FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10 ; rule 13]
1. TITLE OF THE INVENTION
"Pharmaceutical compositions containing Irbesartan"
2. APPLICANT
(1) NAME: USV LIMITED
(2) NATIONALITY: Indian Company incorporated under the
Companies Act 1956
(3) ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field of the invention:
The present invention relates to pharmaceutical compositions comprising Irbesartan or a pharmaceutically acceptable salt thereof optionally in combination with a diuretic. More particularly, the invention relates to compositions of Irbesartan and Hydrochlorothiazide and process for their preparation.
Background of the invention:
Cardiovascular diseases (CVD) cause millions of death around the world. Major risk factors associated with CVD include high blood pressure, high blood cholesterol, tobacco smoking, myocardial infarction, systemic lupus erythematosus, hemodialysis, congestive cardiac failure, insulin resistance diabetes mellitus, obesity, hyperhomocysteine levels, physical inactivity/ sedentary lifestyle, stress, strokes and others. In 2003, the global death due to CVD was 16.7 million.
Hypertension means high blood pressure in the arteries, which carry blood from heart to all the tissues and organs of the body. Hypertension may be associated with various vascular pathologies such as ventricular hypertrophy, atherosclerosis, arteriolar sclerosis and necrosis, heart failure, renal ischemia, intracranial hemorrhage and encephalopathy. It has been well established that higher the levels of either systolic or diastolic blood pressure greater is the risk of death due to cardiovascular diseases. Early treatment of hypertension can reduce the risk of morbidity and mortality due to cardiovascular diseases.
Irbesartan is an angiotensin II receptor antagonist and is used in the treatment of cardiovascular disorders such as hypertension and heart failure.
Irbesartan is chemically described as 2-Butyl-3- [p- (o-lH-tetrazol-5-ylphenyI) benzyl]-1,3-diazaspiro [4.4]-non-l-en-4-one. Its empirical formula is C25H28N6O and its molecular weight is 428.5 Irbesartan is a white to off white crystalline powder. It is a nonpolar compound with a partition coefficient (octanol/water) of 10.1 at pH of 7.4, practically insoluble in water (> 10000 parts of solvent required

for one part of solute), 0.01 mg/ml, slightly soluble in alcohol and Methylene Chloride.
Several compositions of Irbesartan are available commercially. Irbesartan is marketed by Sanofi-Bristol Myers Squibb as Aprovel® and is available in the form of tablets containing 75mg, 150mg and 300mg of Irbesartan. Aprovel® contains lactose, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, poloxamer 188, silicon dioxide and magnesium stearate as inactive.
Irbesartan is used alone or in combination with other drugs such as diuretics. Hydrochlorothiazide is a diuretic and belongs to the thiazide class of diuretics, acting on the kidney to reduce sodium (Na) reabsorption in the distal convoluted tubule which inturn reduces the osmotic pressure in the kidney, causing less water to be reabsorbed by the collecting ducts and thereby leads to an increased urinary output. Hydrochlorothiazide is used in the treatment of hypertension either alone or with other antihypertensive agents to enhance the effectiveness of other antihypertensive drugs in severe forms of hypertension.
Hydrochlorothiazide is 6-chloro-3, 4-dihydro-2H-l, and 2,4-benzothiadiazine-7-sulfonamidel, 1-dioxide. Its empirical formula is C7H8CIN3O4S2. Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.7 Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution.
Combination of Irbesartan and Hydrochlorothiazide has been found to be more effective than either drug given alone. Irbesartan and Hydrochlorothiazide combination is marketed by Sanofi-Bristol-Myers Squibb as CoAprovel® and is available in the form of tablets containing Irbesartan/Hydrochlorothiazide 150/12.5mg, 300/12.5mg and 300/25mg. CoAprovel contains lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hypromellose, silicon dioxide, magnesium stearate, titanium dioxide, macrogol, caraauba wax, pregelatinised starch, red and yellow ferric oxide.

EP0454511 discloses the process for preparation of Irbesartan and compositions of Irbesartan.
EP0747050 discloses pharmaceutical compositions containing Irbesartan alone or in combination with a diuretic. Particularly, said compositions comprises about 20 to 50% irbesartan; about 1 to 70% diluent; about 10 to 20% binder; about 4 to 8% disintegrant; about 0.25 to 5.0% antiadherent; about 0.5 to 1.5% lubricant; and about 1 to 6% surfactant.
EP1750862 discloses pharmaceutical compositions containing greater than
70% w/w Irbesartan and optionally containing at least one additional active
ingredient such as Hydrochlorothiazide.
WO2006013545 discloses pharmaceutical compositions containing more than 70% by weight of irbesartan alone or in combination with about 2% to about 20% by weight of Hydrochlorothiazide. The document further discloses a process for the preparation comprising the steps of: i) blending irbesartan with one or more pharmaceutically acceptable excipients and optionally Hydrochlorothiazide; ii) granulating to obtain a wet mass; iii) screening the wet mass to form granules; iv) drying and sizing the granules and v) compressing the granules into tablets.
US6342247 discloses that the use of the surfactant, poloxamer improves the aqueous granulation of Irbesartan, eases the ejection of tablets after compression and accelerates the dissolution of Irbesartan.
WO2006067601 discloses that for a combination of Irbesartan and Hydrochlorothiazide, the addition of poloxamer is important for satisfactory compression and complete dissolution of Irbesartan. '601 discloses a composition wherein the contact between Hydrochlorothiazide and poloxamer is minimized. However, in a combination of Irbesartan and Hydrochlorothiazide the use of poloxamer and polyvinyl pyrrolidone increases the degradation of Hydrochlorothiazide.

