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
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 pharmaceutical^ acceptable salts thereof wherein the said composition can be prepared by dry granulation method, when particle size of losartan is less than about 30pm and by direct compression method when particle size of losartan is between 30 and 100pm.
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 pharmaceutical^ acceptable salts thereof wherein the said composition can be prepared by dry granulation method, when particle size of losartan is less than about 30pm and by direct compression method when particle size of losartan is between 30 and 100pm.
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.

FORMULA I
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).
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European Patent EP511767 (A1) describes direct compression tablet formulation of Losartan.
U.S. Patent Application No 2006004207 relates to crystalline and amorphous alkali and earth-alkali salts of Losartan, their preparation, purification and isolation procedure. Also describes pharmaceutical compositions containing crystalline potassium salts of Losartan.
U.S. Patent Application No 20050142190 describes preparation of solid pharmaceutical compositions comprising a mixture of an amorphous active pharmaceutical ingredient (Losartan) and at least one pharmaceutical^ acceptable inactive ingredient.
U.S. Patent Application No 2006241305 relates to an amorphous form of Losartan potassium, processes for preparing amorphous Losartan potassium and pharmaceutical compositions that include the amorphous Losartan potassium.
U.S. Patent Application No 20060210620 relates to spray dried, co-precipitated amorphous losartan dosage forms and processes for their preparation.
International (PCT) Publication WO2007026261 describes formulations and dosage units containing losartan and/or its salts and a process for making the same.
The present inventors while working on the Losartan formulation have noticed that the particle size of losartan and method of formulation i.e. dry granulation, or direct compression, plays an important role in formulating the dosage form. It was found that when the particle size of losartan is less than about 30pm and the losartan tablets are formulated by direct compression method, it resulted in sticking problem during compression and also poor flow property. The above problem was solved in two ways. First was to use a dry granulation or compaction method to formulate tablet dosage form instead of direct
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compression method and second was to use losartan particles having particle size between 30 and 100pm. Hence it was noticed that when particle size of losartan is less than about 30pm, tablets can be formulated by dry granulation or compaction method and when particle size of losartan is between 30 and 100pm, tablets can be formulated by direct compression method.
In one of the aspects of present invention there is provided a pharmaceutical composition of losartan or pharmaceutical^ acceptable salts thereof comprising losartan particles, wherein atleast 90% of the losartan particles have particle size between 30 and 100pm and the said composition is prepared by direct compression method.
The composition of the present invention comprises Losartan as an active ingredient and is present in the form of potassium salt.
In the composition of the present invention the particle size can be determined by methods like e.g., Malvern, Hiac/Royko Model 9064 sizing counter, Coulter Counter sizing counter, optical microscopy, scanning electron microscopy, and by conventional methods known to those of skill in the art.
Another aspect of the present invention provides a method for preparing pharmaceutical composition comprising Losartan or pharmaceutically acceptable salts thereof wherein the said method comprises the steps of:
a) blending losartan particles and one or more pharmaceutically acceptable excipients wherein atleast 90% of the losartan particles have particle size between 30 and 100pm,
b) optionally compressing the blend of step a) into solid oral dosage form.
In the composition of the present invention blending of losartan particles and one or more pharmaceutically acceptable excipients can be done by methods known to ordinary skilled in the art.
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The solid oral dosage form of the present invention include but not limited to one or more of tablet, capsule, powder, sachet, pills, granule and the like and is meant for oral administration.
Another aspect of the present invention provides a pharmaceutical composition of losartan or pharmaceutically acceptable salts thereof comprising Losartan particles, wherein atleast about 90% of the losartan particles have particle size less than about 30um and the said composition is prepared by dry granulation or compaction method.
As used herein, "about" means plus or minus approximately ten percent of the indicated value, such that "about 30 microns" indicates approximately 27 to 33 microns, "about 90%" indicates approximately 81% to 99%
Another aspect of the present invention provides a method for preparing pharmaceutical composition comprising Losartan or pharmaceutically acceptable salts thereof wherein the said method comprises the step of:
a) compacting Losartan particles and one or more pharmaceutically acceptable excipients wherein atleast about 90% of the losartan particles have particle size less than about 30pm
b) converting compacts of step a) into granules
c) optionally blending the granules of step b) with pharmaceutically acceptable excipients.
In the composition of the present invention compaction of losartan particles and one or more pharmaceutically acceptable excipients can be done by methods known to ordinary skilled in the art like roll compacter.
In the composition of the present invention compacts of losartan particles can be converted to granules by methods known to ordinary skilled in the art.
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The composition of the present invention exhibits a dissolution profile such that within 30 minutes more than 75% of losartan is released, wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 900 ml of deaerated water at 37°C ± 0.5°C. The said composition exhibits similar dissolution profile as that of Cozaar® tablet (commercially available Losartan potassium tablets).
The pharmaceutically acceptable excipients comprise one or more 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 one or more of cellulose ethers include one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose and other suitable cellulose ethers or from polymethacrylates and copolymers thereof with methacrylic 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.
The pharmaceutical composition of the present invention can be prepared by dry granulation or direct compression method. The dry granulation method involves the step of compacting losartan particles and one or more pharmaceutically acceptable excipients wherein atleast about 90% of the losartan particles have particle size less than about 30pm using roll compacter. Converting the compacts into granules followed by blending it with pharmaceutically acceptable excipients and optionally compressing it to form a tablet. The direct compression method involves the step of blending losartan particles and one or more pharmaceutically acceptable excipients wherein atleast about 90% of the losartan particles have
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particle size between 30 and 100pm. The blend can be optionally lubricated and filled into capsule or compressed to form a tablet. The obtained tablets can be optionally coated with aqueous dispersion of Opadry.
Figure 1 is a graph of comparative study of the dissolution profile of a composition according to the invention i.e. Losartan tablets 100 mg (Example 3 and Example 6) compared to that of commercially available Cozaar® tablet 100 mg strength.
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.
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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 q.s q.s q.s
* D(0.9) = 12pm, D (o.5) = 5.1pm and D (0.1) = 1pm.
Procedure: The pharmaceutical 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.
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Examples 4-6
Table 2: Composition of Losartan potassium tablets

