FIELD OF INVENTION
The present invention relates to a stable solid oral dosage forms comprising Angiotensin II receptor antagonists and optionally Hydrochlorothiazide (HCTZ), prepared by wet granulation technique. It also discloses a process to make the same.
BACKGROUND OF THE INVENTION AND RELATED PRIOR ART
Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field.
The invention relates to a solid dosage form comprising Angiotensin II receptor antagonists optionally containing HCTZ and a wet granulation process for said solid oral dosage forms.
Angiotensin II receptor antagonists include compounds having differing structural features. For example, mention may be made of the compounds which are listed in the EP 443983. Preference is given to {S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'(1H-tetrazol-5-yl) biphenyl-4-yl methyl] amine [Valsartan] of the formula and its pharmaceutically utilizable salts. U.S. patent No: 5399578 describe the preparation of Valsartan and its pharmaceutically acceptable salt. Valsartan tablets are marketed by Novartis as DIOVAN containing 40, 80, 160 and 320 mg of valsartan.
The angiotensin II receptor antagonist Valsartan is known to be effective in the treatment of--congestive heart failure and reducing blood pressure irrespective of age, sex or race and is also well tolerated. Its combination with HCTZ Is also known for the treatment of hypertension.
HCTZ is a loop diuretic and is chemically described as 6-chloro-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfonamlde-1, 1-dioxide. The combination of valsartan and'HCTZ is Indicated for treatment of hypertension in patients failing to achieve the desired effect with monotherapy. Fixed-dose combination tablets are marketed by Novartis as DIOVAN HCT in

doses of 80 mg/12.5 mg; 160 mg/12,5 mg and 160 mg/25 mg of valsartan/ HCTZ respectively.
The oral administration of such pharmaceutical agents as tablets or capsules has certain advantages over parenteral administration such as i.v. or i.m. Diseases requiring treatment with painful injectable formulations are considered to be more serious than those conditions which can be treated with oral -dosage forms. However, the major advantage with oral formulations is held to be their suitability for self administration whereas parenteral formulations have to be administered in most cases by a physician or paramedical personnel.
Valsartan is difficult to formulate and heretofore it has not been possible to make oral formulations in the form of tablets utilizing wet granulation, in a reliable and robust way. Both valsartan and HCTZ are fluffy materials having low density. Thus, preparation of solid dosage forms of acceptable size and suitable for oral administration is a challenging task- There are multiple formulation patents for angiotensin Jl receptor antagonist, containing Valsartan as active substance,
U.S. patent Nos: 6,294,197, 6,485,745 and 6,858,228 describe a solid oral dosage form of Valsartan and optionally hydrochlorthiazide (HCTZ) prepared by compression/ dry granulation method having more than 35% by weight based on total weight of the compressed solid oral dosage form, of the active ingredient. Valsartan tablets of 40mg, 80mg, 160mg and 320mg strengths are available in the market,
U.S. patent application No: 2003/0152620 relates to solid oral dosage forms comprising more than about 65% by weight of Valsartan or a pharmaceutically acceptable salt thereof or hydrate thereof. The compositions are at least 1,2 times more bioavailable than conventional Valsartan capsule and having a C^ax of about at least 0.77 mg/l, e.g. up to 3.5 mg/l, e.g. 1.3 mg/l when administered as a dose of 40 mg in a single dose human bioavailability study.
WO 2005/041941 discloses a formulation containing Valsartan which is obtainable by direct tabletting.
WO 2007/052307. WO 2007/049291 also describe a solid oral dosage form containing Valsartan prepared by compression/ dry granulation method, containing less than 35% by