In view of the aforementioned drawbacks associated with prior art compositions it is apparent that there still exists a need for stable compositions which possess good shelf life stability and do not degrade on long term storage.
Object of Invention:
An object of the present invention is to provide pharmaceutical compositions comprising Irbesartan or a pharmaceutic ally acceptable salt thereof optionally in combination with a diuretic.
Another object of the invention is to provide pharmaceutical compositions comprising Irbesartan in combination with Hydrochlorothiazide wherein said composition comprises less than 70% Irbesartan and are free of surfactants, povidone, starch and/or pregelatinized starch.
Yet another object of the invention is to provide a process for preparation of pharmaceutical compositions comprising Irbesartan and Hydrochlorothiazide; said process being efficient, economic, simple, less time consuming in comparison to the prior art processes and suitable for commercial scale preparation.
Summary of Invention:
The present invention provides pharmaceutical compositions comprising Irbesartan or a pharmaceutically acceptable salt thereof optionally in combination with a diuretic. More particularly, the invention provides compositions of Irbesartan and Hydrochlorothiazide and process for their preparation. Said compositions are used for the treatment of hypertension and heart failure.
According to one aspect, the invention provides pharmaceutical composition comprising (a) Irbesartan or a pharmaceutically acceptable salt thereof and (b) optionally a diuretic; and wherein said composition comprises less than about 70% by weight of Irbesartan or a pharmaceutically acceptable salt thereof and is free of surfactant. Preferably, the diuretic is Hydrochlorothiazide.

According to another aspect, the invention provides pharmaceutical composition comprising Irbesartan and Hydrochlorothiazide, wherein said composition is free of starch and/or pregelatinised starch.
According to another aspect, the invention provides pharmaceutical composition comprising Irbesartan and Hydrochlorothiazide, wherein said composition is free of povidone.
According to another aspect, the invention provides pharmaceutical composition comprising Irbesartan and optionally Hydrochlorothiazide wherein said Irbesartan has particle size distribution such that atleast 10% particles have particle size less than 5 microns or atleast 50% particles have particle size less than 10 microns or atmost 10% particles have particle size greater than 20 microns.
According to another aspect, the invention provides pharmaceutical composition comprising Irbesartan and Hydrochlorothiazide wherein said composition exhibits a dissolution profile such that after about 10 minutes, at least about 75% of the Irbesartan is released; after about 15 minutes, from about 80% to about 90% of Irbesartan is released; after about 20 minutes, from about 85% to about 95% of Irbesartan is released; after about 30 minutes, more than about 90% of Irbesartan is released using USP apparatus II by placing the tablet in 1000ml of 0.1N hydrochloric acid at 37 deg C with paddle speed of 50 rpm.
Preferably, the ratio of Irbesartan to Hydrochlorothiazide is in the range of about 30:1 to about 3:1. Preferably, said Irbesartan has particle size distribution such that about 50% particles have particle size less than 10 microns and said Hydrochlorothiazide has particle size distribution such that about 50% particles have particle size less than 20 microns.
According to one aspect, the invention provides pharmaceutical composition comprising Irbesartan and Hydrochlorothiazide; wherein said composition exhibits one or more of the following characteristics:

(a) less than about 70% by weight of Irbesartan or a pharmaceutically acceptable salt thereof;
(b) free of surfactant;
(c) free of povidone;
(d) free of starch and/or pregelatinised starch;
(e) polymerized ethylene oxide having number average molecular weight less than or equal to 1,00,000;
(f) said composition exhibits a dissolution profile such that after about 10 minutes, at least about 75% of the Irbesartan is released; after about 15 minutes, from about 80% to about 90% of Irbesartan is released; after about 20 minutes, from about 85% to about 95% of Irbesartan is released; after about 30 minutes, more than about 90% of Irbesartan is released using USP apparatus II by placing the tablet in 1000ml of 0.1N hydrochloric acid at 37 deg C with paddle speed of 50 rpm;
(g) said composition comprises Irbesartan having particle size distribution such that atleast 10% particles have particle size less than 5 microns or atleast 50% particles have particle size less than 10 microns or atmost 10% particles have particle size greater than 20 microns.
According to one aspect, the invention provides a process for preparation of pharmaceutical compositions of Irbesartan and Hydrochlorothiazide, said process comprises the steps of:
(a) granulating Irbesartan and one or more pharmaceutically acceptable excipients with a binder solution to form granules;
(b) separately granulating Hydrochlorothiazide and one or more pharmaceutically acceptable excipients with a binder solution to form granules;
(c) mixing the granules of Irbesartan with granules of Hydrochlorothiazide and one or more lubricants;
(d) compressing the mixture into tablets;
(e) optionally coating the tablets.

Additional aspects and/or advantages of the present invention will be evident from the description that follows.
Description of the invention:
The present invention provides pharmaceutical compositions comprising Irbesartan or a pharmaceutically acceptable salt thereof optionally in combination with a diuretic such as Hydrochlorothiazide. Said compositions are used for the treatment of hypertension.
Particularly, the invention provides compositions of Irbesartan and Hydrochlorothiazide and process for their preparation. Preferably, said compositions may be provided as tablet dosage forms.
Irbesartan is a fluffy material with low bulk and tap densities. Due to these properties it is difficult to formulate the drug into a tablet that would posses uniformity of weight and desired hardness. Irbesartan is sticky and adheres to punches and dies causing tabletting problems. Hydrochlorothiazide, being fluffy material further contributes to poor tabletting properties. Low aqueous solubility of Irbesartan and Hydrochlorothiazide also poses a challenge to formulation.
Prior art teaches the use of surfactants for improved granulation and dissolution of Irbesartan. Prior art further teaches that for a combination of Irbesartan and Hydrochlorothiazide, the addition of poloxamer is important for satisfactory compression and complete dissolution of Irbesartan. However, in a combination of Irbesartan and Hydrochlorothiazide the use of a surfactant such as poloxamer and polyvinyl pyrrolidone increases the degradation of Hydrochlorothiazide.
The inventors of the present invention have developed combination of Irbesartan and Hydrochlorothiazide; wherein said combinations are devoid of surfactants.
According to one embodiment, the present invention provides pharmaceutical composition comprising (a) Irbesartan or a pharmaceutically acceptable salt thereof

