FIELD OF THE INVENTION

The present invention relates to stable pharmaceutical compositions comprising angiotensin II receptor blocker(s), process for preparation, and method of using the same. Particularly, the present invention relates to stable pharmaceutical compositions comprising azilsartan, process for preparation and method for treatment of hypertension and associated disorders.

BACKGROUND OF THE INVENTION

Hypertension, also referred to as high blood pressure and sometimes called arterial hypertension, is a condition in which the arteries have persistently elevated blood pressure. Every time the human heart beats, it pumps blood to the whole body through the arteries. Hypertension can lead to damaged organs, as well as several illnesses, such as renal failure, aneurysm, heart failure, stroke, or heart attack.

The normal level for blood pressure is below 120/80, where 120 represent the systolic measurement (peak pressure in the arteries) and 80 represents the diastolic measurement (minimum pressure in the arteries). Blood pressure between 120/80 and 139/89 is called prehypertension (to denote increased risk of hypertension), and a blood pressure of 140/90 or above is considered hypertension. Hypertension may be classified as primary (essential) or secondary. Primary hypertension is the term for high blood pressure with unknown cause. It accounts for about 95% of cases. Several environmental factors influence blood pressure. Lifestyle factors that lower blood pressure include reduced dietary salt intake, increased consumption of fruits and low fat products (Dietary Approaches to Stop Hypertension-DASH diet), exercise, weight loss and reduced alcohol intake (Whelton PK, He J, Appel LJ, Cutler JA, Havas S, Kotchen TA et al. (2002). "Primary prevention of hypertension: Clinical and public health advisory from The National High Blood Pressure Education Program". JAMA 288 (15): 1882-8). Secondary hypertension is the term for high blood pressure with a known direct cause, such as kidney disease, tumors, or birth control pills. Hypertension can also be caused by endocrine conditions, such as Cushing's syndrome, hyperthyroidism, hypothyroidism, acromegaly, Conn's syndrome or hyperaldosteronism, hyperparathyroidism and pheochromocytoma {Dluhy RG, Williams GH. Endocrine hypertension. In: Wilson JD, Foster DW, Kronenberg HM, eds. Williams Textbook of Endocrinology. 9th ed. Philadelphia, Pa: WB Saunders; 1998:729-49).

Hypertension can be managed by recommended preventive lifestyle changes such as dietary
changes, physical exercise and weight loss.

Further, several classes of medications called as
'antihypertensive drugs'are prescribed for the management of hypertension. A class of drugs which are useful in the treatment of hypertension belong to Angiotensin II receptor blocker(s)/antagonists.

These are a group of pharmaceuticals that modulate the renin-angiotensin-aldosterone system. These substances block the activation of angiotensin II ATI receptors. Blockage of ATI receptors directly causes vasodilation, reduces secretion of vasopressin, and reduces production and secretion of aldosterone, among other actions. The combined effect reduces blood pressure.

Azilsartan medoxomil is an angiotensin II receptor antagonist, poorly soluble in aqueous solution, belongs to biopharmaceutics class IV, i.e. low solubility and low permeability. It is a prodrug, and is hydrolyzed to azilsartan in the gastrointestinal tract during absorption. The potassium salt of azilsartan medoxomil, also known as azilsartan kamedoxomil is chemically described as (5-Methyl-2-oxo-l,3-dioxol-4-yl)methyl-2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4yl] methyl}-lH-benzimidazole-7-carboxylate monopotassium salt. Its empirical formula is C30H23KN4O8, molecular formula is 606.62 and structural formula is as follows:

Azilsartan kamedoxomil is currently marketed as Edarbi immediate release oral tablets for the treatment of hypertension to lower blood pressure.

Each Edarbi® tablet contains 42.68 or 85.36mg of azilsartan kamedoxomil, which is equivalent to containing 40 mg or 80 mg respectively, of azilsartan medoxomil and the following inactive ingredients: mannitol, fumaric acid, sodium hydroxide, hydroxypropyl cellulose, croscarmellose sodium, microcrystalline cellulose, and magnesium stearate.

US 5,583,141 patent discloses the compound azilsartan.

US 7,157,584 patent discloses azilsartan medoxomil or a pharmaceutically acceptable salt thereof.

