DESC:FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The present invention particularly relates to pharmaceutical compositions comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient that show desired stability as well as dissolution profile. The present invention also relates to a method of preparing pharmaceutical compositions comprising azilsartan medoxomil that are stable and has desired dissolution profile. In addition, the present invention relates to a simple and cost effective process for the preparation of pharmaceutical compositions comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof.

The present invention also relates to stable pharmaceutical compositions comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof as a first active agent, optionally a second active agent(s), and optionally one or more other pharmaceutically acceptable excipient(s). The present invention further relates to use of the pharmaceutical compositions for the treatment of hypertension and associated disorders.

BACKGROUND OF THE INVENTION

Blood pressure (BP) is the pressure of circulating blood on the walls of blood vessels. It is usually expressed in terms of the Systolic blood pressure (SBP) and Diastolic blood pressure (DBP). SBP is the peak pressure exerted on the walls of the arteries during the contraction phase of the ventricles of the heart while DBP is the minimum pressure exerted on the vessel walls when the heart muscle relaxes between two heart beats. BP is influenced by multiple factors like the muscular efficiency of the heart, the blood volume and viscosity, the age and health of the individual, and the state of the vascular wall. The mean arterial blood pressure is the product of cardiac output and peripheral vascular resistance.

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. It is defined as a SBP of at least 140 mmHg and/or a DBP of at least 90 mmHg. Blood pressure between 120/80 mmHg and 139/89 mmHg is called prehypertension to denote increased risk of hypertension.

Hypertension affects about 20% of the adult population in developed countries. In the adult population aged 60 years or older, this percentage increases to about 60% to 70% in general. Hypertension is also associated with an increased risk of other physiological complications including stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease and renal impairment. (Fagard, R. H., Am. J. Geriatric Cardiology, 11 (1), 23-28 (2002); Brown, M J and Haycock, S; Drugs, 59 (Suppl 2), 1-12 (2000)).

Hypertension may be classified as primary (essential) or secondary. Primary hypertension is the term for high blood pressure with unknown cause that accounts for about 95% of cases and Secondary hypertension is the term for high blood pressure with a known direct cause, such as kidney disease, tumors. It is also caused by endocrine conditions, such as Cushing's syndrome, hyperthyroidism, hypothyroidism, acromegaly, Conn's syndrome or hyperaldosteronism, hyperparathyroidism and pheochromocytoma. Hypertension can be managed by non-medication measures such as lifestyle changes such as dietary changes, physical exercise, weight loss and alike as well as medication measures. Several classes of medications called as 'antihypertensive drugs' belong to various chemical and pharmacological categories have been developed for the management of hypertension. However, the efficacy and safety of such drugs vary from patient to patient and there remains need for more effective treatment.

One of the class of antihypertensive drugs is Angiotensin II receptor blockers (ARB) or antagonists. Angiotensin II can act directly on blood vessels to cause increase in blood pressure. It also stimulates the release of aldosterone which is a potent vasoconstrictor that causes significant increase in blood pressure, but can also change the baseline filtering activity of the kidneys. Aldosterone causes the kidneys to retain both salt and water, which, over time, increases the amount of water in the body resulting into rise in blood pressure. ARBs specifically antagonize or block the action of angiotensin II type 1 receptors resulting in vasodilation, reduced secretion of vasopressin, and reduced production and secretion of aldosterone. The combined effect is a reduction in blood pressure.

Azilsartan is a selective AT1 subtype angiotensin II receptor antagonist. It is approved by USFDA as Edarbi® immediate release oral tablets containing azilsartan medoxomil for the treatment of hypertension. Azilsartan medoxomil is a prodrug, which is hydrolyzed to azilsartan in the gastrointestinal tract during absorption. Each Edarbi® tablet contains 42.68 or 85.36 mg azilsartan kamedoxomil, as the potassium salt of azilsartan medoxomil, which is equivalent to containing 40 mg or 80 mg respectively of azilsartan medoxomil. Azilsartan medoxomil is chemically described as (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate monopotassium salt. Azilsartan kamedoxomil is a white to nearly white powder which is practically insoluble in water and freely soluble in methanol.