weight based on total weight of the compressed solid oral dosage form, of the active ingredient.
These afore-mentioned prior art apply a method of dry granulation/ direct tabletting for production of tablets of Valsartan, hence there is a need for a process to make stable formulation utilizing wet granulation.
We have now found a solid oral dosage form made by utilizing wet granulation technique, containing Valsartan or a pharmaceuttcally acceptable salt thereof optionally in combination with HCTZ which can be produced according to a reliable and robust process, said solid oral dosage forms are smaller, for a given amount of active agent.
OBJECTS OF THE INVENTION
According to the invention, there is provided a stable solid oral dosage form comprising a) an active agent comphsing an effective amount of Valsartan and its pharmaceutically acceptable salt thereof; b) optionally containing HCTZ and c) pharmaceutically acceptable additives, wherein the formulation process utilizes wet granulation technique for manufacturing the said solid dosage form
Another object of the invention in its preferred form to provide a stable, compressed solid oral valsartan formulation having comparable in-vitro dissolution and bioequivalence [in-vivo] profile similar to that of DIOVAN®
In at least one embodiment of the invention, the granules to be compressed to form the tablet of the invention described herein, are manufactured by the wet granulation process. Wet granulation involves agitation of a powder {the active drug) by convention in the presence of a liquid (the binder solution) followed by drying. For preparing the granules, which are to be eventually compressed into the tablet, Valsartan is first granulated, with a binder solution, in a granulator (e.g. a fluidized bed granulator manufactured by Glatt (Germany) or Aeromatic (Switzerland)) or a rapid mixer granulator (RMG)). An especially preferred embodiment of the invention is a solid oral dosage form, which contain as the active agent a) a unit dose of about 28 to 50% w/w of Valsartan.

In another embodiment of the invention, the tablet contains greater than 10% of a disintegrating agent, preferably greater than 13% of which the crosspovidone appears to be the preferable one.
In a further embodiment, the invention is a solid oral dosage form, v^hich contain microcrysta!line cellulose (MCC) in an amount about 25% to 55% w/w of the dosage form,
SUMMARY OF THE INVENTION
According to the invention, there is provided a stable solid oral dosage form comprising a) an active agent comprising an effective amount of Valsartan and its pharmaceutically acceptable salt thereof; b) optionally containing HCTZ and c) pharmaceutically acceptable additives, wherein the formulation process utilizes wet granulation technique for manufacturing the said solid dosage form
According to the invention there is provided a stable solid pharmaceutical formulation for use
in Hypertension & Post myocardial infarction, ^ _.
According to one aspect of the invention there is also provided a process to make the same.
As presently contemplated, in one broad form, the invention provides a process to make a pharmaceutical formulation comprising the following steps:
a. Mixing Valsartan and pharmaceutically acceptable additives
b. granulating Valsartan and at ieast one pharmaceutically acceptable additive, using a
binder solution;
c. drying and milling product of step [b]:
d. compressing milled product of step [c] into tablets or filling it into capsules,
DETAILED DESCRIPTION INCLUDING PREFERRED EMBODIMENTS OF THE INVENTION:
This invention relates to solid oral dosage forms of valsartan, comprising a) an active agent comprising an effective amount of Valsartan or a pharmaceutically acceptable salt thereof: and b) pharmaceutically acceptable.additives suitable for the preparation of solid oral dosage

forms, wherein the process of making said dosage form requires use of wet granulation technique.
"Solid oral dosage form" includes granules, tablets, capsules filled with granules and the like prepared by conventional methods well known to a person skilled in the art.
By "effective amount", it is meant that the amount of active agent, which halts or reduces the progress of the condition being treated or which otherwise completely or partly cures or acts palliatively on the condition, A person skilled in the art can easily determine such an amount by routine experimentation and with an undue burden.
In a stable solid dosage form according to the invention wherein, active agent consists entirely of Valsartan or a pharmaceutically acceptable salt thereof, it is preferred if the active agent is present in the amount of from 10 - 320 mg e.g. 40, 80, 160 or 320 mg.
The active agent Valsartan is particularly suitable for combination with other active agents, e.g. HCTZ. Valsartan is preferably in its free form, that is, not in one of its salt forms.
The preparation of Valsartan is described in the U.S. patent No 5,399,578 which is incorporated herein by reference. A pharmaceutically acceptable salt of Valsartan can be prepared in a manner known per se. Thus for example, acid addition salts are obtained by treatment with an acid or a suitable ion exchange agent. Such salts can be converted to free acid in a conventional manner by treatment with a suitable basic agent.
Wet granulation process for manufacturing of tablet granules may either utilize fluidized bed granulator or a rapid mixer granulator. In case of fluidized bed granulation process the binder {e.g. povidone) is first dissolved or dispersed in a suitable solvent (e.g. water). The binder solution is then top sprayed onto the drug in a granulator to form granules, while in case of rapid mixer granulation process the drug and excipients are mixed in RMG and then binder (e.g. povidone) dissolved or dispersed in a suitable solvent (e.g. water) is poured into RMG to from wet mass which is subsequently passed through suitable sieve to form granules.
The granules formed are subsequently dried and then screened prior to blending with the lubricant. In certain embodiments, the dried granules are sieved through a 1.4 mm mesh

