The present invention relates to oral tablet of valsartan and optionally Hydrochlorothiazide (HCTZ), and process of preparation thereof.
Valsartan is a non-peptide, orally active and specific angiotensin II antagonist on AT! receptor subtype. Chemically it is N-(1-oxopentyl)-N-{[2'—(1H-tetrazole-5-yl)[1,1'-biphenyl]-4-yl] methyl]-L-valine. Hydrochlorothiazide is a thiazide diuretic. Chemically it is 6-chloro-3, 4-dihydro 2H-1, 2, 4-benzothiadiazine-7-sulfonamide 1, 1-dioxide. Tablets of valsartan, and fixed dose combination tablets of valsartan and HCTZ are marketed by Novartis under the trade name of DIOVAN * (strengths 40, 80, 160, and 320 mg,) and DIOVAN COMP® (strengths 80/12.5, 160/12.5, and 160/25 mg) respectively.
Pharmaceutical composition comprising valsartan alone or in combination with HCTZ is well known in the art. For example US patent Nos. 6,485,745 and US 6,294,197 disclose solid compressed dosage form of valsartan alone or in combination with HCTZ, 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.
However there has always been a need to develop an alternative compressed dosage forms comprising valsartan and optionally HCTZ in an amount of less than 35% by weight based on the total weight of the dosage form, which is bioequivalent to the commercially available product.
Hence in one general aspect there is provided oral valsartan tablet, comprising:
(i) Compact A comprising valsartan, microcrystalline cellulose, crospovidone along with one or more
other pharmaceutically acceptable excipients, and
(ii) Compact B comprising microcrystalline cellulose along with one or more other pharmaceutically
acceptable excipients,
Wherein valsartan is present in an amount of less than 35% by weight based on total weight of the tablet.
In another general aspect there is provided oral valsartan and HCTZ tablet comprising:
(i) Compact A comprising valsartan, HCTZ, microcrystalline cellulose, crospovidone along with one or
more other pharmaceutically acceptable excipients, and
(ii) Compact B comprising microcrystalline cellulose 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 total weight of
the tablet.
In another general aspect there is provided oral valsartan and HCTZ tablet comprising:
(i) Compact A comprising valsartan, microcrystalline cellulose, crospovidone along with one or more
other pharmaceutically acceptable excipients, and
(ii) Compact B comprising HCTZ, microcrystalline cellulose 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 total weight of
the tablet.
In another general aspect there is provided a process for the preparation of oral valsartan tablet comprising:
(i). Blending valsartan, microcrystalline cellulose, crospovidone and one or more other
pharmaceutically acceptable excipients,
(ii). Compacting the blend, milling and sifting through proper sieve to achieve the desired particle
size granules of compact A,
(iii). Blending microcrystalline cellulose along with one or more other pharmaceutically
acceptable excipients,
(iv). Compacting the blend, milling and sifting through proper sieve to achieve the desired particle
size granules of compact B.
(v). Blending compact A compact B and one or more other pharmaceutically acceptable
excipients and compressing to form tablet, Wherein valsartan is present in an amount of less than 35% by weight based on total weight of the tablet.
In another general aspect there is provided a process for the preparation of oral valsartan and HCTZ tablet comprising:
(i). Blending valsartan and HCTZ, microcrystalline cellulose, crospovidone, and one or more
other pharmaceutically acceptable excipients,
(ii). Compacting the blend, milling and sifting through proper sieve to achieve the desired particle
size granules (compact A),
(iii). Blending microcrystalline cellulose along with one or more other pharmaceutically
acceptable excipients,
(iv). Compacting the blend, milling and sifting through proper sieve to achieve the desired particle
size granules (compact B),
(v). Blending compact A, compact B, and one or more other pharmaceutically acceptable
excipients and compressing to form tablet,
Wherein the active agents are present in an amount of less than 35% by weight based on total
weight of the tablet.
In another general aspect there is provided a process for the preparation of oral valsartan and HCTZ tablet, comprising:
(i). Blending valsartan, microcrystalline cellulose, crospovidone, and one or more other
pharmaceutically acceptable excipients,
(ii). Compacting the blend, milling and sifting through proper sieve to achieve the desired particle
size granules (compact A),
(iii). Blending HCTZ, microcrystalline cellulose along with one or more other pharmaceutically
acceptable excipients,
(iv). Compacting the blend, milling and sifting through proper sieve to achieve the desired particle
size granules (compact B),
(v). Blending compact A, compact B, and one or more other pharmaceutically acceptable
excipients and compressing to form tablet,
Wherein the active agents are present in an amount of less than 35% by weight based on total weight of the tablet.