US 5583141 patent discloses the compound azilsartan. US 7157584 patent discloses azilsartan medoxomil or a pharmaceutically acceptable salt thereof. US 7572920 patent relates to a composition comprising azilsartan kamedoxomil or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. US 20100016382 patent application further 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 20110201658 patent application discloses a pharmaceutical package including a preparation containing azilsartan or a salt thereof, and a desiccant. US 20120100093 patent application discloses a medicinal package comprising an azilsartan preparation capable of giving out smells, a packaging component and a chemical absorption-type desiccant. US 9066936 patent further 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 teaches that azilsartan is unstable in the neutral pH range, at which pharmaceutical preparations are generally produced and solubility of azilsartan is low at a pH range where it is stable. The objective of this patent was to simultaneously achieve the stability and solubility of azilsartan which is accomplished by use of a pH control agent(s) that specifically has pH of about 2 to about 5. WO 2014102628 patent application discloses a stable pharmaceutical composition comprising azilsartan medoxomil, or a pharmaceutically acceptable salt thereof, and a polymeric carrier which is selected from the group consisting of polyvinyl pyrrolidone, copovidone, or a mixture thereof.

There remains a need to provide the pharmaceutical compositions containing the actives like azilsartan having stability and solubility concerns. It is a challenge to design the pharmaceutical compositions of such actives which are stable and also achieve desired dissolution and bioavailability parameters.

Inventors of the present invention have surprisingly found that the pharmaceutical compositions of the present invention are stable when prepared without the use of pH control agent(s) and also simultaneously achieve desired solubility profile. This is contrary to the teachings of the existing prior arts that require use of the pH control agent(s) which provide the pH in a strict narrow range of about 2 to about 5 to prepare stable pharmaceutical compositions of azilsartan with desired dissolution characteristics.

SUMMARY OF THE INVENTION

The present invention provides pharmaceutical compositions comprising therapeutically effective amount of angiotensin II receptor blocker and one or more other pharmaceutically acceptable excipient(s). The present invention provides stable pharmaceutical compositions comprising therapeutically effective amount of azilsartan medoxomil or a pharmaceutically acceptable salt thereof and one or more other pharmaceutically acceptable excipient(s).

Pharmaceutical compositions of the present invention comprising therapeutically effective amount of azilsartan medoxomil or a pharmaceutically acceptable salt thereof are stable and when subjected to conditions of 40°C/75% RH for a period of three months, results in less than 0.5% of desethyl azilsartan, desethyl azilsartan medoxomil, azilsartan medoxomil amide, ethyl azilsartan and other related substances originating from the decomposition of azilsartan medoxomil. Contrary to the existing prior arts, these pharmaceutical compositions are prepared without the use of pH control agent(s).

An aspect of the present invention provides pharmaceutical compositions comprising therapeutically effective amount of azilsartan medoxomil or a pharmaceutically acceptable salt thereof and one or more other pharmaceutically acceptable excipient(s), the compositions are stable and also achieve desired dissolution.

Another aspect of the present invention provides stable pharmaceutical compositions comprising therapeutically effective amount of azilsartan medoxomil or a pharmaceutically acceptable salt thereof, a cyclodextrin component and one or more other pharmaceutically acceptable excipient(s). An aspect of the present invention further provides stable pharmaceutical compositions comprising therapeutically effective amount of azilsartan medoxomil or a pharmaceutically acceptable salt thereof, hydroxypropyl beta-cyclodextrin and one or more other pharmaceutically acceptable excipient(s). The compositions of the present invention simultaneously achieve desired stability characteristics and dissolution profile.

In an another aspect, the present invention provides process for the preparation of stable oral pharmaceutical compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipient(s), wherein the process comprises of the following steps:
i) blending azilsartan medoxomil with one or more pharmaceutically acceptable excipients,
ii) dissolving/dispersing a granulating agent in granulating solventiii) granulating the blend of step i) using granulating agent prepared in step ii)
iv) optionally adding one or more other pharmaceutically acceptable excipients to the blend in step iii)
v) compressing the granules of step iii) or the blend of step iv) into a suitable sized tablets or filling into suitable sized capsules.

In an another aspect, the present invention provides process for the preparation of stable oral pharmaceutical compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof, a cyclodextrin component and optionally one or more pharmaceutically acceptable excipient(s), wherein the process comprises of the following steps:
i) blending azilsartan medoxomil, a cyclodextrin component and one or more pharmaceutically acceptable excipients,
ii) dissolving/dispersing a granulating agent in granulating solvent
iii) granulating the blend of step i) using granulating agent prepared in step ii)
iv) optionally adding one or more other pharmaceutically acceptable excipients to the blend in step iii)
v) compressing the granules of step iii) or the blend of step iv) into a suitable sized tablets or filling into suitable sized capsules.