screen. Blending of the granules with the lubricant, and if necessary, any additional inert excipients, such as for example a glidant, can be performed in a V-blender or any other suitable blending apparatus. Glidants can improve the flowability of the powder. This is especially important during tablet production at high production speeds and during direct compaction. However, because the requirement for adequate flow is high, a glidant is often also added to a granulation before tabletting. The blended granules are subsequently pressed into tablets or filled into hard gelatin capsules.
The solid oral dosage form may further comprise pharmaceutically acceptable additives known in the art. The term 'pharmaceutically acceptable additive' includes 'pharmaceutically acceptable excipient' within its ambit and the singular term includes plural as well. Pharmaceutically acceptable additives such as a binders/ granulating agent, disintegrants, lubricants, glidants, fillers or diluents and the like
Disintegrants, which include but are not limited to, cross linked polyvinylpyrrolidone {Crospovidone, polyplasdone XL, Kollidon CL); starches such as maize starch and dried starch sodium starch glycolate; gums such as alginic acid, sodium alginate, guar gum; croscarmellose sodium; croscarmellose calcium; cellulose products such as microcrystalline cellulose and its salts, microfine cellulose, low substituted hydroxypropylcellulose and mixtures thereof. Most preferably disintegrants are crosslinked polyvinylpyrrolidone, crosslinked carboxymethylcellulose and crosslinked sodium carboxymethylcellulose.
Binders/ Granulating agent, which include, but are not limited to, alkyl celluloses such as
methyl cellulose, ethyl cellulose; hydroxyalkylcelluloses such as hydroxypropylcellulose, low
substituted hydroxypropylcellulose, hydroxypropyl methylcellulose, sodium
carboxymethylcellulose; microcrystalline cellulose; gelatin, acacia, starches, e.g. potato starch, wheat starch, corn starch, pregelatinised maize starch and polyvinylpyrrolidone.
Glidants improve the flowability of the powder making up the tablet during production. Glidants can be selected from the group consisting of; silicon dioxide, colloidal silicon dioxide, fumed silicon dioxide, sodium aluminosilicate, calcium silicate, powdered cellulose, microcrystalline cellulose, corn starch, sodium benzoate, calcium carbonate, magnesium carbonate, asbestos free talc, metallic stearates, calcium stearate, magnesium stearate, zinc

stearate, stearowet C, starch, starch 1500, magnesium lauryl sulfate, or magnesium oxide,, where colloidal silicon dioxide is the preferred glidant.
Lubricants may be selected from the group of magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, hydrogenated cottonseed oil, sodium benzoate, sodium lauryl sulfate, polyethylene glycol, talc etc.
Fillers or diluents, which include, but are not limited to confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, mannitol, sucrose, starch, lactose, dicalcium phosphate, xylitol. sorbitol, talc, micro-crystalline cellulose and the like can be used.
The amount of each type of additive employed, e,g- glidant, binder, disintegrant, filler or diluent and lubricant may vary within ranges conventional in the art.
It is a characteristic of the present solid oral dosage forms that they contain only a relatively small amount of additives given the high content of active agent. This enables the production of physically small unit dosage forms. The total amount of additives in a given unit dosage may be about 75 % or less by weight based on the total weight of the solid oral dosage form, more particularly about 50 % or less.
In a preferred embodiment, there is provided a process of making the stable solid oral dosage forms as hereinabove described comprising the steps of i) blending the active agent and pharmaceulically acceptable additives, ii) subjecting the blend to wet granulation to form granules iiJ) drying the granules and iv) compressing the granules to form the solid oral dosage form. The compression of granulate to tablet cores can be carried out in a conventional tabletting machine, eccentric tabletting machine or a rotary compression machine.
The tablets were further coated by using any of the conventional coating techniques, such as pan or perforated pan, well known to the persons skilled in the art. The coating layer comprise of one or more excipients selected from the group comprising coating agents, opacifiers, taste-masking agents, colouring agents, antitacking agents and the like.