and (b) optionally a diuretic; and wherein said composition comprises less than about 70% by weight of Irbesartan or a pharmaceutically acceptable salt thereof and is free of surfactant.
According to another embodiment, the present invention provides pharmaceutical composition comprising (a) Irbesartan or a pharmaceutically acceptable salt thereof and (b) a diuretic; and wherein said composition comprises less than about 70% by weight of Irbesartan or a pharmaceutically acceptable salt thereof and is free of surfactant. Preferably, the diuretic is Hydrochlorothiazide.
According to one embodiment, the present invention provides pharmaceutical composition comprising (a) Irbesartan or a pharmaceutically acceptable salt thereof and (b) optionally a diuretic; and wherein said composition is free of starch and/or pregelatinised starch.
According to one embodiment, the present invention provides pharmaceutical composition comprising (a) Irbesartan or a pharmaceutically acceptable salt thereof and (b) optionally a diuretic; and wherein said cornposition is free of povidone.
According to preferred embodiment, the invention provides pharmaceutical composition comprising (a) Irbesartan or a pharmaceutically acceptable salt thereof and (b) Hydrochlorothiazide; and wherein said composition is free of povidone.
According to another embodiment, the present invention provides pharmaceutical composition comprising (a) Irbesartan or a pharmaceutically acceptable salt thereof and (b) optionally a diuretic; and wherein said Irbesartan has particle size distribution such that atleast 10% particles have particle size less than 5 microns or atleast 50% particles have particle size less than 10 microns or atmost 10% particles have particle size greater than 20 microns.
In the practice of the present invention, Hydrochlorothiazide has particle size distribution such that about 50% particles have particle size less than 20 microns

and 90% particles have particle size less than 35 microns.
It was surprisingly found that by formulating Irbesartan having particle size of about 50% particles less than 10 microns significantly influences the dissolution of Irbesartan.
Thus according to a preferred embodiment, the invention provides pharmaceutical composition comprising (a) Irbesartan or a pharmaceutically acceptable salt thereof and (b) Hydrochlorothiazide; wherein said Irbesartan has particle size distribution such that about 50% particles have particle size less than 10 microns and said Hydrochlorothiazide has particle size distribution such that about 50% particles have particle size less than 20 microns.
According to one embodiment, the invention provides pharmaceutical composition comprising Irbesartan, wherein said composition is free of surfactant and wherein said Irbesartan has particle size distribution such that atleast 10% particles have particle size less than 5 microns or atleast 50% particles have particle size less than 10 microns or atmost 10% particles have particie size greater than 20 microns.
According to one embodiment, the present invention provides pharmaceutical composition comprising (a) Irbesartan or a pharmaceutically acceptable salt thereof and (b) optionally a diuretic; and wherein said composition exhibits a dissolution profile such that after about 10 minutes, at least about 75% of the Irbesartan is released; after about 15 minutes, from about 80% to about 90% of Irbesartan is released; after about 20 minutes, from about 85% to about 95% of Irbesartan is released; after about 30 minutes, more than about 90% of Irbesartan is released using USP apparatus II by placing the (ablet in 1000ml of 0.1 N hydrochloric acid at 37 deg C with paddle speed of 50 rpm.
According to a preferred embodiment, the present invention provides pharmaceutical composition comprising (a) Irbesartan or a pharmaceutically acceptable salt thereof and (b) Hydrochlorothiazide; and wherein said composition

exhibits a dissolution profile such that after about 10 minutes, at least about 75% of the Irbesartan is released; after about 15 minutes, from about 80% to about 90% of Irbesartan is released; after about 20 minutes, from about 85% to about 95% of Irbesartan is released; after about 30 minutes, more than about 90% of Irbesartan is released using USP apparatus II by placing the tablet in 1000ml of 0.1N hydrochloric acid at 37 deg C with paddle speed of 50 rpm.
According to another embodiment, the invention provides pharmaceutical compositions comprising Irbesartan and Hydrochlorothiazide wherein said composition is free of surfactant and exhibits a dissolution profile such that after about 10 minutes, at least about 75% of the Irbesartan is released; after about 15 minutes, from about 80% to about 90% of Irbesartan is released; after about 20 minutes, from about 85% to about 95% of Irbesartan is released; after about 30 minutes, more than about 90% of Irbesartan is released using USP apparatus II and by placing the tablet in l000mL of 0.1N hydrochloric acid at 37 deg C with paddle speed of 50 rpm.
According to another embodiment, the invention provides pharmaceutical compositions comprising Irbesartan and Hydrochlorothiazide wherein said composition is free of surfactant and comprising less than about 70% by weight of Irbesartan and wherein said composition exhibits a dissolution profile such that after about 10 minutes, at least about 75% of the Irbesartan is released; after about 15 minutes, from about 80% to about 90% of Irbesartan is released; after about 20 minutes, from about 85% to about 95% of Irbesartan is released; after about 30 minutes, more than about 90% of Irbesartan is released using USP apparatus II and by placing the tablet in lOOOmL of 0.1N hydrochloric acid at 37 deg C with paddle speed of 50 rpm.
According to another embodiment, the pharmaceutical composition of Irbesartan and Hydrochlorothiazide exhibits a dissolution profile such that after about l0minutes, atleast about 90% of the Hydrochlorothiazide is released using USP