Present invention further provides a simple and cost effective process to prepare the stable pharmaceutical compositions comprising therapeutically effective amount of azilsartan medoxomil or a pharmaceutically acceptable salt thereof and one or more other pharmaceutically acceptable excipient(s).

One aspect of the present invention relates to stable pharmaceutical compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof prepared by an anhydrous granulation process. Another aspect of the present invention provides stable pharmaceutical compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof prepared by a granulation process using an anhydrous solvent(s), which further optionally contains a hydrous solvent(s).

Another aspect of the present invention relates to stable pharmaceutical compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof prepared by a granulation process using a mixture of an anhydrous solvent(s) and a hydrous solvent(s).
Another aspect of the present invention also relates to the application of specified compression force to prepare pharmaceutical compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof that are stable and also shows desired dissolution characteristics.

Yet another aspect of the present invention provides stable pharmaceutical compositions comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof as a first active agent, optionally a second active agent(s), and optionally one or more other pharmaceutically acceptable excipient(s). Yet another aspect of the present invention provides stable pharmaceutical compositions comprising therapeutically effective amount of azilsartan medoxomil or a pharmaceutically acceptable salt thereof as a first active agent, optionally a second active agent(s), a cyclodextrin component and one or more other pharmaceutically acceptable excipient(s).

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

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides pharmaceutical compositions comprising therapeutically effective amount of angiotensin II receptor blocker and one or more other pharmaceutically acceptable excipient(s). Particularly present invention provides pharmaceutical compositions comprising therapeutically effective amount of azilsartan medoxomil as an angiotensin II receptor blocker and one or more other pharmaceutically acceptable excipient(s).

In accordance with the present invention, the "azilsartan" unless indicated otherwise in the 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 medoxomil which is a prodrug of azilsartan active. Azilsartan medoxomil is hydrolyzed to azilsartan in the gastrointestinal tract during absorption.

The term "therapeutically effective amount" is defined to mean the amount or quantity of the active drug azilsartan, which is sufficient to elicit an appreciable biological response when administered to the patient. A person skilled in the art can easily determine such an amount by routine experimentation and with an undue burden. Therapeutically effective amount of azilsartan medoxomil in the respect of this invention is usually between 40 and 80 mg, usually administered once daily, although amounts outside this range and different frequencies of administration are feasible for use in therapy under prescribed medical conditions. As mentioned, dosage forms of the present invention are useful, inter alia, in the prevention and/or treatment of hypertension and associated disorders.

Azilsartan medoxomil or its pharmaceutically acceptable salt(s) may be present in crystalline or amorphous forms and may include salts with inorganic bases and organic bases. Inorganic bases may include, but not limited to, salts with alkali metals such as sodium or potassium, or alkaline earth metals such as calcium or magnesium. Organic bases may include, but not limited to, salts of ethanolamines, tromethamine, trimethylamine, triethylamine, tertiary butylamine, pyridine and dicyclohexylamine. Preferably azilsartan medoxomil is in the form of azilsartan kamedoxomil in the present invention, which is a potassium salt of azilsartan medoxomil. The concentration of azilsartan medoxomil, or a pharmaceutically acceptable salt thereof, used in the pharmaceutical composition ranges from 10% w/w to 50% w/w by weight of the pharmaceutical composition.

An important aspect of the present invention provides compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof that are stable. It is required that compositions comprising azilsartan as an active are chemically stable as degradation by oxidation, hydrolysis, isomerization, photolysis, polymerization, or any other method of degradation, 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.

The term "stable", as used herein, refers to the pharmaceutical composition of the present invention, when subjected to conditions of 40°C/75% RH for a period of three months, results in less than 0.5% of desethyl azilsartan, desethyl azilsartan medoxomil, azilsartan medoxomil amide, ethyl azilsartan and other related substances originating from the decomposition of azilsartan medoxomil. Pharmaceutical compositions of the present invention comprising azilsartan medoxomil are found to be stable. The stability of the compositions achieved without using any pH control agent which is contrary to the prior art mentioned in the earlier paragraphs and it is one of the important aspect of the present invention.