Coating agents which are useful in the coating process, include, but are not limited to, polysaccharides such as maltodextrin, alkyl celluloses such as methyl or ethyl cellulose, hydroxyalkylceiluloses (e.g. hydroxypropylcellulose or hydroxypropylmethylcellulose); polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinylpyrrolidone and vinyl acetate (e.g. marketed under the brand name of Plasdone) and polymers based on methacrylic acid such as those marketed under the brand name of Eudragit.
These may be applied in the form of aqueous or non-aqueous systems or combinations of aqueous and non aqueous systems as approphate. Additives can be included along with the film formers to obtain satisfactory films. These additives can include plasticizers such as dibutyl phthalate, triethyl citrate, polyethylene glycol and the like, antitacking agents such as talc, stearic acid, magnesium stearate and colloidal silicon dioxide and the like, surfactants such as polysorbates and sodium lauryl sulphate and opacifying agents such as titanium dioxide and the like. All these excipients can be used at levels well known to the persons skilled in the art.
The invention relates to a pharmaceutical tablet made by wet granulation technique, comprising a therapeutically effective amount of valsartan and pharmaceutically acceptable excipients, wherein the tablet exhibits dissolution profile similar to that of DIOVAN® formulation.
More particularly, the invention covers a pharmaceutical tablet made by wet granulation technique, comprising a therapeutically effective amount of valsartan and pharmaceutically acceptable excipients exhibiting a dissolution profile similar to that of DIOVAN® formulation, wherein the tablet comprises:
a) valsartan in the range of 28% to 50% by weight;
b) binder is povidone;
c) filler in the range of 25% to 55% by weight;
d) disintegrant in the range of 10% to about 15% by weight; and
e) other pharmaceutically acceptable excipients.
In one embodiment, the pharmaceutical tablet uses crospovidone as the disintegrant.

More particularly, the tablet of the present invention comprises a therapeutically effective amount of valsartan and pharmaceutically acceptable excipients, comphsing essentially of valsartan in the range of 28% to 50% by weight, binder solution contains povidone, filler in the range of 25% to 55% by weight, disintegrant in the range of 10% to about 15%, other pharmaceutically acceptable excipients, such that the tablet is bioequivalent to commercially available DIOVAN® formulation.
As regards the dissolution profile, the pharmaceutical tablet exhibits the following dissolution profile for valsartan, when tested in a USP II apparatus (Paddle) at 50 RPM, 1000ml of 0.067 M phosphate buffer pH 6.8 at 37 ± 0,5 °C 94 to 96 % of the valsartan is released within 10 min;
96 to 97 % of the valsartan is released within 15 min;
97 to 99 % of the valsartan is released within 30 min;
98 to 99 % of the valsartan is released within 45 min;
The process for preparation pharmaceutical tablet according to present invention can also be prepared by following process steps:
a) blending valsartan with pharmaceutically acceptable diluent and disintegrant,
b) granulating blend of step [a] using a solution of povidone in water,
c) drying the granules of step [b],
d) blending granules of step [c] with extragranular excipients and lubricants,

d) compressing blend of step [d] to form tablets.
e) optionally coat the tablet with a coating agent.
Although the invention has been described with reference to specific examples, it will be appreciated by those skilled in the art that the invention may be embodied in other forms.
The following examples further exemplify the invention and are not intended to limit the scope of the invention.