apparatus II and by placing the tablet in l000mL of 0.1N hydrochloric acid at 37 deg C with paddle speed of 50rpm.
According to another embodiment, the invention provides pharmaceutical compositions comprising Irbesartan and Hydrochlorothiazide wherein said composition is free of surfactant and exhibits a dissolution profile such that after about 15 minutes, at least about 85% of Irbesartan is released and after about 20 minutes, atleast about 90% of Irbesartan is released; using USP apparatus II and by placing the tablet in lOOOmL of 0.1N hydrochloric acid at 37 deg C with paddle speed of 50 rpm.
According to one embodiment, the present invention provides pharmaceutical composition comprising (a) Irbesartan or a pharmaceutic ally acceptable salt thereof and (b) Hydrochlorothiazide; wherein the ratio of Irbesartan to Hydrochlorothiazide is in the range of about 30:1 to about 3:1.
Preferably, the ratio of Irbesartan to Hydrochlorothiazide is in the range of about preferably 28 : 1 to 5 : 1.
In the practice of the present invention, Irbesartan is present in the composition in an amount from 50mg to 500mg; preferably in an amount from 75mg to 300mg. In the practice of the present invention, 75mg or 150mg or 300mg of Irbesartan is combined with 12.5mg or 25mg of Hydrochlorothiazide.
According to one embodiment, the present invention provides pharmaceutical composition comprising (a) Irbesartan or a pharmaceutic ally acceptable salt thereof and (b) Hydrochlorothiazide; wherein said composition is free of atleast one of the excipient selected from the group consisting of surfactant, povidone, starch and pre gelatinised starch.
According to one embodiment, the present invention provides pharmaceutical composition comprising (a) Irbesartan or a pharmaceutically acceptable salt thereof and (b) Hydrochlorothiazide; wherein said composition comprises a binder and

wherein said binder is a polymerized ethylene oxide having number average molecular weight less than or equal to 1,00,000.
According to one embodiment, the present invention provides pharmaceutical composition comprising Irbesartan and Hydrochlorothiazide; wherein said composition exhibits one or more of the following characteristics:
(a) less than about 70% by weight of Irbesartan or a pharmaceutically acceptable salt thereof;
(b) free of surfactant;
(c) free of povidone;
(d) free of starch and/or pregelatinised starch;
(e) polymerized ethylene oxide having number average molecular weight less than or equal to 1,00,000;
(f) said composition exhibits a dissolution profile such that after about 10 minutes, at least about 75% of the Irbesartan is released; after about 15 minutes, from about 80% to about 90% of Irbesartan is released; after about 20 minutes, from about 85% to about 95% of Irbesartan is released; after about 30 minutes, more than about 90% of Irbesartan is released using USP apparatus II by placing the tablet in 1000ml of 0.1N hydrochloric acid at 37 deg C with paddle speed of 50 rpm;
(g) said composition comprises Irbesartan having particle size distribution such that atleast 10% particles have particle size less than 5 microns or atleast 50% particles have particle size less than 10 microns or atmost 10% particles have particle size greater than 20 microns.
According to another embodiment, the present invention provides pharmaceutical composition comprising Irbesartan and Hydrochlorothiazide; wherein said composition exhibits all of the following characteristics:
(a) less than about 70% by weight of Irbesartan or a pharmaceutically acceptable salt thereof;
(b) free of surfactant;

(c) free of povidone;
(d) free of starch and/or pregelatinised starch;
(e) Polymerized ethylene oxide having number average molecular weight less than or equal to 1,00,000,-

(f) said composition exhibits a dissolution profile such that after about 10 Minutes, at least about 75% of the Irbesartan is released; after about 15 Minutes, from about 80% to about 90% of Irbesartan is released; after about 20 minutes, from about 85% to about 95% of Irbesartan is released; after about 30 minutes, more than about 90% of Irbesartan is released using USP apparatus II by placing the tablet in 1000ml of 0.1N hydrochloric acid at 37 deg C with paddle speed of 50 rpm;
(g) said composition comprises Irbesartan having particle size distribution such that atleast 10% particles have particle size less than 5 microns or atleast 50% particles have particle size less than 10 microns or atmost 10% particles have particle size greater than 20 microns.
According to still another embodiment, the present invention provides pharmaceutical composition comprising Irbesartan and Hydrochlorothiazide; wherein said composition exhibits all of the following characteristics:
(a) less than about 70% by weight of Irbesartan or a pharmaceutically acceptable salt thereof;
(b) free of surfactant;
(c) free of starch and/or pregelatinised starch;
(d) said composition exhibits a dissolution profile such that after about 10 minutes, at least about 75% of the Irbesartan is released; after about 15 minutes, from about 80%) to about 90% of Irbesartan is released; after about 20 minutes, from about 85% to about 95% of Irbesartan is released; after about 30 minutes, more than about 90% of Irbesartan is released using USP apparatus II by placing the tablet in 1000ml of 0.1N hydrochloric acid at 37 deg C with paddle speed of 50 rpm;
(e) said composition comprises Irbesartan having particle size distribution

