FORM 2
THE PATENT ACT 1970
(39 of 1970) &The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
PHARMACEUTICAL COMPOSITIONS COMPRISING SOLID DISPERSION
OF IRBESARTAN OR SALT 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 comprisingirbesartan or salts thereof in solid dispersion with one or morepharmaceutically acceptable dispersing agents optionally along with otherpharmaceutically acceptable excipients.
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 irbesartan or salts thereof in solid dispersion with one or more pharmaceutically acceptable dispersing agents optionally along with other pharmaceutically acceptable excipients.
Irbesartan is an angiotensin II receptor (AT1 subtype) antagonist. Irbesartan is a non-peptide compound. Its empirical formula is C25H28N6O. Irbesartan is a white to off-white crystalline powder with a molecular weight of 428.5. It is a nonpolar compound with a partition coefficient (octanol/water) of 10.1 at pH of 7.4. Irbesartan is slightly soluble in alcohol and methylene chloride and practically insoluble in water. Its structural formula is:

Irbesartan, which is chemically 2-n-butyl-4-spirocyclopentane-1-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]- 2-imidazolin-5-one, is a potent, long-acting angiotensin II receptor antagonist which is particularly useful in the treatment of cardiovascular ailments such as hypertension and heart failure.
Irbesartan is a fluffy material with relatively low bulk and tap densities. These properties make it difficult to formulate it into tablet dosage form with desirable tablet properties. In addition, irbesartan also has certain undesirable flow characteristics i.e. sticky and adheres to surfaces of tablet punches and dies causing problems in tabletting.
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Irbesartan being hydrophobic poses problem of low aqueous solubility, which also presents a challenge in disintegration and complete drug release.
US Patent No. 5,270,317 discloses irbesartan or salts thereof, process of making irbesartan or salts thereof and its pharmaceutical compositions.
US Patent No. 6,342,247 and International Publication No. WO2006013545 discloses pharmaceutical compositions containing irbesartan, alone or in combination with a diuretic with a high relative amount of irbesartan.
US Patent No. 6,800,761 discloses a crystalline form of irbesartan having a specific crystal habit, pharmaceutical compositions containing it, processes for preparing it, and method for treating cardiovascular diseases utilizing it.
US Application No. 20050271720 disclose pharmaceutical compositions containing irbesartan with a high relative amount or concentration of irbesartan.
International Publication No. WO2006050923 discloses a form of irbesartan with specific chargeability, process of preparing it and pharmaceutical compositions containing it.
International Publication No. WO2005025566 discloses pharmaceutical compositions of irbesartan with Cellactose and other pharmaceutically acceptable excipients.
The present inventors while working on the irbesartan formulation have surprisingly found that when irbesartan or salt thereof is melted along with one or more pharmaceutically acceptable dispersing agents, the dispersing agent coats irbesartan or salts thereof resulting in increased solubility of irbesartan or salts thereof leading to improved dissolution profile. This further leads to better bioavailability of irbesartan or salts thereof.
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It was further noticed that solid dispersion of irbesartan or salts there of results in improved flow properties of irbesartan or salts thereof thus preventing the problems like sticking and picking observed during tabletting of irbesartan or salts thereof.
One of the aspects of the present invention provides a pharmaceutical composition comprising irbesartan or salts thereof in solid dispersion with one or more pharmaceutically acceptable dispersing agents optionally along with other pharmaceutically acceptable excipients.
The solid dispersion of irbesartan or salts there of contains irbesartan or salts thereof in an amount of about 1% to about 60% by weight and pharmaceutically acceptable dispersing agent from about 40% to about 99% by weight.
Pharmaceutically acceptable dispersing agents may include one or more of pyrrolidones, polyvinyl pyrrolidone vinyl acetate copolymers, polyvinyl alcohols, acrylate polymers, cellulosic polymers, polyethylene glycols, polyethylene glycol copolymers, polyethylene glycol derivatives, polyethylene-propylene glycol copolymers, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylenes, saccharides, poloxamines, chitosan, phosphatidylcholines, miglyol, polyester polymers or copolymers and the like.
Solid dispersions can be prepared by various methods like rotary evaporation, spray drying, lyophilization, fusion, melt extrusion, solvent controlled precipitation, supercritical fluid technology and all other techniques well known in the art.
In another aspect of the present invention there is provided a process of preparing pharmaceutical composition, which process comprises of:
a) mixing irbesartan with one or more pharmaceutically acceptable dispersing agents,
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b) granulating said mixture of step a) by melting, mixing, congealing, optionally with one or more pharmaceutically acceptable excipients.
In yet another aspect of the present invention there is provided a pharmaceutical composition, which comprises of irbesartan or salts thereof in solid dispersion with one or more pharmaceutically acceptable dispersing agent optionally along with other pharmaceutically acceptable excipients; and wherein the formulation exhibits a dissolution profile such that within 30 minutes more than 75% of irbesartan is released, wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 1000 ml of 0.1 N Hcl at 37 °C ± 0.5°C.
The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients are selected from a group comprising one or more of povidone, starch, polyethylene glycol, stearic acid, gums, hydroxypropylmethyl cellulose, polyethylene glycol, microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium sulfate, kaolin, powdered sugar, magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, colloidal silicon dioxide, talc, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
The pharmaceutical composition of the present invention may be prepared by melting the mixture of irbesartan, PEG 6000 and poloxamer followed by congealing. Congealed solid may be sized into granules. Granules may be mixed with other pharmaceutically acceptable excipients and may be formulated into suitable dosage form.
The pharmaceutical composition of the present invention can be present in the form of granules, pellets, beads, spheroids, tablet, minitablet, microtablet, capsule, granules in capsule, pellets in capsule, minitablet in capsule or combinations thereof.
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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.
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EXAMPLE 1
Table 1: Composition of Irbesartan tablets