EXAMPLES 1

S. No.
2. Ingredients mg/ tab

Valsartan 40.00

Cellulose Microcrystalline Ph.Eur. (RQ 101) 17,50
3, Crospovidone Ph.Eur, 5,00
4. Povidone K30 Ph.Eur. (Kol!idone30) 2,50
5. Purified Water Ph.Eur. qs
6. Cellulose Microcrystalline Ph.Eur, (RQ 102) 7,45 ■
7. Crospovidone Ph.Eur. 6,25
8. Silica, Colloidal Anhydrous Ph.Eur, (Aerosil 200 Pharma) 0.50
9, Magnesium Stearate Ph.Eur. {Magnesium Stearate VG) 0.80
Core Tablet wt (mg) 80
10. Opadry Yellow (03F82657) 2.00
11 Opadry Pink {03F84645) -
12 Opadry Yellow 03F82659 -
13. Purified Water Ph.Eur, qs
Coated Tablet wt (mg) 82

1, Sift Valsartan, Cellulose Microcrystalline RQ (101), and Crospovidone through Quadro Comill fitted with appropriate Screen.
2, Sift Cellulose Microcrystalline (RQ102), Crospovidone and Silica, Colloidal Anhydrous through Quadro Comill fitted with appropriate Screen, Sift Magnesium stearate through Quadro Comill fitted with appropriate Screen Dissolve Povidone in Purified Water with constant stirring to get clear solution. Load material of step 1 into Rapid Mixer Granulator and mix.
Granulate the material of step 5 with binder solution of step 4 in Rapid Mixer Granulator,
Dry the wet mass of step 6 in dryer till LOD is in NMT 3,0% (IR moisture balance at 80 °C)
9
Mill the granules of step 7 through Quadro Comil fitted with appropriate screen. Load the material of step 2 and step 8 into the Blender and blend.
10. Add the material of step 3 into it and blend.
11. Compress the tablet with appropriate tooling using Rotary Compression Machine.
12. Disperse Opadry yellow 03F82659 in purified water with constant stirring to get a homogenous coating suspension.

13. Coat the core tablets of step 11 with coating suspension of Step 12 in automatic coating machine.
EXAMPLES 2:

S. No. Ingredients mg/tab
1. Valsartan USP 40.000
2. Lactose monohydrate USNF ( Pharmatose 200m) 31.250
3. Microcrystalline Cellulose USNF (Avicel PHI01) 29.900
4. Crospovidone USNF {Polyplasdone XL) (Part -1) 7.750
5. Colloidal silicon dioxide USNF {Aerosi! 200 ) {Part -1) 0,675
6. Povidone K30 USNF (Kollidone30) 1.350
7. Purified Water USP q,s.
8, 9. Microcrystalline Cellulose USNF (Avicel PH102) 10.400

Crospovidone USNF (Polyplasdone XL) (Part -2) 11.250
10,^ Colloidal silicon dioxide USNF (Aerosil 200 ) (Part -2) 0.675
11. Magnesium Stearate USNF{Magnesium Stearate VG) 1.750
Core Tablet weight (mg) 135.000
12. Opadry Yellow (03F82657) 3.375
13. Purified Water USP " q.s
Coated Tablet weight (mg) 138.375
Brief IVIanufacturing Process:
1, Sift Valsartan, Lactose monohydrate, part of Microcrystalline Cellulose (Avicel PHI01)
and Crospovidone (Part -1) through Quadro Comill fitted with appropriate Screen.
2. Sift Colloidal silicon dioxide (Part-1) and remaining quantity of Microcrystalline
Cellulose (Avicel PH101) through Quadro Comil fitted with appropriate Screen.
3, Sift Microcrystalline Cellulose (Avicel PH102) through Quadro Comil fitted with appropriate Screen,
4, Sift colloidal silicon dioxide (Part-2) and Crospovidone (Part -2) through Quadro Comil fitted with appropriate Screen,
5, Sift Magnesium stearate through Quadro Comil fitted with appropriate Screen.