In another general aspect there is provided a method of prevention or treatment of hypertension in a mammal by administering oral tablet comprising valsartan alone and in combination with HCTZ, wherein the active agents are present in an amount of less than 35% by weight based on total weight of the tablet.
The term "valsartan" as used herein includes valsartan acid as well as it's pharmaceutically acceptable salts such as valsartan sodium, valsartan potassium, valsartan calcium, valsartan magnesium, and the like. The term "HCTZ" and "valsartan" also include their isomers, enantiomers, stereoisomers solvates, hydrates, and the like. Valsartan and HCTZ may be present 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 HCTZ 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. Avicel PH-101 is the logical choice for intragranular incorporation as it ensures faster and more trouble-free processing. Avicel PH 101 promotes rapid and even wetting; speeds drying; reduces screen blockage; minimizes 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 the tablet.
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 tablet.
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, low substituted hydroxypropyl cellulose, and the like.
Examples of diluents may include 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 silicon dioxide, stearic acid, 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 oral tablet of valsartan alone or in combination with HCTZ tablet may be prepared using conventional methods of dry granulation. The granules may be further compressed into tablets using conventional techniques. Alternatively direct compression technique may be used.
In one of the embodiment oral valsartan tablet may be prepared by a process comprising:
(i). Sifting valsartan, microcrystalline cellulose, crospovidone, and colloidal silicon dioxide
separately,
(ii). Transferring the material of step- (i) into a non-shear blender and blending to form a uniform
blend,
(iii). Sifting magnesium stearate and blending with the blend of step-(ii),
(iv). Compacting the blend of step-(iii) in horizontal feed roller compactor,
(v). Milling the compacts in oscillating granulator to achieve desired sized granules (compact A),
(vi). Sifting pregelatinized starch, microcrystalline cellulose and lubricants/glidants,
(vii). Compacting the material of step-(vi) in horizontal feed roller compactor,
(viii). Milling the compacts in oscillating granulator to achieve desired sized granules (compact
B), and
(ix). Mixing compact A and compact B granules, and lubricants/glidants in non-shear blender, and compressing into tablets using suitable toolings.
In another embodiment valsartan and HCTZ tablet, may be prepared by a process comprising:
(i) Sifting HCTZ and talc, and mixing,
(ii) Sifting valsartan, crospovidone, colloidal silicon dioxide, microcrystalline cellulose, and pregelatinized starch,
(iii) Transferring the material of step (i) and (ii) to a non shear blender and mixing,
(iv) Sifting magnesium stearate,
(v) Transferring the material of step (iv) to the non shear blender and mixing,
(vi) Compacting the blend of step (v) in a roller compactor,
(vii) Milling the compacts to achieve desired sized granules (compact A),
(viii) Sifting microcrystalline cellulose, pregelatinized starch, lactose and colloidal silicon
dioxide,
(ix) Compacting the blend of step (viii) in a roller compactor,
(x). Milling the compacts in oscillating granulator to achieve desired sized granules (compact
B), and
(xi). Mixing compact A, compact B granules, and lubricants/glidants in non-shear blender,
and compressing into tablets using suitable toolings.
In another embodiment valsartan and HCTZ tablet may be prepared by a process comprising:
(i). Sifting valsartan, microcrystalline cellulose, crospovidone, and colloidal silicon dioxide
separately,
(ii). Transferring the material of step- (i) into a non-shear blender and blending to form a uniform
blend,
(iii). Sifting magnesium stearate and blending with the blend of step-(ii),
(iv). Compacting the blend of step-(iii) in horizontal feed roller compactor,
(v). Milling the compacts in oscillating granulator to achieve desired sized granules (compact A),
(vi). Sifting of HCTZ, pregelatinized starch, microcrystalline cellulose, and lubricants/glidants,
(vii). Compacting the material of step-(vi) in horizontal feed roller compactor,
(viii). Milling the compacts in oscillating granulator to achieve desired sized granules (compact
B), and
(ix). Mixing compact A and compact B granules, and lubricants/glidants in non-shear blender,
and compressing into tablets using suitable toolings.
Tablets prepared in any of the above embodiments may be coated with one or more nonfunctional coating layers comprising one or more film forming polymers and pharmaceutically acceptable excipients, 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: Valsartan tablet compositions

(Table Removed)
Procedure
1. Valsartan, microcrystalline cellulose (Avicel PH 101), colloidal silicon dioxide, and crospovidone
were sifted together through # 25 BSS (600n), and transferred into a non-shear blender and
blended.
2. Magnesium stearate was sifted through # 36 BSS (420^) 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 (71 On), the retentions if any, were further
milled and resifted through # 22 BSS (71 On) and collected in a double polythene bag.