such that atleast 10% particles have particle size less than 5 microns or atleast 50% particles have particle size less than 10 microns or atmost 10% particles have particle size greater than 20 microns.
According to one embodiment, the invention provides pharmaceutical composition comprising Irbesartan and Hydrochlorothiazide; wherein said composition comprises less than about 70% by weight of Irbesartan, about 1% to about 5% by weight of Hydrochlorothiazide, about 30% to about 50% by weight of diluent, about 0.1% to about 5% by weight of binder, about 5% to about 10% by weight of disintegrant, about 1% to about 2% by weight of lubricant and about 1% to about 2.5% by weight of glidant.
According to another embodiment, the invention provides pharmaceutical composition comprising Irbesartan and Hydrochlorothiazide; wherein said composition comprises about 40% to about 50% by weight of Irbesartan, about 1.5% to about 4% by weight of Hydrochlorothiazide, about 38% to about 42% by weight of diluent, about 0.1% to about 2% by weight of binder, about 5% to about 10% by weight of disintegrant, about 1% to about 2% by weight of lubricant and about 1% to about 2.5% by weight of glidant.
Suitable pharmaceutically acceptable excipients that may be used according to the present invention include, but are not limited to diluents/fillers, binders, disintegrants, lubricants, glidants, coating agents, colorants, solvents and the like.
Diluents/ fillers include, but are not limited to microcrystalline cellulose, lactose, dibasic calcium phosphate, sugar derivatives, dextrates, dextrins and mixtures thereof and may be used in an amount from 30.0% to 60.0% by weight of the total composition.
Disintegrants include, but are not limited to one or more of crospovidone, carboxy methylcellulose calcium, sodium starch glycollate, starch, croscarmellose sodium and combinations thereof. Disintegrant may be used in an amount from 3.0% to

15.0% by weight of the total composition.
Binders include, but are not limited to polyvinyl alcohol, polyethylene oxide, polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose and mixtures thereof. Binders may be used in an amount from 1% to 10% by weight of the total composition.
Lubricants and glidants include talc, colloidal silicon dioxide, magnesium stearate, hydrogenated castor oil, stearic acid, sodium stearyl fumarate and the like and may be used in an amount from 2.0% to 15.0% by weight of the total composition.
According to one embodiment, the invention provides a process for preparation of pharmaceutical compositions comprising Irbesartan and Hydrochlorothiazide, said process comprises the steps of:
(a) granulating Irbesartan and one or more pharmaceutic ally acceptable excipients with a binder solution to form granules;
(b) separately granulating Hydrochlorothiazide and one or more pharmaceutically acceptable excipients with a binder solution to form granules;
(c) mixing the granules of Irbesartan with granules of Hydrochlorothiazide and one or more lubricants;
(d) compressing the mixture into tablets;
(e) optionally coating the tablets.
According to another embodiment, the invention provides a process for preparation of pharmaceutical compositions comprising Irbesartan and Hydrochlorothiazide, said process comprises the steps of:
(a) granulating Irbesartan and one or more pharmaceutically acceptable excipients with a binder solution to form granules;
(b) mixing the granules of Irbesartan with Hydrochlorothiazide and one or more lubricants;
(c) compressing the mixture into tablets;

(d) optionally coating the tablets.
According to one embodiment, the invention provides a process for preparation of pharmaceutical compositions comprising Irbesartan and Hydrochlorothiazide; which process does not involve the use of surfactants, povidone, starch and/or pregelatinised starch.
According to a preferred embodiment, the invention provides a process for preparation of pharmaceutical compositions comprising Irbesartan and Hydrochlorothiazide, said process comprises the steps of:
(a) granulating Irbesartan and one or more pharmaceutically acceptable excipients;
(b) separately granulating Hydrochlorothiazide and one or more pharmaceutically acceptable excipients;
(c) compressing the granules of step (a) and step (b) to form bilayered tablet;
wherein said process does not involve the use of atleast one of the excipient selected from the group consisting of Surfactant, povidone, starch and pregelatinised starch; and
wherein said composition comprises Irbesartan having particle size distribution such that atleast 10% particles have particle size less than 5microns or.atleast 50% particles have panicle size less than 10 microns or atmost 10% particles have particle size greater than 20 microns.
According to a preferred embodiment, the invention provides a process for preparation of pharmaceutical compositions comprising Irbesartan and Hydrochlorothiazide, said process comprises the steps of:
(a) granulating Irbesartan and one or more pharmaceutically acceptable excipients with a binder solution to form granules;
(b) separately granulating Hydrochlorothiazide and one or more pharmaceutically acceptable excipients with a binder solution to form

granules;
(c) mixing the granules of Irbesartan with granules of Hydrochlorothiazide and one or more lubricants;
(d) compressing the mixture into tablets;
(e) optionally coating the tablets;
wherein said composition is free from surfactants and povidone and exhibits a dissolution profile such that after about 10 minutes, at least about 75% of the Irbesartan is dissolved after about 15 minutes, from about 80% to about 90% of Irbesartan is released; after about 20 minutes, from about 85% to about 95% of Irbesartan is released; after about 30 minutes, more than about 90% of Irbesartan is released using USP apparatus II and by placing the tablet in 1000mL of 0.1N hydrochloric acid at 37 deg C with paddle speed of 50 rpm; and
wherein said composition comprises Irbesartan having particle size distribution such that atleast 10% particles have particle size less than 5 microns or atleast 50% particles have particle size less than 10 microns or atmost 10% particles have particle size greater than 20 microns.
According to another preferred embodiment, the invention provides a process for preparation of pharmaceutical compositions comprising Irbesartan and Hydrochlorothiazide, said process comprises the steps of:
(a) granulating Irbesartan and one or more pharmaceutically acceptable excipients using polymerized ethylene oxide having number average molecular weight less than or equal to 1,00,000 as a binder to form granules;
(b) separately granulating Hydrochlorothiazide and one or more pharmaceutically acceptable excipients using a water soluble polymer as binder to form granules;
(c) mixing the granules of Irbesartan with granules of Hydrochlorothiazide and one or more lubricants;
(d) compressing the mixture into tablets;