6. Dissolve Povidone in Purified Water with constant stirring to get clear solution.
7. Load material of step 1 and step 2 into Rapid Mixer Granulator and mix.
8. Granulate the material of step 7 with binder solution of step 6 in Rapid Mixer Granulator.

9. Dry the wet mass of step 8 in dryer till LOD is NMT 3.0% w/w (IR moisture balance at 80 °C)
10. Mill the granules of step 9 through Quadro Comil fitted with appropriate screen.
11. Load the matehal of step 3, step 4 and step 10 into the Blender and blend.
12. Add the material of step 5 into it and blend.
13. Compress the tablet with appropnate tooling using Rotary Compression Machine,
14. Disperse Opadry Yellow 03F82657 in purified, water with constant stirring to get a homogenous coating suspension.
15. Coat the core tablets of step 13 with coating suspension of Step 14 in automatic coating machine.
EXAMPLES 3:

S. No. Ingredient mg/tab
1. Valsartan 40.00
2, Lactose monohydrate 23.75
3. Microcrystalline cellulose 45.00
4. Crospovidone 20.00
5. Polyvinyl pyrrolidone 4,00
6. Colloidal Silicon Dioxide 0,50
7. Magnesium stearate 1,75
8. Purified water Q,S
Core Tablet wt (mg) 135
9, Opadry 3,375
10 Purified water ■ qs
Coated T "ablet wt(mg) 138.375
Brief manufacturing procedure:
1. Sift ingredient no, 1, 2, 3 (part quantity) & 4 (part quantity) and blend,
2. Dissolve Povidone in purified water with continuous stirring.
3. Granulate the blend of step 1 with binder solution of step 2,
4. Dry the wet granules of step 3.
5. Sift the dried granules of step 4
6. Sift the ingredient no, 3 (remaining quantity), 4 (remaining quantity), 6 & 7,
7. Blend the materials of step 5 & 6,
8. Compress the blend of step 7 into tablets,
9. Disperse ingredient no, 9 in water with continuous stirring
10. Coat the core tablets of step 8 with the coating dispersion of step 9
12

EXAMPLES 4:

S. No. Ingredient mg/tab
1. Valsartan 160.00
2, Cellulose Microcrystalline 70.00
3. Crospovidone 20,00
4. Povidone K30 10.00
5. Punfied Water q.s
6, Cellulose Microcrystalline 29.80
7, Crospovidone 25.00
8. Silica, Colloidal Anhydrous 2.00
Magnesium Stearate 3.20
Core Tablet wt (mg) 320.00
9. Opadry Yellow (03F82657) —
10 Opadry Pink (03F84645) ~
Opadry Yellow 03F82659' 8.00
Purified Water qs
Coated 1 fablet wt (mg) 328.00
1. Sift Valsartan, Cellulose Microcrystalline RQ (101), and Crospovidone throug Quadro Comill fitted with appropriate Screen.
2. Sift Cellulose Microcrystalline (RQ.102), Crospovidone and Silica, Colloids Anhydrous through Quadro Comill fitted with appropriate Screen.
3. Sift Magnesium stearate through Quadro Comill fitted with appropriate Screen
4. Dissolve Povidone in Purified Water with constant stirring to get clear solution.
5. Load material of step 1 into Rapid Mixer Granulator and mix.
6. Granulate the material of step 5 with binder solution of step 4 in Rapid Mixe Granulator.
7. Dry the wet mass of step 6 in dryer till LOD is in NMT 3.0% (IR moisture balancf at 80 °C)
8. Mill the granules of step 7 through Quadro Comil fitted with appropriate screen.
9. Load the material of step 2 and step 8 into the Blender and blend.
10. Add the material of step 3 into it and blend.
11. Compress the tablet with appropriate tooling using Rotary Compression Machine.
12. Disperse Opadry yellow 03F82659 in purified water with constant stirring to get ; homogenous coating suspension.