US 7,572,920 patent discloses composition comprising azilsartan kamedoxomil or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

US 2010/0016382 patent publication discloses a solid pharmaceutical composition comprising azilsartan or salt thereof, polyethylene glycol having a melting point of 20°C to 90°C and hydroxypropyl cellulose having a viscosity of about 1 to about 4 mPa as measured at 20°C using a 2% aqueous solution.

US 2011/0201658 patent publication discloses a pharmaceutical package including a pharmaceutical preparation containing azilsartan or a salt thereof, and a desiccant.

US 2012/0100093 patent publication discloses a medicinal package comprising a medicinal preparation (azilsartan) capable of giving out smells, a packaging component and a chemical absorption-type desiccant.

US 2010/0121071 patent publication discloses a solid pharmaceutical composition comprising azilsartan or a salt thereof and a pH control agent, wherein the pH control agent has pH of about 2 to about 5. This patent publication further discloses that azilsartan is unstable in the neutral pH range, at which pharmaceutical preparations are generally produced. The objective of the said invention was to simultaneously achieve the stability and dissolution property accomplished by the presence of a pH control agent and further, by adjusting, with a pH control agent, the pH range of a solid preparation thereof to a suitable pH in order to solve the stability and dissolution issues of azilsartan.

The inventors of the present invention have surprisingly found that azilsartan is still stable at higher pH range values and shows enhanced dissolution, which also is a significant advancement over the teachings of the art. Accordingly, inventors of the present invention have developed stable pharmaceutical compositions comprising azilsartan, a pH regulating agent having a pH of not less than about 5, optionally with other pharmaceutically acceptable excipient(s).

SUMMARY OF THE INVENTION

An aspect of the present invention provides stable pharmaceutical compositions comprising therapeutically effective amount of angiotensin II receptor blocker, at least one pH regulating agent(s), and one or more other pharmaceutically acceptable excipient(s).

Another aspect of the present invention provides stable pharmaceutical compositions comprising therapeutically effective amount of azilsartan, at least one pH regulating agent(s), and optionally one or more other pharmaceutical ly acceptable excipient(s).

An aspect of the present invention provides stable pharmaceutical compositions comprising therapeutically effective amount of azilsartan, at least one pH regulating agent(s) having a pH of not less than about 5, and optionally one or more other pharmaceutically acceptable excipient(s). Another aspect of the present invention provides stable pharmaceutical compositions comprising azilsartan as a first active agent, optionally a second active agent(s), a pH regulating agent(s) having a pH of not less than about 5, and optionally one or more other pharmaceutically acceptable excipient(s).

In an aspect, the present invention provides process for the preparation of stable oral
pharmaceutical compositions of azilsartan, wherein the process comprises of the following steps:

i) treating azilsartan with at least one pH regulating agent(s),

ii) optionally adding one or more other pharmaceutically acceptable excipients, and

iii) formulating the material of step (i) and (ii) into a suitable dosage form.

In another aspect, the present invention provides process for the preparation of stable oral pharmaceutical compositions of azilsartan, wherein the process comprises of the following steps:

i) treating azilsartan with pH regulating agent(s),

ii) optionally adding a second active agent(s),

iii) optionally adding one or more other pharmaceutically acceptable excipients, and

iv) formulating the material of step (i), (ii) and (iii) into a suitable dosage form.

An aspect of the present invention also relates to method of using such compositions for the treatment of hypertension and associated disorders.

DETAILED DESCRIPTION OF THE INVENTION

The term "particle size" unless indicated otherwise in the specification relates to particles of azilsartan free base as well as pharmaceutically acceptable salt, amorphous or crystalline, anhydrous, esters, or isomer or derivative, hydrate, prodrug or solvates thereof. Azilsartan with specific "particle size" and distribution, or surface area would provide a fast dissolution of the active ingredient, would be easy to prepare and stable while maintaining the beneficial properties with respect to fast solubility and bioavailability. Particularly, according to the present invention, azilsartan having an average particle size less than about 200 microns, and/or surface area less that about 5 m7gm are useful.

The term "composition" or "formulation" or "dosage form" or "medicinal preparation" as used herein synonymously include solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, layered tablets (e.g. bilayer or trilayer), beads, particles and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration.

The term "therapeutically effective amount" is defined to mean the amount or quantity of the active drug (e.g. azilsartan), which is sufficient to elicit an appreciable biological response when administered to the patient.