In an aspect of the present invention, stable compositions of the azilsartan medoxomil or pharmaceutically acceptable salt thereof comprise one or more cyclodextrin component(s). The cyclodextrin component as used herein, is intimately mixed with azilsartan medoxomil. Cyclodextrin component acts as a solubilizer and stabilizer for azilsartan medoxomil. Various cyclodextrins that can be used in the present invention include but not limited to cyclodextrin, a- cyclodextrin, ß- cyclodextrin, ?- cyclodextrin, hydroxypropyl-ß-cyclodextrin, sulfobutyl ether ß-cyclodextrin sodium salt, methylated ß-cyclodextrin, branched ß and ?- cyclodextrin, hydroxypropyl-?-cyclodextrin or combination thereof. Cyclodextrin component may further include, but not limited to, chemically modified cyclodextrins, for example, methylated, acetylated, hydroxypropylated cyclodextrins or alike. In one embodiment of the present invention, cyclodextrin component is selected from the group comprising of ß- cyclodextrin, hydroxypropyl-ß-cyclodextrin, hydroxypropyl- ?-cyclodextrin or mixtures thereof.

In an embodiment of this invention, the ratio of azilsartan medoxomil or a pharmaceutically acceptable salt thereof to a cyclodextrin component is selected from about 1: 10 to about 10: 1 based on weight.

Another important aspect of the present invention provides a stable pharmaceutical composition comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof prepared by an anhydrous granulation process comprising azilsartan medoxomil, or a pharmaceutically acceptable salt thereof. Yet another important aspect of the present invention provides a stable pharmaceutical composition comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof prepared by a granulation process using a mixture of an anhydrous solvent(s) and a hydrous solvent(s).

Another embodiment of the present invention provides a stable pharmaceutical composition comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof prepared by a granulation process using an anhydrous granulation solvent(s) which further optionally contains a hydrous solvent(s) and comprises a cyclodextrin component selected from group comprising of hydroxy propyl ß -cyclodextrin, hydroxy propyl ? - cyclodextrin or a mixture thereof, wherein the ratio of azilsartan medoxomil, or a pharmaceutically acceptable salt thereof, to the cyclodextrin component is from about 1: 10 to about 10: 1 based on weight. In another aspect of the present invention provides a stable pharmaceutical composition comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof and a cyclodextrin component selected from above group which is prepared by a granulation process using a mixture of an anhydrous solvent(s) and a hydrous solvent(s).

Granulating solvent used in the present invention include, but not limited to, anhydrous, hydrous, or mixture thereof. The term "anhydrous granulation", as used herein, refers to a wet granulation process carried out using anhydrous solvents without the use of water. Suitable anhydrous solvents include, but not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, isopropyl alcohol, toluene, tetrahydrofuran, chloroform, methylene chloride, or mixtures thereof. In an embodiment of the present invention, acetone is preferred as an anhydrous solvent. The anhydrous solvent as a wet granulating agent is used in an amount of 10% to 80% w/w. The present invention also incorporates the use of a granulation process using an anhydrous solvent(s), which further optionally contains a hydrous solvent such as water. The present invention further incorporates the use of a granulation process that uses a mixture of an anhydrous solvent(s) and a hydrous solvent(s). In an embodiment of the present invention, a mixture of acetone and water is a preferred granulating solvent.

In yet another embodiment, the present invention provides stable pharmaceutical compositions comprising azilsartan medoxomil as a first active agent, optionally a second active agent(s), and optionally one or more other pharmaceutically acceptable excipient(s). Second active agent(s) that can be used in the present invention include, but not limited to, antihypertensive agent(s) or a hypoglycemic agent(s). Antihypertensive agents may be further selected from, but not limited to, diuretics, calcium channel blockers, and ACE inhibitors. Diuretics include, but not limited to, chlorthalidone, chlorothiazide, hydrochlorothiazide, and alike or pharmaceutically acceptable salts thereof. Calcium channel blockers include, but not limited to, amlodipine, felodipine, isradipine, nicardipine, nifedipine, diltiazam, verapamil or a pharmaceutically acceptable salts thereof. ACE inhibitors include, but not limited to, benazepril, benazeprilat, captopril, enalapril, enaprilat, fosinopril, imidapril, lisinopril, perindopril, quinapril, ramipril, or a pharmaceutically acceptable salt thereof.