(e) optionally coating the tablets;
wherein said composition is free from surfactants and exhibits a dissolution profile such that after about 10 minutes, at least about 75% of the Irbesartan is dissolved after about 15 minutes, from about 80% to about 90% of Irbesartan is released; after about 20 minutes, from about 85% to about 95% of Irbesartan is released; after about 30 minutes, more than about 90% of Irbesartan is released using USP apparatus II and by placing the tablet in l000mL of 0.1N hydrochloric acid at 37 deg C with paddle speed of 50 rpm; and
wherein said composition comprises Irbesartan having particle size distribution such that atleast 10% particles have particle size less than 5 microns or atleast 50% particles have particle size less than 10 microns or atmost 10% particles have particle size greater than 20 microns.
According to another embodiment, the invention provides a process for preparing a bilayered, solid oral pharmaceutical dosage form comprising Irbesartan and Hydrochlorothiazide, said process comprising the steps of:
(a) preparing granules of Irbesartan and one or more pharmaceutically acceptable excipients;
(b) preparing granules of Hydrochlorothiazide and one or more pharmaceutically acceptable excipients;
(c) compressing the granules of step (a) and step (b) to form bilayered tablet; wherein said process does not involve the use of atleast one of the excipient selected from the group consisting of surfactant, povidone, starch and pregelatinised starch.
The process of preparation of pharmaceutical compositions according to the present invention are efficient, economic, simple, and less time consuming in comparison to the various prior art processes. Further, the process as described herein are suitable for commercial scale preparation of stable combinations of Irbesartan and Hydrochlorothiazide.

Pharmaceutical compositions according to the present invention are found to be stable. Long term stability studies are under progress.
Another embodiment of the invention provides a method for treating hypertension by orally administering to the subject a pharmaceutical composition comprising a combination of Irbesartan and Hydrochlorothiazide; wherein said composition has the characteristics as described herein.
As used herein, the term "composition" unless otherwise defined refers to granules and/or solid oral pharmaceutical dosage forms of the invention that contain
As used herein, the term "excipient" refers to a pharmaceutically acceptable ingredient that is commonly used in the pharmaceutical technology for preparing granules and/or solid oral pharmaceutical dosage forms.
As used herein, the term "tablet" is intended to encompass compressed pharmaceutical dosage formulations of all shapes and sizes, whether coated or uncoated.
The present invention is further illustrated by reference to the following examples, which does not limit the scope of the invention in any way. It will be apparent to those skilled in the art that many modifications, both to the materials and methods, can be practiced without departing from the purpose and scope of the disclosure.
Examples: Example 1
Irbesartan (300g), lactose monohydrate (99g), microcrystalline cellulose (105g), and croscarmellose sodium (20g) were sifted using a suitable mesh sieve and were mixed in a suitable mixer. Binder solution was prepared by dissolving polyethylene oxide (9g) in water. The dry mix was granulated with binder solution and the granules were dried and sifted through suitable mesh. Hydrochlorothiazide (25g), and microcrystalline cellulose (75.7g) were sifted using suitable mesh and

were mixed in a suitable mixer. Binder solution was prepared by dissolving polyvinyl alcohol (1.3g) in water. The dry mix was granulated with binder solution. The granules were dried and sifted through suitable mesh. Both the granules were mixed and lubricated with croscarmellose sodium (25g), colloidal silicon dioxide (9g), magnesium stearate (17g) and the lubricated blend was compressed to get tablets. The tablets were coated.
Example 2
Irbesartan (300g), lactose monohydrate (99g), microcrystalline cellulose (105g), and croscarmellose sodium (20g) were sifted using a suitable mesh and were mixed in a suitable mixer. Binder solution was prepared by dissolving polyethylene oxide (9g) in water. The dry mix was granulated with binder solution. The granules were dried and sifted through suitable mesh sieve. Hydrochlorothiazide (25g) and microcrystalline cellulose (75.4g) were sifted using suitable mesh and were mixed in a suitable mixer. Binder solution was prepared by dissolving polyethylene oxide (1.6g) in methylene dichloride. The dry mix was granulated with binder solution. The granules were dried and sifted through suitable mesh. Both the granules were mixed and lubricated with croscarmellose sodium (25g), colloidal silicon dioxide (9g), magnesium stearate (17g). The lubricated blend was compressed to get tablets. The tablets were coated.
Example 3
Irbesartan (300g), lactose monohydrate (99g), microcrystalline cellulose (105g), and croscarmellose sodium (20g) were sifted using a suitable mesh and were mixed in a suitable mixer. Binder solution was prepared by dissolving polyethylene glycol (9g) in water. The dry mix was granulated with binder solution. The granules were dried and sifted through suitable mesh. Hydrochlorothiazide (25g) and microcrystalline cellulose (75.7g) were sifted using suitable mesh and were mixed in a suitable mixer. Binder solution was prepared by dissolving polyvinyl alcohol (1.3g) in water. The dry mix was granulated with binder solution. The granules were dried and sifted through suitable mesh. Both