In accordance with the present invention, the term "azilsartan" unless indicated otherwise in the entire specification refers to azilsartan in the form of free base or its pharmaceutically acceptable salt, amorphous, crystalline or any isomer or derivative, hydrate or solvate, prodrug or combinations thereof. Preferably azilsartan is in the form of azilsartan kamedoxomil, which is potassium salt of azilsartan medoxomil. The phrase "substantially pure polymorphic form of azilsartan or its salt thereof, unless otherwise specified is to be understood as a substance free of other polymorphic and/or pseudopolymorphic forms at amounts detectable with typical analytical methods such as X-ray powder diffraction and/or solid state infrared absorption, i.e. containing less than 10% of other polymorphic and/or pseudopolymorphic forms.

The term "excipient" means a pharmacologically inactive component such as a diluent, disintegrant, carrier, or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient. The phrase "medicinal package" unless indicated otherwise in the entire specification refers to bottle or blister pack or pouch or any corresponding packing known to a person skilled in the art in which the dosage form or the medicinal preparation is packed. The term "desiccant" unless indicated otherwise in the entire specification refers to a substance used to remove/suppress/decrease the odor/smell or to absorb moisture which prevents degradation/decomposition of the active agent(s). The desiccant may be placed in the internal space of the medicinal package, irrespective of any particular limit, so long as the amount is sufficient to remove the odorous material, that is, sufficient to suppress or reduce the smell. The amount of the desiccant can vary depending on kind or shape of the desiccant, distance from the medicinal preparation capable of giving out smells, amount of the compound giving out smells, type of formulation, volume of the space where the medicinal preparation and the desiccant are placed, amount of the existing or produced odorous material, preservation condition of the medicinal package.

As used in this specification, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus for example, a reference to "a process" includes one or more process, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

In an embodiment the present invention provides stable pharmaceutical compositions comprising therapeutically effective amount of angiotensin II receptor blocker, a pH regulating agent(s) with one or more other pharmaceutically acceptable excipient(s).

In another embodiment the present invention provides stable pharmaceutical compositions comprising therapeutically effective amount of azilsartan, a pH regulating agent(s) and optionally one or more other pharmaceutically acceptable excipient(s).

In one of the embodiments, the present invention provides stable pharmaceutical compositions comprising therapeutically effective amount of azilsartan, at least one pH regulating agent(s) having a pH of not less than about 5, and optionally one or more other pharmaceutically acceptable excipient(s).

In another embodiment, the present invention provides stable oral pharmaceutical compositions comprising azilsartan as an active agent(s) from about 0.1% w/w to about 99% w/w of the composition, a pH regulating agent from about 0.1% w/w to about 50% w/w of the composition, and optionally with one or more other pharmaceutically acceptable excipient(s) from about 0.8% to about 99% w/w of the composition based on total weight of the composition.

In an embodiment, the present invention provides stable pharmaceutical compositions comprising azilsartan as a first active agent, a second active agent(s), a pH regulating agent(s), and optionally one or more other pharmaceutically acceptable excipient(s).

Yet another embodiment of the present invention provides stable pharmaceutical compositions comprising azilsartan, a pH regulating agent(s), at least one desiccant, and optionally one or more other pharmaceutically acceptable excipient(s).

Yet another embodiment of the present invention provides stable pharmaceutical compositions comprising azilsartan, a pH regulating agent(s), at least one antioxidant, and optionally one or more other pharmaceutical^ acceptable excipient(s).

Yet another embodiment of the present invention provides stable pharmaceutical compositions comprising azilsartan, a pH regulating agent(s), at least one desiccant, at least one antioxidant, and optionally one or more other pharmaceutically acceptable excipient(s). In an aspect, the present invention provides process for the preparation of stable oral pharmaceutical compositions of azilsartan, wherein the process comprises of the following steps:

i) treating azilsartan with pH regulating agent(s),

ii) optionally adding one or more other pharmaceutically acceptable excipients, and

iii) formulating the material of step (i) and (ii) into a suitable dosage form.

In another aspect, the present invention provides process for the preparation of stable oral pharmaceutical compositions of azilsartan, wherein the process comprises of the following steps:

i) treating azilsartan with a pH regulating agent(s),

ii) optionally adding a second active agent(s),

iii) optionally adding one or more other pharmaceutically acceptable excipients, and

iv) formulating the material of step (i), (ii) and (iii) into a suitable dosage form.

