FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
PHARMACEUTICAL COMPOSITION COMPRISING LOSARTAN OR SALTS THEREOF AND METHOD OF PREPARING THE SAME
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a pharmaceutical composition comprising Losartan or salts thereof in admixture with pharmaceutically acceptable excipients and a method for the preparation of said composition wherein the composition is prepared by dry granulation method.
The following specification particularly describes the invention and the manner
in which it is to be performed.
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4. DESCRIPTION
The present invention provides a pharmaceutical composition comprising Losartan or salts thereof in admixture with pharmaceutically acceptable excipients and a method for the preparation of said composition wherein the composition is prepared by dry granulation method.
Losartan, an angiotensin II receptor (type AT1) antagonist is a non-peptide molecule. It is commercially available as potassium salt under the trade name of Cozaar®. Chemically Losartan is 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt (Formula I). It is indicated for the treatment of hypertension, hypertensive patients with left ventricular hypertrophy and nephropathy in type 2 diabetic patients.

US Patent Nos. 5,138,069 and 5,153,197 relates to substituted imidazoles useful as angiotensin II blockers. Also discloses processes for their preparation, pharmaceutical compositions containing substituted imidazoles and pharmaceutical methods using them, alone and in conjunction with other drugs, especially diuretics and non-steroidal anti-inflammatory drugs (NSAID's).
European Patent EP511767 (A1) discloses direct compression tablet formulation of Losartan.
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US Patent Application 2006004207 relates to crystalline and amorphous alkali and earth-alkali salts of Losartan, their preparation, purification and isolation procedure. Also discloses pharmaceutical compositions containing crystalline potassium salts of Losartan.
U.S Patent Application 20050142190 discloses a preparation of solid pharmaceutical compositions comprising a mixture of an amorphous active pharmaceutical ingredient (Losartan) and at least one pharmaceutical^ acceptable inactive ingredient.
PCT Application WO2004076442 relates to polymorphic forms of Losartan potassium, processes for producing them. It also relates to the preparation of two polymorphic forms of Losartan potassium, referred to as 'Form A' and 'Form B' and pharmaceutical compositions that include the 'Form A' and 'Form B'.
PCT Application WO2004039352 relates to an amorphous form of Losartan potassium, processes for preparing amorphous Losartan potassium and pharmaceutical compositions that include the amorphous Losartan potassium.
PCT Application WO2004064834 relates to spray dried, co-precipitate amorphous Losartan dosage forms and processes for their preparation.
However, there remains a need for new processes in preparing stable pharmaceutical composition of Losartan that provides ease of manufacturing, cost effectiveness and a stable formulation. The present inventors while working on Losartan oral pharmaceutical composition have surprisingly found a method for the preparation of pharmaceutical composition of Losartan or salt thereof wherein the composition can be prepared by dry granulation method and the said method provides
• Ease of manufacturing
• Reduced manufacturing time
• A stable formulation
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• A formulation that exhibits a dissolution profile such that after 30 minutes 75% or more of Losartan is released and exhibits similar dissolution profile as that of Cozaar® tablet (commercially available Losartan potassium tablets).
In one of the aspects of present invention there is provided a pharmaceutical composition comprising Losartan or pharmaceutically acceptable salts thereof in admixture with pharmaceutically acceptable excipients wherein the said composition is prepared by dry granulation method.
In yet another aspect of the present invention there is provided a method for preparing pharmaceutical composition comprising Losartan or pharmaceutically acceptable salts thereof wherein the said method comprises the step of
a) compacting the blend comprising Losartan or pharmaceutically acceptable salts alongwith pharmaceutically acceptable excipients
b) converting compacts of step a) into granules
c) blending the granules of step b) with pharmaceutically acceptable excipients
The pharmaceutical composition comprises of Losartan as an active ingredient and is present in the form of potassium salt. The pharmaceutical composition can be prepared by dry granulation method. The pharmaceutical composition comprises of two phases one is intragranular phase and other is extragranular phase. The intragranular phase comprises of Losartan potassium, microcrystalline cellulose, anhydrous lactose, pregelatinized starch, L-HPC and magnesium stearate. The intragranular ingredients are compacted using Roll compactor to form flakes and then flakes are sized using suitable apparatus to get granules of desired size. The obtained granules are blended with extragranular phase comprising pregelatinized starch, L-HPC and magnesium
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stearate. The obtained blend is compressed to form a tablet using a suitable tooling and the tablets can be optionally coated with aqueous dispersion of Opadry.
The tablets obtained by the above process exhibits a dissolution profile such that after 30 minutes 75% or more of Losartan is released in 900 ml of deaerated water at 50 rpm. The said tablet also exhibits similar dissolution profile as that of Cozaar® tablet (commercially available Losartan potassium tablets).
The pharmaceutical composition can be granule, powder, sachet, capsule or compressed to form tablets. The pharmaceutical composition is meant for oral administration.
The pharmaceutically acceptable excipients can be selected from the group of diluents, lubricants, disintegrants, film forming agents, coloring agents and the like.
Suitable diluents can be one or more of microcrystalline cellulose, mannitol, starch, lactose and pre-gelatinized starch. Suitable lubricants can be one or more of talc, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate. Suitable disintegrants can be one or more of starch, pregelatinized starch, L-HPC, croscarmellose sodium, crospovidone, sodium starch glycolate and the like. Suitable film forming agents can be selected from the group of cellulose ethers include one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose and other suitable cellulose ethers or from poly (meth)acrylates and copolymers thereof with (meth)acrylic acid. Suitable coloring agents include those that are approved for use by United States Food and Drug Administration (FDA) and are well known to those skilled in the art.
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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.
Examples 1-3
Table 1: Composition of Losartan potassium tablets

