one or more other
pharmaceutically acceptable excipients.
D. Compacting the blend milling and sifting through proper sieve to achieve
the desired particle size granules (compact B),
E. Blending compact A compact B and one or more other pharmaceutically
acceptable excipients and processing to form suitable solid dosage form,
8. The solid dosage form according to claim 1 wherein the dosage form is
prepared by the process comprising:
A. Blending valsartan, microcrystalline cellulose, crospovidone, and one or
more other pharmaceutically acceptable excipients,
B. compacting the blend milling and sifting through proper sieve to achieve
the desired particle size granules (compact A),
C. Blending, amlodipine and microcrystalline cellulose along with one or more
other pharmaceutically acceptable excipients.
D. Compacting the blend milling and sifting through proper sieve to achieve
the desired particle size granules (compact B),
E. Blending compact A compact B and one or more other pharmaceutically
acceptable excipients and processing to form suitable solid dosage form,
9. The solid dosage form according to claim 7 or 8 wherein the dosage form is
coated with one or more nonfunctional coating layers comprising one or more
film forming polymers.
10. A solid dosage form comprising valsartan and amlodipine and the process of
preparation thereof, as described and illustrated in the examples herein.