the granules were mixed and lubricated with croscarmellose sodium (25g), colloidal silicon dioxide (9g), magnesium Stearate (17g). The lubricated blend was compressed to get tablets. The tablets were coated.
Example 4
Irbesartan (300g), lactose monohydrate (99 g), microcrystalline cellulose (105g), and croscarmellose sodium (20g) were sifted using a suitable mesh and were mixed in a suitable mixer. Binder solution was prepared by dissolving polyethylene glycol (9g) in water. The dry mix was granulated with binder solution. The granules were dried and sifted through suitable mesh. Hydrochlorothiazide (25g) and microcrystalline cellulose (75.4g) were sifted using suitable mesh and were mixed in a suitable mixer. Binder solution was prepared by dissolving polyethylene oxide (1.6g) in methylene dichloride. The dry mix was granulated with binder solution. The granules were dried and sifted through suitable mesh. Both the granules were mixed and lubricated with croscarmellose sodium (25g), colloidal silicon dioxide (9g) and magnesium stearate (17g). The lubricated blend was compressed to get tablets. The tablets were coated
Example 5
Irbesartan (300g), Hydrochlorothiazide (25g), lactose monohydrate (70.5), microcrystalline cellulose (70g), and croscarmellose sodium (20g) were sifted using a suitable mesh and were mixed in a suitable mixer. Binder solution was prepared by dissolving polyethylene glycol in water. The dry mix was granulated binder solution. The granules were dried and sifted through suitable mesh. This blend was lubricated with croscarmellose sodium (20g), colloidal silicon dioxide (7.5g) and magnesium stearate (14g) and compressed to get tablets. The tablets were then coated.
Example 6
Irbesartan (300g), lactose monohydrate (107.6), microcrystalline cellulose (107.4g), and croscarmellose sodium (20g) were sifted using a suitable mesh sieve

and were mixed in a suitable mixer. Binder solution was prepared by dissolving polyethylene oxide (9g) in water. The dry mix was granulated with binder solution. The granules were dried and sifted through suitable mesh. Hydrochlorothiazide (25g) was sifted using suitable mesh. Irbesartan granules were mixed with sifted Hydrochlorothiazide and lubricated with croscarmellose sodium (25g), colloidal silicon dioxide (9g) and magnesium stearate (14g). The lubricated blend was compressed to get tablets. The tablets were coated.
Example 7
Irbesartan (300g), lactose monohydrate (107.6), microcrystalline cellulose (107.4g), and croscarmellose sodium (20g) were sifted using a suitable mesh sieve and were mixed in a suitable mixer. Binder solution was prepared by dissolving polyethylene glycol (9g) in water. The dry mix was granulated with binder solution. The granules were dried and sifted through suitable mesh. Hydrochlorothiazide (25g) was sifted using suitable mesh. Irbesartan granules were mixed with sifted Hydrochlorothiazide and lubricated with croscarmellose sodium (25g), colloidal silicon dioxide (9g) and magnesium stearate (14g). The lubricated blend was compressed to get tablets. The tablets were coated
Example 8
Irbesartan (300g), lactose monohydrate (70.5g), microcrystalline cellulose (60.5g), and croscarmellose sodium (20g) were sifted using a suitable mesh sieve and were mixed in a suitable mixer. Binder solution was prepared by dissolving hyroxypropyl methylcellulose (18g) in water. The dry mix was granulated with binder solution. The granules were dried and sifted through suitable mesh. The dried granules were lubricated with croscarmellose sodium (20g), colloidal silicon dioxide (lOg) and magnesium stearate (9g). The lubricated blend was compressed to get tablets. The tablets were film coated.
Example 9
A dissolution study was conducted using a tablet containing Irbesartan and

Hydrochlorothiazide prepared according to Example 2. The dissolution test was carried out by USP apparatus II by placing the tablet in l000mL of 0.1N hydrochloric acid at 37 deg C with paddle speed of 50 rpm and the in-vitro release profile is as shown in Table 1.
Table 1

Time (minutes) Drug release (%)

Irbesartan Hydrochlorothiazide
10 83.4 94.9
15 89.9 96.4
20 93.1 97.3
30 96.6 99.0
Example 10
Bioequivalence study
A bioequivalence study was conducted on 11 healthy, adult, human subjects under fasting conditions. The drug release was evaluated in vivo in a randomized, open label, balanced, two treatment, two period, two sequence, single dose, two way crossover, pilot bioequivalence study of fixed dose combination of Irbesartan 300mg and Hydrochlorothiazide 25mg tablets prepared according to Example 2 with CoAprovel®300mg/25mg (Irbesartan 300mg and Hydrochlorothiazide 25mg) tablets of Sanofi pharma Bristol-Mayer Squibb SNC.
Pharmacokinetics parameters such as AUCo-t, AUCo-inf and Cmax were calculated.
Reference R: CoAprovel by Innovator ( Sanofi-aventis And Bristol-myers Squibb )
Test T: Irbesartan Hydrochlorothiazide tablets prepared according to Example 2.
AUCo-t = Area under the plasma concentration versus time curve, from time zero
to the last measurable concentration.
AUCo-inf = Area under the plasma concentration versus time curve, from time
zero to infinity.
Cmax - maximum plasma concentration.

Results on in-vivo study of compositions prepared according to Example 2 is as shown in Table 2 and 3.
Table 2 shows the summary of Pharmacokinetics parameters such as AUC0.t, AUCo-inf and Cmax for Irbesartan.
Table 2

Parameters Fasting conditions T/R ratio (%)
Cmax (ng/ml) 86.47
AUG., (ng*hr/ml) 104.72
AUCO-INF (ng*hr/ml) 104.34
Table 3 shows the summary of Pharmacokinetics parameters such as AUC0.t, AUCo-inf and Cmax for Hydrochlorothiazide.
Table 3

Parameters Fasting conditions T/R ratio (%)
Cmax (ng/ml) 111.22
AUCo-, (ng*hr/ml) 100.05
AUCO-INF (ng*hr/ml) 100.56
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