No. Ingredients Quantity / Tablet (mg)
Example 1 Example 2 Example 3
Intragranular Phase
1 Losartan Potassium 25.0 50.0 100.0
2 Micro Crystalline Cellulose 19.375 38.75 77.5
3 Anhydrous Lactose 12.5 25.0 50.0
4 Pregelatinized Starch 6.25 12.5 25.0
5 Low substituted Hydroxypropyl Cellulose 2.5 5.0 10.0
6 Magnesium Stearate 0.25 0.5 1.0
Extragranular Phase
7 Pregelatinized Starch 6.25 12.5 25.0
8 Low substituted Hydroxypropyl Cellulose 2.5 5.0 10.0
9 Magnesium Stearate 0.375 0.75 1.5
Average weight of Core Tablet 75.0 150.0 300.0
10 Opadry coating q.s q.s q.s
Average weight of Coated Tablet 77.5 155.0 310.0
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Procedure: The pharmaceutical analgesic compositions mentioned in examples 1 2 and 3 comprise of Intragranular phase and Extragranular phase. The intragranular ingredients without magnesium stearate are sifted using suitable sifter and then blended using suitable blender. The obtained blend is lubricated with presifted magnesium stearate and then compacted using Roll compactor to form flakes. The flakes are then sized using suitable apparatus to get granules of desired size. The obtained granules are blended with presifted extragranular ingredients comprising pregelatinized starch and L-HPC. The granule blend is lubricated with magnesium stearate. The obtained blend is compressed to form a tablet using a suitable tooling and the tablets are optionally coated with aqueous dispersion of Opadry.
Table 2: Drug release data of Losartan tablets 100 mg (Example 3) and Cozaar® tablet 100 mg.
Time (min) Cozaar® tablet % Drug released Example 3 % Drug released
0 0 0
10 33.0 27.0
20 64.0 62.0
30 77.0 79.0
45 99.0 96.0

For determination of drug release, USP Type 2 Apparatus, 50 rpm is used wherein 900ml of deaerated water is used as a medium.
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WE CLAIM:
1. A pharmaceutical composition comprising Losartan or pharmaceutical^ acceptable salts thereof in admixture with pharmaceutically acceptable excipients wherein the said composition is prepared by dry granulation method.
2. A method for preparing pharmaceutical composition comprising Losartan or pharmaceutically acceptable salts thereof wherein the said method comprises the step of
a) compacting the blend comprising Losartan or pharmaceutically acceptable salts alongwith pharmaceutically acceptable excipients
b) converting compacts of step a) into granules
c) blending the granules of step b) with pharmaceutically acceptable excipients.
3. As per claim land 2, Losartan is present in the form of potassium salt.
4. As per claim 1 and 2, the said composition exhibits a dissolution profile similar to Cozaar® tablet in 900 ml of deaerated water at 50 rpm.
5. As per claim 1 and 2, the said composition exhibits a dissolution profile such that after 30 minutes 75% or more of Losartan is released in 900 ml of deaerated water at 50 rpm.
6. As per claim 1 and 2, wherein pharmaceutically acceptable excipients is selected from a group comprising of one or more of diluent, lubricant, disintegrant, film forming agent, coloring agent.
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7. As per claim 1 and 2, the said composition is meant for oral administration
8. As per claim 1 and 2, the said composition is powder, granule, sachet, capsule, tablet