5. The granules of step - 4 were passed through # 60 BSS (250u.), 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. Pregelatinized starch, microcrystalline cellulose (Avicel PH 102), talc, colloidal silicon dioxide and
magnesium stearate, were sifted through # 36 BSS (420(i).
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 (71 On), the retentions if any, were further
milled and resifted through # 22 BSS (71 On) and collected in a double polythene bag.
9. The material of step - 8 was sifted through # 60 BSS (250^), 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 (355 n).
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.
Example 2: Valsartan and HCTZ tablet compositions

(Table Removed)
Procedure
1. HCTZ and talc were sifted through #30 BSS (500n) and mixed.
2. Valsartan, crospovidone, colloidal silicon dioxide, microcrystalline, and pregelatinized starch
were sifted through #22 BSS (71 O^i) or equivalent sieve using suitable mill.
3. The material of step 1 and 2 were transferred to a non shear blender and mixed.
4. Magnesium stearate was sifted through # 30 BSS (500^) or equivalent sieve using suitable
mill.
5. The material of step 4 was transferred to the non shear blender and mixed.
6. The blend of step 5 was compacted in a roller compactor.
7. The compacts were milled through #22 BSS (710^) or equivalent sieve attached to a suitable
mill.
8. The granules of step 7 were sifted over #60 BSS(250n) attached to a mechanical sifter. The
oversize and undersize were collected.
9. The undersize were compacted and step 6, 7 and 8 were repeated till the undersize fraction
of #60BSS (250^) is less than 30% w/w (Compact A).
10. Microcrystalline Cellulose, pregelatinized Starch, lactose and colloidal silicon dioxide were
sifted through #30 BSS (500^) or equivalent sieve using suitable mill.
11. The blend of step 10 was compacted in a roller compactor.
12. The compacts were milled through #22 BSS (710n) or equivalent sieve attached to a suitable
mill.
13. The granules of step 12 were sifted over #60 BSS (250n) attached to a mechanical sifter. The
oversize and undersize were collected.
14. The undersize were recompacted and step 11, 12 and 13 were repeated till the undersize
fraction of #60BSS (250^) is less than 65% w/w (Compact B).
15. Magnesium stearate was sifted through #30 BSS (500u) or equivalent sieve using suitable
mill, and blended with material of step 14.
16. The material of step 9 and 14 were transferred to a non shear blender and mixed.
17. The material of step 15 was transferred to the blender of step 16 and mixed.
18. The blend of step 17 was compressed to tablet using approved tooling.
19. Opadry was dispersed in purified water under mechanical stirring.
20. Tablets of step 18 were c.oatec' using the dispersion of Step 19 to get a target weight build up of
2 to 3% w/w.

WE CLAIM:
1. An oral valsartan tablet comprising:
a. Compact A comprising valsartan, microcrystalline cellulose, crospovidone along with one
or more other pharmaceutically acceptable excipients, and
b. Compact B comprising microcrystalline cellulose along with one or more other
pharmaceutically acceptable excipients,
wherein valsartan is present in an amount of less than 35% by weight based on total weight of the tablet.
2. The oral valsartan tablet according to claim 1 wherein the tablet comprises HCTZ either in
compact A or compact B.
3. The oral valsartan tablet according to claim 1 wherein the tablet comprises microcrystalline
cellulose in an amount of 5% to 60% of total weight of tablet.
4. The oral valsartan tablet according to claim 1 wherein the tablet comprises crospovidone in an
amount of 2 % to 40 % of tota1 weight of tablet.
5. The oral valsartan tablet according to claim 1 wherein the tablet comprises one or more other
pharmaceutically acceptable excipients selected from the group consisting of binders,
disintegrants, plasticizers, lubricants/glidants, opacifiers, and film-forming polymers.
6. The oral valsartan tablet according to claim 1 wherein the dosage form is prepared by the process
comprising:
(i). Blending valsartan, microcrystalline cellulose, crospovidone and one or more other
pharmaceutically acceptable excipients,
(ii). compacting the blend, milling and sifting through proper sieve to achieve the desired particle
size granules (compact A),
(iii). Blending, microcrystalline cellulose along with one or more other pharmaceutically
acceptable excipients.
(iv). Compacting the blend, milling and sifting through proper sieve to achieve the desired particle
size granules (compact B),
(v). Blending compact A, compact B and one or more other pharmaceutically acceptable
excipients and compressing into tablet,
7. The oral valsartan tablet according to claim 2 and 6 wherein the process of claim 6, step (i) or (iii)
comprise HCTZ.
8. The oral valsartan tablet according to claim 6 or 7 wherein the tablet is coated with one or more
nonfunctional coating layers comprising one or more film forming polymers.
9. A tablet comprising valsartan alone or in combination with HCTZ and the process of preparation thereof, as described and illustrated in the examples herein.