No Ingredients % Composition
Solid dispersion
1 Irbesartan 10-60
2 PEG 6000 40-60
3 Poloxamer 3-20
Other excipients
4 Lactose 1-70
5 Croscarmellose sodium 1-5
6 Microcrystalline cellulose 5-30
7 Silicon dioxide 0.25-5
8 Magnesium stearate 0.25-2
Procedure: Irbesartan, poloxamer and PEG 6000 are melted and mixed at 80-100°C to form a homogenous dispersion followed by congealing while mixing at room temperature. Congealed solid is sized through sieve to get granules of uniform size. Granules thus obtained are mixed with lactose, microcrystalline cellulose, silicon dioxide, croscarmellose sodium and lubricated with magnesium stearate. Lubricated granules are compressed using suitable tooling.
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WE CLAIM:
1. A pharmaceutical composition comprising irbesartan or salts thereof in solid dispersion with one or more pharmaceutically acceptable dispersing agents optionally along with other pharmaceutically acceptable excipients.
2. The pharmaceutical composition of claim 1, wherein solid dispersion of irbesartan or salts thereof contains irbesartan or salts thereof in an amount from about 1% to about 60% by weight and pharmaceutically acceptable dispersing agent from about 40% to about 99% by weight.
3. The pharmaceutical composition of claim 1, wherein pharmaceutically acceptable dispersing agent comprises one or more of polyvinyl pyrrolidones, polyvinyl pyrrolidone vinyl acetate copolymers, polyvinyl alcohols, acrylate polymers, cellulosic polymers, polyethylene glycols, polyethylene glycol copolymers, polyethylene-propylene glycol copolymers, polyoxyethylene-polyoxypropylene copolymer, polyethylene glycol derivatives, polyoxyethylenes, saccharides, poloxamines, chitosan, phosphatidylcholines, miglyol, polyester polymers or copolymers and the like.
4. A process of preparing pharmaceutical composition, which process comprises of:

a) mixing irbesartan with one or more pharmaceutically acceptable dispersing agents,
b) granulating said mixture of step a) by melting, mixing, congealing, optionally with one or more pharmaceutically acceptable excipients.
5. A pharmaceutical composition, which comprises of irbesartan or salts
thereof in solid dispersion with one or more pharmaceutically acceptable
dispersing agent optionally along with other pharmaceutically acceptable
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excipients; and wherein the formulation exhibits a dissolution profile such that within 30 minutes more than 75% of irbesartan is released, wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 1000 ml of 0.1 N Hcl at 37 °C ± 0.5°C.
6. The pharmaceutical composition of claim 1 comprises one or more of granules, pellets, beads, spheroids, tablet, minitablet, microtablet, capsule, granules in capsule, pellets in capsule, minitablet in capsule.
7. The pharmaceutical composition of claim 1, wherein pharmaceutically acceptable excipients comprises one or more of povidone, starch, polyethylene glycol, stearic acid, gums, hydroxypropylmethyl cellulose, polyethylene glycol, microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium sulfate, kaolin, powdered sugar, magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, colloidal silicon dioxide, talc, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.

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ABSTRACT
The present invention provides a pharmaceutical composition comprising irbesartan or salts thereof in solid dispersion with one or more pharmaceutically acceptable dispersing agents optionally along with other pharmaceutically acceptable excipients. The invention also relates to processes for the preparation of such compositions.
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