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 AND HYDROCHLOROTHIAZIDE
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 pharmaceutically acceptable salts thereof and hydrochlorothiazide 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.
1

4. DESCRIPTION
The present invention provides a pharmaceutical composition comprising losartan or pharmaceutically acceptable salts thereof and hydrochlorothiazide 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.

Hydrochlorothiazide belongs to the thiazide class of diuretics. Chemically hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide (Formula II). Its empirical formula is C7H8CIN3O4S2 . Hydrochlorothiazide is commercially available in combination with losartan under the trade name of Hyzaar®. Hyzaar® tablets are indicated for the treatment of Hypertension.
2

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).
International (PCT) Publication WO9409778 describes pharmaceutical composition comprising about 0.1-1000 mg of an Angiotensin-ll antagonist and an effective non-pharmacological dose of a diuretic.
The present inventors while working on the combination formulation of Losartan and hydrochlorothiazide 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 in losartan and hydrochlorothiazide tablets is less than about 30pm, and tablet is 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 compression method and second was to use losartan particles having particle size between 30 and 100mm. Hence it was noticed that when particle size of losartan is less than about 30mm, tablets can be formulated by dry granulation or compaction method and when particle size of losartan is between 30 and 100mm, tablets can be formulated by direct compression method.
3

In one of the aspects of the present invention there is provided a pharmaceutical composition of losartan or pharmaceutically acceptable salts thereof and hydrochlorothiazide comprising losartan particles, wherein atleast 90% of the losartan particles have particle size between 30 and 100mm and the said composition is prepared by direct compression method.
The composition of the present invention comprises Losartan and Hydrochlorothiazide as an active ingredients and Losartan 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 and Hydrochlorothiazide wherein the said method comprises the steps of:
a) blending losartan particles, hydrochlorothiazide and optionally 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, hydrochlorothiazide and one or more pharmaceutically acceptable excipients can be done by methods known to ordinary skilled in the art.
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.
4

Another aspect of the present invention provides a pharmaceutical composition of losartan or pharmaceutically acceptable salts thereof and hydrochlorothiazide 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.
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 and hydrochlorothiazide wherein the said method comprises the step of:
a) compacting Losartan particles, hydrochlorothiazide and optionally 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, hydrochlorothiazide and optionally 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.
The pharmaceutically acceptable excipients comprise one or more of diluents, lubricants, disintegrants, film forming agents, coloring agents and the like.
5

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, hydrochlorothiazide 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, hydrochlorothiazide and one or more pharmaceutically acceptable excipients wherein atleast about 90% of the losartan particles have 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.
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.
6

Examples 1-2
Table 1: Composition of Losartan potassium and Hydrochlorothiazide tablets.

No. Ingredients Quantity / Tablet (mg)
Example 1 Example 2
Intragranular Phase
1 Losartan Potassium* 50.0 100.0
2 Hydrochlorothiazide 12.5 25.0
3 Micro Crystalline Cellulose 124.5 249.0
4 Anhydrous Lactose 80.0 160.0
5 Pregelatinized Starch 6.0 12.0
6 Magnesium Stearate 1.0 2.0
Extragranular Phase
7 Pregelatinized Starch 14,0 28.0
8 Magnesium Stearate 2.0 4.0
9 Opadry q.s. q.s.
*D(o. 9) = 12mm, D(o.5) = 5.1mm and D(o.i) = 1mm.
Procedure: The pharmaceutical compositions mentioned in examples 1 and 2 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 ingredient comprising pregelatinized starch. 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.
7

Examples 3 - 4
Table 2: Composition of Losartan potassium and Hydrochlorothiazide tablets

No. Ingredients Quantity / Tablet (mg)
Example 3 Example 4
1 Losartan Potassium* 50.0 100.0
2 Hydrochlorothiazide 12.5 25.0
3 Micro Crystalline Cellulose 124.5 249.0
4 Anhydrous Lactose 80.0 160.0
5 Pregelatinized Starch 20.0 40.0
6 Magnesium Stearate 3.0 6.0
7 Opadry q.s. q.s.
*D(0. 9) = 52mm, D(o.5) = 15mm and C )(o.i) = 3mm
Procedure: The pharmaceutical compositions mentioned in examples 3 and 4 are prepared by direct compression method. Losartan, Hydrochlorothiazide, Microcrystalline Cellulose, Anhydrous Lactose, Pregelatinized Starch are blended together in suitable blender 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.
8

WE CLAIM:
1. A pharmaceutical composition of losartan or pharmaceutically acceptable salts thereof and hydrochlorothiazide comprising losartan particles, wherein atleast 90% of the losartan particles have particle size between 30 and 100mm and the said composition is prepared by direct compression method.
2. A method for preparing pharmaceutical composition comprising Losartan or pharmaceutically acceptable salts thereof and Hydrochlorothiazide wherein the said method comprises the steps of:

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

3. A pharmaceutical composition of losartan or pharmaceutically acceptable salts thereof and hydrochlorothiazide 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 and Hydrochlorothiazide wherein the said method comprises the step of:
a) compacting Losartan particles, hydrochlorothiazide and optionally one or more pharmaceutically acceptable excipients wherein atleast about 90% of the losartan particles have particle size less than about 30pm
9

b) converting compacts of step a) into granules
c) optionally blending the granules of step b) with pharmaceutically acceptable excipients.

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 is meant for oral administration.
7. A pharmaceutical composition of claim 1 and 3 comprises one or more of a tablet, capsules, powder, disc, caplet, granules, pellets, sachets.

10