In an embodiment, the pH regulating agent is selected from but not limited to group comprising basic amino acids selected from meglumine, lysine, arginine, and the like; alkaline amino silicates such as magnesium aluminometasiiicate (Neusilin®) and the like; alkali metal hydroxides selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide and the like; alkali metal carbonates selected from sodium carbonate, sodium hydrogen carbonate, magnesium carbonate, calcium carbonate; alkali metal oxides selected from calcium oxide, magnesium oxide and the like; ammonia, synthetic hydrotalcite, and the like; weak acids selected from citric acid, malic acid, lactic acid, phosphoric acid and trisodium citrate and the like used either alone or in combinations thereof. In an embodiment, pH regulating agent has a buffering ability at said pH and is selected from but not limited to group
comprising sodium dihydrogen phosphate, sodium phosphate, sodium citrate dihydrate, sodium acetate, sodium tartrate, disodium succinate, and the like, and mixtures thereof.

In an embodiment, the present invention discloses the effect of Magnesium aluminometa silicate type I-B, commercially available substances such as Neusilin FH2®. Neusilin FH2® is totally a synthetic magnesium aluminometasilicate (MAS) with exceptional excipient properties to improve API delivery and the quality of pharmaceutical preparations. Moreover, Neusilin FH2® has extremely large specific surface area, which helps in dissolution of API. Neusilin FH2® improves powder flowability and stabilizes the deliquescent drugs. In an embodiment, the second active agent(s) is selected from but not limited to calcium channel antagonist, beta blocker, diuretic or an insulin sensitizer.

In an embodiment, the calcium channel antagonist is selected from but not limited to manidipine, nifedipine, amlodipine, efonidipine, nicardipine, lercanidipine and the like thereof. In another embodiment, the beta blocker is selected from but not limited to metoprolol, atenolol, propranolol, carvedilol, pindolol and the like thereof.

In an embodiment, the diuretic is selected from but not limited to xanthine derivatives (e.g., theobromine and sodium salicylate, theobromine and calcium salicylate etc.), thiazide preparations (e.g. cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide etc.), anti-aldosterone preparations (e.g., spironolactone, triamterene etc.), carbonic anhydrase inhibitors (e.g., acetazolamide etc.), chlorobenzene sulfonamide preparations (e.g., chlortalidone, mefruside, indapamide etc.), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like thereof.

In an embodiment, the insulin sensitizer is selected from but not limited to pioglitazone hydrochloride, troglitazone, rosiglitazone; .alpha.-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate etc.); biguanides (e.g., phenformin, metformin, buformin etc.); sulfonylureas (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole etc.); repaglinide, senaglinide, nateglinide, mitiglinide or its calcium salt hydrate; amyrin agonists (e.g., pramlintide etc.), phosphotyrosine phosphatase inhibitors(e.g., vanadic acid etc.), dipeptidylpeptidase IV inhibitors; beta.3 agonists; gluconeogenesis inhibitors (e.g., glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist etc.), SGLT (sodium-glucose cotransporter) inhibitors (e.g., T-1095 etc.) and the like thereof.

"Pharmaceutically acceptable excipient(s)" are components added to pharmaceutical formulation in addition to the active ingredient azilsartan. Excipients may be added to facilitate manufacture, enhance stability, enhance product characteristics, enhance bioavailability, enhance patient acceptability, etc. Pharmaceutically acceptable excipient(s) includes, but not limited to, one or more of diluents/fillers, binders, disintegrants, lubricants, glidants, compression aids, colors, sweeteners, preservatives, surfactants, suspending agents, dispersing agents, film formers, flavors, printing inks, etc. Exemplary "diluents" include, but are not limited to, microcrystalline cellulose, lactose, mannitol, sorbitol, sugar, starches, modified starches, pregelatinized starch, talc, kaolin, sucrose, dextrates, dextrin, maltodextrin, dextrose, mannitol, sorbitol, xylitol, lactitol, calcium carbonate, calcium sulfate, dibasic calcium phosphate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like used either alone or in combinations thereof. The diluent may be used in the range of about 20-98% by weight of the composition. Exemplary "binders" include, but are not limited to, hydroxypropyl cellulose, hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, povidone, starches such as corn starch, potato starch, modified starches, sugars, guar gum, pectin, wax binders, methylcellulose, carboxymethylcellulose, hydroxyethyl cellulose, copolyvidone, carboxymethylcellulose sodium, ethyl cellulose, gelatin, liquid glucose and pregelatinized starch and the like used either alone or in combinations thereof. The binder may be used in the range of about 0.5-10% by weight of the composition.