1J. uoal the core tablets of step 11 with coating suspension of Step 12 in automatic coating machine.
EXAMPLES 5:

S. No. Ingredient mg/tab
1. Valsartan 320,00
2, Lactose monohydrate 250.00
3. Microcrystaliine Cellulose 239.20
4, Crospovidone 62.00
5. Colloidal silicon dioxide 5.40
6. Povidone K30 10.80
7. Purified Water q.s
8. Microcrystaliine Cellulose 83,20
9. Crospovidone 90,00
10. Colloidal silicon dioxide 5.40
11. Magnesium Stearate 14.00
Core Tablet wt (mg) 1080.00
12. Opadry Brown (03F86922) 27.00
13. Purified Water q.s
Coated 1 'ablet wt (mg) 1107.00
1. Sift Valsartan, Cellulose Microcrystaliine RQ (101), and Crospovidone through Quadro Comill fitted with appropriate Screen.
2. Sift Cellulose Microcrystaliine (RQ102), lactose, Crospovidone and Silica, Colloidal Anhydrous through Quadro Comill fitted with appropriate Screen.
3. Sift Magnesium stearate through Quadro Comill fitted with appropriate Screen
4. Dissolve Povidone in Purified Water with constant stirhng to get clear solution.
5. Load material of step 1 into Rapid Mixer Granulator and mix.
6. Granulate the material of step 5 with binder solution of step 4 in Rapid Mixer Granulator.
7. Dry the wet mass of step 6 in dryer till LOD is in NMT 3,0% (IR moisture balance at 80 X)
8. Mill the granules of step 7 through Quadro Comil fitted with appropriate screen.
9. Load the material of step 2 and step 8 into the Blender and blend.
10- Add the material of step 3 into it and blend.
11. Compress the tablet with appropriate tooling using Rotary Compression Machine,
14

12. Disperse Opadry yellow 03F82659 in purified water with constant stirring to get a homogenous coating suspension.
13. Coat the core tablets of step 11 with coating suspension of Step 12 in automatic coating machine.
EXAMPLES 6:

S. No. Ingredient mg/tab
1. Valsartan 320.0
2. Lactose monohydrate 190.0
3. Microcrystalline cellulose 240.0
4. Crospovidone 80.0
5. Polyvinyl pyrrolidone 32.0
6. Purified water Qs.
7. Microcrystalline cellulose 120.0
8. Crospovidone 80.0
9. Coiloidal Silicon Dioxide 4.0
Magnesium stearate 14.0
Core Tablet wt (mg) 1080.00
9. Opadry yellow(03F82659) 27,00
10 Purified water qs ..
Coated 1 'ablet wt (mg) 1107.00
1. Sift Valsartan, Cellulose Microcrystalline RQ (101), and Crospovidone through Quadro Comill fitted with appropriate Screen.
2. Sift Cellulose Microcrystalline (RQ102), lactose, Crospovidone and Silica, Coiloidal Anhydrous through Quadro Comill fitted with appropriate Screen.
3. Sift Magnesium stearate through Quadro Comill fitted with appropriate Screen
4. Dissolve Povidone in Purified Water with constant stirhng to get clear solution.
5. Load material of step 1 into Rapid Mixer Granulator and mix.
6. Granulate the material of step 5 with binder solution of step 4 in Rapid Mixer Granulator.
7. Dry the wet mass of step 6 in dryer till LOD is in NMT 3.0% (IR moisture balance at 80 °C)
8. Mill the granules of step 7 through Quadro Comil fitted with appropriate screen.
9. Load the material of step 2 and step 8 into the Blender and blend.
10- Add the material of step 3 into it and blend.

11. Compress the tablet with appropriate tooling using Rotary Compression Machine.
12. Disperse Opadry yellow 03F82659 in purified water with constant stirring to get a homogenous coating suspension.
13. Coat the core tablets of step 11 with coating suspension of Step 12 in automatic coating machine.
Dissolution Study: The dissolution test is done using USP II apparatus (Paddle) at 50 RPM, 1000ml of 0.067 M phosphate buffer pH 6.8 at 37 ± 0.5 X.