Hypoglycemic agents include, but not limited to, repaglinide, nateglinide, glimepiridum, glibenclamidum, gliclazidum, metformin, miglitol, acarbose, pioglitazone, rosiglitazone or a pharmaceutically acceptable salt thereof.

In an embodiment of the present invention the said second active is selected from diuretics that include, but not limited to, chlorthalidone, chlorothiazide and hydrochlorothiazide or pharmaceutically acceptable salts thereof.

The said second active agent is used in a therapeutically effective amount that is useful for the prevention and/or treatment of hypertension and associated disorders and may further shows synergistic therapeutic effect when combined with azilsartan medoxomil or a pharmaceutically acceptable salt thereof.

One embodiment of the present invention provides process for the preparation of stable oral pharmaceutical compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipient(s), wherein the process comprises of the following steps:
i) blending azilsartan medoxomil with one or more pharmaceutically acceptable excipients,
ii) dissolving/dispersing a granulating agent in granulating solvent
iii) granulating the blend of step i) using granulating agent prepared in step ii)
iv) optionally adding one or more other pharmaceutically acceptable excipients to the blend in step iii)
v) compressing the granules of step iii) or the blend of step iv) into a suitable sized tablets or filling into suitable sized capsules.

In an another embodiment, the present invention provides process for the preparation of stable oral pharmaceutical compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof, a cyclodextrin component and optionally one or more pharmaceutically acceptable excipient(s), wherein the process comprises of the following steps:
i) blending azilsartan medoxomil, cyclodextrin component and one or more pharmaceutically acceptable excipients,
ii) dissolving/dispersing a granulating agent in granulating solvent
iii) granulating the blend of step i) using granulating agent prepared in step ii)
iv) optionally adding one or more other pharmaceutically acceptable excipients to the blend in step iii)
v) compressing the granules of step iii) or the blend of step iv) into a suitable sized tablets or filling into suitable sized capsules.

In yet another embodiment, a pharmaceutical composition of the present invention is prepared according to the processes described above and comprises azilsartan medoxomil as a first active agent, optionally a second active agent(s), and optionally one or more other pharmaceutically acceptable excipient(s).

Application of a specified compression force to prepare the dosage forms of the present invention is another important aspect of present invention. Applying the specified compression force to the granules or the blend prepared according to the present invention results into dosage forms having desired dissolution as well as stability profile. The compression force is applied by an upper and lower punch to carry out the compression step. The compression force (N) applied during the compression step of the process of the present invention is in the range of from 50 to 300 N, preferably from 50 to 200 N, more preferably from 50 to 150 N.

In an another embodiment of the present invention, stable pharmaceutical compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof of the present invention show desired dissolution characteristics. The composition(s) according to the present invention, when tested for in- vitro dissolution profile, exhibits dissolution such that the amount of the drug equivalent to 85 % dissolves within 30 minutes. To study the dissolution criterion, the suitable dissolution test is selected and it is carried out in an aqueous media non-buffered or buffered to a pH range (1 to 7.8) found in the gastrointestinal tract and controlled at 370C (± 100C), that maintain a physiological relevance. Various dosages, such as tablets, capsules can be studied for dissolution profile, in a standard prescribed manner. When the dosage form is a tablet, typically paddles rotating at 50-75 rpm are used to test the dissolution rate of the tablets. The amount of dissolved active can be determined using suitable analytical techniques such as UV or HPLC.

Since in-vivo-in-vitro relationships are established, the dissolution (in-vitro) test, in addition to its application as a quality control technique, can more preferably be used to predict the biological (in-vivo) performance of the tablet. In one of the embodiment, the dissolution test is performed in 900 mL of dissolution medium at 370 C., using USP Apparatus 2 (paddles) method at a rotation speed of 50 rpm. Samples are removed after 5, 10, 15, 20, 30, 45, and 60 minutes from test initiation and analyzed for azilsartan medoxomil. Phosphate buffer, pH 7.8 deaerated solution has been used as dissolution medium.

The term "composition" or "formulation" or "dosage form" 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 "excipient" as used herein means a pharmacologically inactive component such as, but not limited to, a diluent or filler, binder, disintegrant, lubricant, glidant, surfactant, colourant or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for human use. Reference to an excipient includes both one and more than one such excipients and the said excipients may be added intragranularly or extragranularly.