We claim,
1. A pharmaceutical composition comprising (a) Irbesartan or a pharmaceutically acceptable salt thereof and (b) optionally a diuretic; and wherein said composition comprises less than about 70% by weight of Irbesartan or a pharmaceutically acceptable salt thereof and is free of surfactant.
2. The composition as claimed in claim 1, wherein the diuretic is Hydrochlorothiazide.
3. The composition as claimed in claim 1, wherein said composition is free of starch and/or pregelatinised starch.
4. The composition as claimed in claim 1, wherein said composition is free of povidone.
5. The composition as claimed in claim 1, wherein said Irbesartan has particle size distribution such that atleast 10% particles have particle size less than 5 microns or atleast 50% particles have particle size less than 10 microns or atmost 10% particles have particle size greater than 20 microns.
6. The composition as claimed in claim 1, wherein said composition exhibits a dissolution profile such that after about 10 minutes, at least about 75% of the Irbesartan is released; after about 15 minutes, from about 80% to about 90% of Irbesartan is released; after about 20 minutes, from about 85% to about 95% of Irbesartan is released; after about 30 minutes, more than about 90% of Irbesartan is released using USP apparatus II by placing the tablet in 1000ml of 0.1N hydrochloric acid at 37 deg C with paddle speed of 50 rpm.
7. The composition as claimed in claim 2, wherein the ratio of Irbesartan to Hydrochlorothiazide is in the range of about 30:1 to about 3:1.
8. The composition as claimed in claim 2, wherein said Irbesartan has particle size distribution such that about 50%o particles have particle size less than 10 microns and said Hydrochlorothiazide has particle size distribution such that about 50% particles have particle size less than 20 microns.

9. The composition as claimed in claim 1, wherein said composition further comprises excipient selected from diluent, binder, disintegrant, lubricant, glidant and coating agents.
10. The composition as claimed in claim 9, wherein the binder is a polymerized ethylene oxide having number average molecular weight less than or equal to 1,00,000.
11. A pharmaceutical composition comprising Irbesartan and Hydrochlorothiazide; wherein said composition exhibits one or more of the following characteristics:

(a) less than about 70% by weight of Irbesartan or a pharmaceutically acceptable salt thereof;
(b) free of surfactant;
(c) free of povidone;
(d) free of starch and/or pregelatinised starch;
(e) polymerized ethylene oxide having number average molecular weight less than or equal to 1,00,000;
(f) said composition exhibits a dissolution profile such that after about 10 minutes, at least about 75% of the Irbesartan is released; after about 15 minutes, from about 80% to about 90% of Irbesartan is released; after about 20 minutes, from about 85% to about 95% of Irbesartan is released; after about 30 minutes, more than about 90% of Irbesartan is released using USP apparatus II by placing the tablet in 1000ml of 0.1N hydrochloric acid at 37 deg C with paddle speed of 50 rpm;
(g) said composition comprises Irbesartan having particle size distribution such that atleast 10% particles have particle size less than 5 microns or atleast 50% particles have particle size less than 10 microns or atmost 10% particles have particle size greater than 20 microns.
12. The composition as claimed in claim 1 or claim 11, wherein the
composition comprises less than about 70% by weight of Irbesartan, about
1% to about 5% by weight of Hydrochlorothiazide, about 30% to about

50% by weight of diluent, about 0.1% to about 5% by weight of binder, about 5% to about 10% by weight of disintegrant, about 1% to about 2% by weight of lubricant and about 1% to about 2.5% by weight of glidant.
13. The composition as claimed in claim 1 or claim 11, wherein the composition comprises about 40% to about 50% by weight of Irbesartan, about 1.5% to about 4% by weight of Hydrochlorothiazide, about 38% to about 42% by weight of diluent, about 0.1% to about 2% by weight of binder, about 5% to about 10% by weight of disintegrant, about 1% to about 2% by weight of lubricant and about 1% to about 2.5% by weight of glidant.
14. A process for preparation of pharmaceutical compositions of Irbesartan and Hydrochlorothiazide as defined in claim 11, wherein said process comprises the steps of:

(a) granulating Irbesartan and one or more pharmaceutically acceptable excipients with a binder solution to form granules;
(b) separately granulating Hydrochlorothiazide and one or more pharmaceutically acceptable excipients with a binder solution to form granules;
(c) mixing the granules of Irbesartan with granules of Hydrochlorothiazide and one or more lubricants;
(d) compressing the mixture into tablets;
(e) optionally coating the tablets.
15. The process for preparation of pharmaceutical compositions of Irbesartan
and Hydrochlorothiazide as defined in claim 11, wherein said process
comprises the steps of:
(a) granulating Irbesartan and one or more pharmaceutically acceptable excipients with a binder solution to form granules;
(b) mixing the granules of Irbesartan with Hydrochlorothiazide and one or more lubricants;
(c) compressing the mixture into tablets;

(d) optionally coating the tablets.
16. The process for preparation of pharmaceutical compositions of Irbesartan
and Hydrochlorothiazide as defined in claim 11, wherein said process
comprises the steps of:
(a) granulating Irbesartan and one or more pharmaceutically acceptable excipients;
(b) separately granulating Hydrochlorothiazide and one or more pharmaceutically acceptable excipients;
(c) compressing the granules of step (a) and step (b) to form bilayered tablet;
wherein said process does not involve the use of atleast one of the excipient selected from the group consisting of surfactant, povidone, starch and pregelatinised starch; and
wherein said composition comprises Irbesartan having particle size distribution such that atleast 10% particles have particle size less than 5microns or atleast 50% particles have particle size less than 10 microns or atmost 10% particles have particle size greater than 20 microns.
17. The composition as claimed in any of the claims 1 to 13 used for the
treatment of hypertension.