Exemplary "disintegrants" include, but are not limited to, croscarmellose sodium, crospovidone, sodium starch glycolate, polacrilin potassium, microcrystalline cellulose, pregelatinized maize
starch and the like used either alone or in combinations thereof. In an embodiment, the disintegrant may be used in the range of about 0.5-20% by weight of the composition. Exemplary "glidants" include, but are not limited to, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, corn starch, DL-leucine and the like, used either alone or in combinations thereof.

Exemplary "lubricants" include, but are not limited to, magnesium stearate, calcium stearate, sodium stearyl fumarate, zinc stearate, stearic acid, fumaric acid, palmitic acid, talc, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols and the like, used either alone or in combinations thereof.

Surfactants are compounds which are capable of improving the wetting of the drug and/or enhancing the dissolution. The surfactants can be selected from hydrophilic surfactants or lipophilic surfactants or mixtures thereof. The surfactants can be anionic, nonionic, cationic, and zwitterionic surfactants. Surfactants according to the present invention are selected from, but not limited to, polyoxyethylene alkylaryl ethers such as polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether; polyethylene glycol (PEG) fatty acid esters such as PEG monolaurate, PEG dilaurate, PEG distearate, PEG dioleate; polyoxyethylene sorbitan fatty acid ester such as polysorbate 40, polysorbate 60, polysorbate 80; sorbitan fatty acid mono esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene castor oil derivates such as polyoxyl castor oil, polyoxyl hydrogenated castor oil, sodium lauryl sulphate and the like, used either alone or in combination thereof.

In an embodiment, the desiccants are selected from but not limited to a synthetic zeolite, silica gel, silica-alumina, an active carbon, metallic oxide such as calcium oxide and the like used either alone or in combinations thereof.

In an embodiment, the antioxidant is selected from but not limited to BHA, BHT, Vitamin E TPGS, sodium citrate, propyl gallate, commercially available substances such as Stabilox® and
the like used either alone or in combinations thereof. In an embodiment, the antioxidant and/or the desiccant are present in the composition and/or in the packaging.

Suitable "granulating solvents" include, but are not limited to, purified water, isopropyl alcohol, dichloromethane, ethanol, acetone, methylene chloride and the like, used either alone or in combinations thereof.

The tablets in accordance with the present invention can be prepared by either direct compression, dry granulation like slugging or roller compaction, or by wet granulation. The wet granulation method may comprise use of aqueous solvent such as water or an organic solvent (non-aqueous) such as dichloromethane, ethanol, acetone, methylene chloride and the like, or a mixture thereof, as the granulating aid.

In an embodiment, the compositions of the present invention may additionally comprise of a colorant in order to produce a desirable color. Colors known to be 'FD&C certified may be used to provide coloring to the product and are within the purview of the present invention. Suitable colorants include natural colorants i.e., pigments and dyes obtained from mineral, plant, and animal sources. Examples of natural colorants include red ferric oxide, yellow ferric oxide, annattenes, alizarin, indigo, rutin, quercetin, and the like. Synthetic colorants may also be used, which is typically an FD&C or D&C dye, e.g., an approved dye selected from the so-called 'coal-tar' dyes, such as a nitroso dye, a nitro dye, an azo dye, an oxazine, a thiazine, a pyrazolone, a xanthene, an indigoid, an anthraquinone, an acridine, a rosaniline, a phthalein, a quinoline, or a 'lake' thereof, i.e. an aluminum or calcium salt thereof. Particularly preferred colorants are food colorants in the 'GRAS' (Generally Regarded as Safe) category.