Table 1: Results of the dissolution study of Example 4, 5 and 6 with DIOVAN

®

Time (mins) Cumulative % Valsartan Dissolved

Example 4 Example 5 Example 6 DIOVAN® Product
Strength Valsartan tablet 160 mg Valsartan tablet 320 mg Valsartan tablet 320 mg Valsartan tablet 320 mg
10 99 98 96 96
15 101 99 97 96
20 101 99 98 98
30 102 100 99 98
45 102 100 99 99
Bioequivalence Study:
Open label, randomized, two period, two-treatment, two sequence, crossover, balanced, single dose, comparative oral bioavailability study in healthy volunteers receiving single dose of valsartan in fasted and fed state using immediate release tablets comprising 320mg valsartan, as test and DIOVAN as reference standard. Study was monitored in terms of the pharmacokinetic parameters C^ax and AUG. The results of the bioequivalence study are given in table 2.
Table 2: Results of the bio-equivalence study

Fasting state
(n=34) Fed state
(n=47)
AUCo_, (|jg hr/ml) AUCo.-. (pg hr/ml) Cmax
(pg/ml) AUCo_, (pg hr/ml) AUCo.«.
{pg hr/ml) Cmax
(pg /ml)
110.83 110.16 108.99 105.26 105,01 107.46

Claims:
1. An oral pharmaceutical composition prepared by wet granulation comprising 1) valsartan
or a pharmaceuticaiiy acceptable salt thereof, 2) povidone, 3) lactose and/ or microcrystalline
cellulose, 4) crospovidone and pharmaceuticaiiy acceptable additives,
wherein the weight ratio of valsartan : crospovidone : lactose and/ or microcrystalline
cellulose is approximately from 1.0: 0.25: 0,35' to 1.0: 0.50: 2.0
and wherein said composition is prepared by granulating valsartan, crospovidone and lactose
and/ or microcrystalline cellulose in an aqueous povidone solution, to obtain an intra-granular
portion of a granulate, and converting said granulate to said oral pharmaceutical dosage
form.
2. A pharmaceutical composition according to claim 1, wherein the weight ratio of valsartan:
crospovidone: lactose and/ or microcrystalline cellulose is 1: 0.475: 1.788.
3- A pharmaceutical composition according to claim 1, wherein said crospovidone is present in an amount from about 10% to about 18% w/w based on the total weight of said composition,
4. A pharmaceutical composition according to claim 1, wherein said lactose and/ or microcrystalline cellulose is present in an amount from about 25% to about 55% w/w based on the total weight of said composition.
5. A pharmaceutical composition according to claim 1, optionally containing an effective amount of HCTZ-
6. A pharmaceutical composition according to claim 1, wherein the percentage of valsartan released form said dosage during in-vitro dissolution is comparable to that of valsartan marketed under the trade name of DIOVAN.
7. The pharmaceutical tablet according to claim 6 that exhibits the following dissolution profile for valsartan, when tested in a USP Type II apparatus at 50 rpm and 37° C, in a 0.067 M phosphate buffer pH 6.8
94 to 96 % of the valsartan is released within 10 min;

96 to 97 % of the valsartan is released within 15 min;
97 to 99 % of the valsartan is released within 30 min;
98 to 99 % of the valsartan is released within 45 min;
8. An oral, compressed pharmaceutical composition comprising of valsartan, which is
bioequivalent to a tablet dosage form of valsartan marketed under the trade name of
DIOVAN, which is prepared by wet granulation technique and wherein said composition
exhibits:
a mean Cmax at 108.99 \jg /ml;
a mean AUCo-i at110.83 pg hr/ml; and
a mean AUCo-«at110,16 pg hr/ml.
10. A process for preparing an oral pharmaceutical composition of valsartan comphsing following steps:
a) wet granuiating.valsartan, crospovidone and lactose and/ or microcrystalline cellulose,
using aqueous povidone solution to obtain an intra-granular portion of a granulate;
b) milling said granulate;
c) mixing said granulate with microcrystalline cellulose, crospovidone and colloidal silicon
dioxide;
d) optionally adding magnesium stearate to obtain a final blend; and
e) compressing said final blend to obtain tablets.
f) optionally film coating said tablets.