“Fillers or diluents” may be selected from, but not limited to, carbohydrates, confectioners sugar, compressible sugars, dextrose, dextrin, fructose, lactitol, xylitol, sorbitol, microcrystalline cellulose, mannitol, lactose, sucrose, maltose, starch, calcium carbonate, calcium sulfate, calcium hydrogen phosphate, or combinations thereof. Fillers or diluents may be used in the range of 10-90 % w/w of total weight of stable oral pharmaceutical composition.

“Binders” may be selected from, but not limited to, potato starch, wheat starch, corn starch, microcrystalline cellulose, celluloses such as hydroxy propyl cellulose, hydroxy propyl methylcellulose, povidone, hydroxy ethyl cellulose, sodium carboxy methyl cellulose, natural gums like acacia, alginic acid, guar gum, liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, or combinations thereof. Binders may be used in the range of 1-15 % w/w of total weight of stable oral pharmaceutical composition.

“Disintegrants” may be selected from, but not limited to, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, sodium alginate, sodium starch glycolate, starches or combinations thereof. Disintegrants may be used in the range of 1-50 % w/w of total weight of stable oral pharmaceutical composition.

“Lubricants” may be selected from, but not limited to, aluminium stearate, zinc stearate, calcium stearate, magnesium stearate, polyethylene glycol, mineral oil, talc, hydrogenated vegetable oil, stearic acid, magnesium aluminum silicate, sodium stearyl fumarate, glyceryl behenate, sodium benzoate or mixtures thereof. Lubricant may be used in the range of 0.1 - 5 % w/w of total weight of stable oral pharmaceutical composition.

“Glidants” may be selected from, but not limited to, silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel or mixtures thereof. Glidant may be used in the range of 0.01 – 4 % w/w of total weight of stable oral pharmaceutical composition.

“Surfactants” are compounds which are capable of improving the wetting of the drug and/or enhancing the dissolution. The surfactants can be selected from, but not limited to, 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 rnonooleate, 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.
“Colorants” may be selected from, but not limited to, iron oxide yellow, iron oxide red, titanium dioxide or mixtures thereof. Colorants may be used in the range of 0.01 – 1.5 % w/w of total weight of stable oral pharmaceutical composition.

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

The pharmaceutical compositions of the present invention may be further coated with a functional or nonfunctional coating. The coating composition may be comprised of pharmaceutically acceptable excipients such as coating agents, binders, plasticizers, coloring agents, and opacifiers. The total weight gain after coating may be about 1% w/w to 10% w/w of the uncoated pharmaceutical composition.

“Coating agents” which are useful in coating process, may be selected from, but not limited to, water soluble polymers such as, but not limited to, polyvinylpyrrolidone or water soluble cellulose such as, but not limited to, hydroxy propyl methyl cellulose or hydroxy propyl cellulose. It may be selected from, but not limited to, soluble agents such as polysorbate 80, polysaccharides such as maltodextrin, acacia, corn, sucrose, gelatin, shellac, cellulose acetate phthalate, lipids, synthetic resins, acrylic polymers, opadry, polyvinyl alcohol, copolymers of vinyl pyrrolidone, vinyl acetate or combinations thereof. These may be applied from aqueous or non- aqueous systems or combinations of aqueous and non-aqueous system as appropriate.

Examples of binders for coating include cellulose or cellulose derivatives such as, but not limited to, methylcellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, and carboxymethyl cellulose sodium, and microcrystalline cellulose, alginic acid, sodium alginate and gelatin, polyvinyl pyrrolidone, copovidone, starch, pregelatinized starch, or mixtures thereof. Examples of plasticizers for coating include, but not limited to, propylene glycol, triethyl citrate, tributyl citrate, dibutyl sebacate, triacetin, polyethylene glycol, diethyl phthalate, acetylated monoglycerides, or mixtures thereof. Examples of opacifiers for coating include, but not limited to, titanium dioxide, talc, calcium carbonate, behenic acid, cetyl alcohol, or mixtures thereof. Antitacking agents such as, but not limited to, talc, stearic acid, magnesium stearate, colloidal silicon dioxide or the like. Examples of coloring agents for coating include, but not limited to, FDA approved colorants such as iron oxide, lake of tartrazine, allura red, lake of quinoline yellow, lake of erythrosine, titanium dioxide, or mixtures thereof. Suitable solvents for the coating include, but not limited to, ethanol, methanol, isopropyl alcohol, methylene chloride, acetone, or mixtures thereof.