In an embodiment, the tablet compositions of the present invention may be film coated. A film forming agent may provide smooth film-forming coating suspensions and enhance the rheological mechanical strength properties of film coating gel matrices. Film forming agents include, for example, polyvinylpyrrolidone, natural gums, starches, and cellulosic polymers. A cellulosic polymer may include a molecule comprising at least one cellulose polymer or derivative modified with small amounts of propylene glycol ether groups attached to the cellulose anhydroglucose chain affording binding properties that enhance the reinforcing film properties of film applications. Examples of cellulosic polymers include, but are not limited to, hydroxypropyl methyl cellulose ("HPMC"), carboxymethyl cellulose ("CMC") or salts thereof, hydroxypropyl cellulose ("HPC"), methylcellulose ("MC"), hydroxyethyl cellulose ("HEC"), and the like. In addition, cellulosic polymers may be characterized as ionic or non-ionic. Ionic cellulosic polymers include, for example, sodium CMC. Non-ionic cellulosic polymers include, for example, HPMC, HPC, HEC, and MC. Varieties of commercially available cellulosic polymers exist and may include, for example, Spectracel® HPMC compositions (available from Sensient Technologies). Further, other commercially available coating materials are available marketed under the brand name Opadry® for example Opadry II Gray which contains: lactose monohydrate NF, hypromellose type 2910 USP, titanium dioxide USP, triacetin USP, and iron oxide black JPE; Opadry II Pink which contains: hypromellose type 2910 USP, titanium dioxide USP, lactose monohydrate NF, polyethylene glycol 3350 NF, triacetin USP, and FD&C Red #40; Opadry II Blue which contains: hypromellose type 2910 USP, lactose monohydrate NF, FD&C Blue #1, polyethylene glycol 3350 NF, FD&C Blue #2, titanium dioxide USP, triacetin USP, and D&C Yellow #10; Opadry II Yellow which contains: hypromellose type 2910 USP, lactose monohydrate NF, titanium dioxide USP, iron oxide yellow NF, polyethylene glycol 3350 NF, and triacetin USP; Opadry II Purple which contains: hypromellose type 2910 USP, lactose monohydrate NF, titanium dioxide USP, D&C Red #27, polyethylene glycol 3350 NF, triacetin USP, and FD&C Blue #1 and the like.

It is also desirable that the compositions are chemically stable as degradation by oxidation, hydrolysis, isomerisation, photolysis, polymerization, or any other method of degradation, either as a result of mixing with excipients or by any other method, could lead to a change in bioavailability and could also lead to toxicity. Chemical stability can be measured by a suitable, stability indicating chromatographic method for determining degradation products (see Aulton Me., Pharmaceutics—The Science of Dosage Form Design, 2.sup.nd Edition, 2002, Churchill Livingstone).

In yet another embodiment, the present invention provides method of using such compositions for treatment of hypertension and associated disorders.

The following examples serve to illustrate the embodiments of the present invention. However, they do not intend to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Manufacturing process:
i) Azilsartan kamedoxomil, lactose monohydrate, povidone, magnesium carbonate, crospovidone and sorbitol were sifted together,

ii) The blend of step (i) was granulated using purified water, followed by drying and milling to
get the granules of desired size.

iii) Lactose monohydrate and crospovidone were sifted together and blended with granules of
step (ii).

iv) The blend of step (iii) was lubricated with magnesium stearate and finally compressed into
tablets or filled into capsules.

EXAMPLE 2: The manufacturing process followed is similar to process of preparation provided for example 1.
""Lost in processing
"q.s. " - quantity sufficient

Manufacturing process:

i) Azilsartan kamedoxomil, lactose monohydrate, hydroxypropyl methylcellulose, meglumine,
croscarmellose sodium and mannitol were sifted together,

ii) The blend of step (i) was granulated using isopropyl alcohol, followed by drying and milling to get the desired size granules.

iii) Mannitol and croscarmellose sodium were sifted together and blended with granules of step
(ii).

iv) The blend of step (iii) was lubricated with magnesium stearate and finally compressed into
tablets using a suitable compression machine.

v) The compressed tablets of step (iv) were coated with Opadry® II purple.

EXAMPLE 4: The manufacturing process followed is similar to process of preparation provided for example 3.
*Lost in processing
"q.s. " - quantity sufficient

Manufacturing process:

i) Azilsartan kamedoxomii, hydrochlorothiazide, xylitol, methylcellulose, sodium hydroxide,
lysine, croscarmellose sodium and mannitol were sifted together,

ii) The blend of step (i) was slugged/compacted and milled to get the desired size granules.

iii) Mannitol and croscarmellose sodium were sifted together and blended with the granules of
step (ii).