No. Ingredients Quantity / Tablet (mg)
Example 4 Example 5 Example 6
1 Losartan Potassium* 25.0 50.0 100.0
2 Microcrystalline Cellulose. 19.375 38.75 77.5
3 Anhydrous Lactose 12.5 25.0 50.0
4 Pregelatinized Starch 12.5 25 50
5 Low substituted Hydroxypropyl Cellulose 5 10 20
6 Magnesium Stearate 0.625 1.25 2.5
7 Opadry q.s q.s q.s
* D (o.9) = 52um, D (0.5) = 15pm and D (0.1) = 3pm
Procedure: The pharmaceutical compositions mentioned in examples 4, 5 and 6 are prepared by direct compression method. Losartan, Microcrystalline Cellulose, Anhydrous Lactose, Pregelatinized Starch, Low substituted Hydroxypropyl Cellulose are blended and the 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 3: Drug release data of Losartan tablets 100 mg (Example 3 and Example 6) and Cozaar® tablet 100 mg strength.

Time (min) % Drug released (Example 3) % Drug released % Drug released (Example 6) (Cozaar® tablet)
0 0 0 0
10 31 31 39
20 63 65 70
30 85 88 88
45 95 100 97
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 of losartan or pharmaceutically acceptable salts thereof comprising losartan particles, wherein atleast 90% of the losartan particles have particle size between 30 and 100um and the said composition is prepared by direct compression method.
2. A method for preparing pharmaceutical composition comprising Losartan or pharmaceutically acceptable salts thereof wherein the said method comprises the steps of:

a) blending losartan particles and one or more pharmaceutically acceptable excipients wherein atleast 90% of the losartan particles have particle size between 30 and 100pm
b) optionally compressing the blend of step a) into solid oral dosage form.

3. A pharmaceutical composition of losartan or pharmaceutically acceptable salts thereof comprising Losartan particles, wherein atleast about 90% of the losartan particles have particle size less than about 30pm and the said composition is prepared by dry granulation or compaction method.
4. A method for preparing pharmaceutical composition comprising Losartan or pharmaceutically acceptable salts thereof wherein the said method comprises the step of:

a) compacting Losartan particles and one or more pharmaceutically acceptable excipients wherein atleast about 90% of the losartan particles have particle size less than about 30pm
b) converting compacts of step a) into granules
c) optionally blending the granules of step b) with pharmaceutically acceptable excipients.
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5. A method of claim 2 and 4 wherein pharmaceutically acceptable excipients comprise of one or more of diluents, lubricants, disintegrants, film forming agents, coloring agents.
6. A pharmaceutical composition of claim 1 and 3 wherein the composition exhibits a dissolution profile such that within 30 minutes more than 75% of losartan is released, wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 900 ml of deaerated water at 37 °C ± 0.5°C.
7. A pharmaceutical composition of claim 1 and 3 comprises one or more of a tablet, capsules, powder, disc, caplet, granules, pellets, sachets.
Dated this 27 TH day of April, 2007
For Wockhardt Limited

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