Another aspect of the present invention provides the compositions comprising azilsartan medoxomil packed or stored into the 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 pharmaceutical compositions are packed or stored.

In an embodiment of the present invention azilsartan medoxomil compositions are packed or stored into the bottle or blister pack or pouch which comprises a desiccant. The term "desiccant" is referred herein to a substance used to remove or suppress or decrease the odor or to absorb moisture which prevents degradation and/or decomposition of the active agent(s). The desiccant may be placed in the internal space of the package containing the composition, in an amount sufficient to remove the odorous material or to suppress or reduce the smell.

In one 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 another aspect of the present invention, azilsartan medoxomil compositions are packed or stored into the bottle or blister pack or pouch which comprises a desiccant and optionally antioxidant(s). The term "antioxidant" is intended to mean an agent that inhibits oxidation, and thus is used to prevent the deterioration of preparations by oxidation due to the presence of oxygen free radicals or free metals in the composition. Examples of antioxidants that can be used in the present invention include, but not limited to ascorbic acid, butylated hydroxyl anisole, butylated hydroxyl toluene, or a mixture thereof. The amount of antioxidants used in the pharmaceutical compositions of the present invention ranges from 0.01% w/w to 2% w/w.

An aspect of the present invention provides a method of using the compositions of the present invention comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof for the treatment of hypertension and associated disorders. Another aspect of the present invention further provides a method of using the compositions of present invention comprising therapeutically effective amount of azilsartan medoxomil or a pharmaceutically acceptable salt thereof and optionally second active agent for the treatment of hypertension and associated disorders.

It should be appreciated that the invention can be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will convey the scope of the invention to those skilled in the art. Other features and embodiments of the invention will become apparent from the following examples, which are given for illustration of the invention rather than for limiting its intended scope.

EXAMPLES
Example 1:

Ingredient Mg/Tablet
Intra-granular
Azilsartan kamedoxomil 85.36
Mannitol 195
Hydroxypropyl cellulose 11
Acetone q.s.
Extra-granular
Croscarmellose sodium 25
Microcrystalline cellulose 35
Magnesium stearate 3.5

Brief manufacturing procedure:
1. Azilsartan kamedoxomil and mannitol were sifted through suitable sieve and loaded into rapid mixing granulator
2. Hydroxy propyl cellulose was dissolved in acetone under stirring
3. Dry mixture of step 1 was granulated with binder solution of step 2
4. Wet mass of step 3 was dried
5. Dried granules of step 4 were milled through suitable screen
6. Microcrystalline cellulose and croscarmellose sodium were sifted through suitable sieve
7. Milled material of step 5 and sifted material of step 6 were blended for suitable time in blender
8. The step 7 material was lubricated with sifted magnesium stearate for suitable time in blender
9. The lubricated blend was compressed into tablets using suitable size punches

Table 1: Dissolution data of the Example 1
Time (Minutes) % Dissolved
5 50
10 69
15 84
30 95

Example 2:

Ingredient Mg/Tablet
Intra-granular
Azilsartan kamedoxomil 85.36
Mannitol 45
Hydroxypropyl cellulose 10
Acetone q.s.
Water q.s.
Extra-granular
Croscarmellose sodium 60
Mannitol 235
Microcrystalline cellulose 60
Magnesium stearate 6
Vanillin improve 1

Brief manufacturing procedure:
1. Azilsartan kamedoxomil and mannitol were sifted through suitable sieve and loaded into rapid mixing granulator
2. Hydroxy propyl cellulose was dissolved in the mixture of acetone and purified water under stirring
3. Dry mixture of step 1 was granulated with binder solution of step 2 using rapid mixing granulator
4. Wet mass of step 3 was dried
5. Dried granules of step 4 were milled through suitable screen
6. Microcrystalline cellulose, vanillin, mannitol and croscarmellose sodium were sifted through suitable sieve
7. Milled material of step 5 and sifted material of step 6 were blended for suitable time in blender
8. The step 7 material was lubricated with sifted magnesium stearate for suitable time in blender
9. The lubricated blend was compressed into tablets using suitable size punches