iv) The blend of step (iii) was lubricated with sifted magnesium stearate and finally compressed
into tablets,

v) The compressed tablets of step (iv) were coated with Opadry® II yellow.
EXAMPLE 6: The manufacturing process followed is similar to example 5.
*Lo$t in processing
"q.s. " - quantity sufficient

Manufacturing process:
i) Azilsartan kamedoxomil, microcrystalline cellulose, hydroxypropyl cellulose, meglumine,
croscarmellose sodium and mannitol were sifted together, ii) The blend of step (i) was granulated using isopropyl alcohol, followed by drying and milling
to get the desired size granules, iii) Croscarmellose sodium and microcrystalline cellulose were sifted together and blended with
granules of step (ii).
iv) The blend of step (iii) was lubricated with sifted magnesium stearate and finally compressed into tablets using a suitable compression machine.
EXAMPLE 8: The manufacturing process followed is similar to example 7.
Manufacturing process:
i) Azilsartan kamedoxomil, microcrystalline cellulose, hydroxypropyl cellulose, meglumine,
croscarmellose sodium and mannitol were sifted together, ii) The blend of step (i) was slugged/compacted and milled to get the desired size granules, iii) Mannitol and croscarmellose sodium were sifted and blended with granules of step (ii). iv) The blend of step (iii) was lubricated with sifted magnesium stearate and finally compressed
into tablets.Manufacturing process:

i). Azilsartan kamedoxomil, sucrose, corn starch, potassium hydroxide, crospovidone and
xylitol were sifted and then blended together,

ii). Glyceryl behenate was sifted separately. Hi).The blend of step (i) was blended with glyceryl behenate of step (ii) and finally compressed into tablets or filled into capsules.

We claim:
Stable pharmaceutical composition comprising therapeutically effective amount of azilsartan, at least one pH regulating agent(s) having a pH of not less than about 5, and optionally one or more other pharmaceutically acceptable excipient(s).

The composition according to claim 1, comprising azilsartan from about 0.1% w/w to about 99% w/w of the composition, a pH regulating agent from about 0.1% w/w to about 50%o w/w of the composition, and optionally with one or more other pharmaceutically acceptable excipient(s) from about 0.8%) to about 99%> w/w of the composition based on total weight of the composition.
The composition according to claim 1 or 2, comprising azilsartan as a first active agent, a second active agent(s), a pH regulating agent(s), and optionally one or more other pharmaceutically acceptable excipient(s).

The composition according to claim 1, comprising azilsartan, a pH regulating agent(s), at least one desiccant, and optionally one or more other pharmaceutically acceptable excipient(s).
The composition according to claim 1, comprising azilsartan, a pH regulating agent(s), at least one antioxidant, and optionally one or more other pharmaceutically acceptable excipient(s).
The composition according to claim 1, comprising azilsartan, a pH regulating agent(s), at least one desiccant, at least one antioxidant, and optionally one or more other pharmaceutically acceptable excipient(s).
The composition according to claim 3, wherein the second active agent(s) is selected from calcium channel antagonist, beta blocker, diuretic or an insulin sensitizer.

The composition according to claims 1 to 7, wherein the pH regulating agent is selected from group comprising basic amino acids selected from meglumine, lysine, arginine; alkaline amino silicates; alkali metal hydroxides selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide; alkali metal carbonates selected from sodium carbonate, sodium hydrogen carbonate, magnesium carbonate, calcium carbonate; alkali metal oxides selected from calcium oxide, magnesium oxide and the like; ammonia, synthetic hydrotalcite, weak acids selected from citric acid, malic acid, lactic acid, phosphoric acid and trisodium citrate, sodium dihydrogen phosphate,
sodium phosphate, sodium citrate dihydrate, sodium acetate, sodium tartrate, disodium succinate used either alone or in combinations thereof.

The composition according to claim 1, wherein the pharmaceutically acceptable excipient is selected from a group comprising of diluents/fillers, binders, disintegrants, lubricants, glidants, compression aids, colors, sweeteners, preservatives, surfactants, suspending agents, dispersing agents, film formers, flavors, printing inks, used either alone or in combinations thereof.

A process for the preparation of pharmaceutical composition according to claim 1, wherein the process comprises of the following steps:

i) treating azilsartan with a pH regulating agent(s),

ii) optionally adding a second active agent(s),

iii) optionally adding one or more other pharmaceutically acceptable excipients, and

iv) formulating the material of step (i), (ii) and (iii) into a suitable dosage form.