Table 2: Dissolution data of the Example 2
Time (Minutes) % Dissolved
5 48
10 70
15 83
30 96

Example 3:

Ingredient Mg/Tablet
Intra-granular
Azilsartan kamedoxomil 85.36
Mannitol 180
Hydroxypropyl ß-cyclodextrin 20
Hydroxypropyl cellulose 10
Acetone q.s.
Extra-granular
Croscarmellose sodium 30
Microcrystalline cellulose 35
Magnesium stearate 3.00

Brief manufacturing procedure:
1. Azilsartan kamedoxomil, hydroxypropyl ß-cyclodextrin and mannitol were sifted through suitable sieve and loaded into rapid mixing granulator
2. Hydroxy propyl cellulose was dissolved in acetone under stirring
3. Dry mix of step 1 was granulated with binder solution of step 2
4. Wet mass of step 3 was dried
5. Dried granules of step 4 were milled through suitable screen
6. Microcrystalline cellulose and croscarmellose sodium were sifted through suitable sieve
7. Milled material of step 5 and sifted material of step 6 were blended for suitable time in blender
8. The step 7 material was lubricated with sifted magnesium stearate for suitable time in blender
9. The lubricated blend was compressed into tablets using suitable size punches

Table 3: Dissolution data of the Example 3
Time (Minutes) % Dissolved
5 30
10 53
15 72
30 98

Example 4:

Ingredient Mg/ Tablet
Intra-granular
Azilsartan kamedoxomil 85.36
Mannitol 120
Hydroxypropyl ß-cyclodextrin 40
Hydroxypropyl cellulose 10
Acetone q.s
Extra-granular
Croscarmellose sodium 25
Microcrystalline cellulose 35
Crospovidone 40
Magnesium stearate 4.00

Brief manufacturing procedure:
1. Azilsartan kamedoxomil, hydroxypropyl ß-cyclodextrin and mannitol were sifted through suitable sieve and loaded into rapid mixing granulator
2. Hydroxy propyl cellulose was dissolved in acetone under stirring
3. Dry mix of step- 1 was granulated with binder solution of step- 2
4. Wet mass of step- 3 was dried
5. Dried granules of step- 4 were milled through suitable screen by Quadro co mill
6. Microcrystalline cellulose, croscarmellose sodium and crospovidone were sifted through suitable sieve
7. Milled material of step- 5 and sifted material of step- 6 were blended for suitable time in blender
8. The step- 7 material was lubricated with sifted magnesium stearate for suitable time in blender
9. The lubricated blend was compressed into tablets using suitable size punches

Table 4: Dissolution data of the Example 4
Time (Minutes) % Dissolved
5 55
10 87
15 93
30 95

,CLAIMS:Claim 1: A stable pharmaceutical composition comprising therapeutically effective amount of azilsartan medoxomil, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
Claim 2: A stable pharmaceutical composition comprising therapeutically effective amount of azilsartan medoxomil, or a pharmaceutically acceptable salt thereof, cyclodextrin component and one or more pharmaceutically acceptable excipients.
Claim 3: A pharmaceutical composition according to claim 1 or claim 2, wherein the composition does not comprise any pH control agent(s).
Claim 4: A pharmaceutical composition according to claim 1 or claim 2, wherein the composition is prepared by anhydrous granulation process.
Claim 5: A pharmaceutical composition according to claim 1 or claim 2, wherein the composition is prepared by granulation process comprising use of anhydrous solvent, optionally further comprising hydrous solvent.
Claim 6: A pharmaceutical composition according to claim 1 or claim 2, wherein the composition is prepared by granulation process comprising use of a mixture of anhydrous solvent and hydrous solvent.
Claim 7: A pharmaceutical composition according to claims 4-6, wherein the composition is prepared using acetone as anhydrous granulating solvent.
Claim 8: A pharmaceutical composition according to claim 6, wherein the mixture of acetone and water is used as granulating solvent.
Claim 9: A pharmaceutical composition according to claim 2, wherein the cyclodextrin component is selected from the group comprising of a- cyclodextrin, ß- cyclodextrin, ?- cyclodextrin or combination thereof.
Claim 10: A process for the preparation of the stable pharmaceutical composition according to claim 1, wherein the process comprises:
i) blending azilsartan medoxomil with one or more pharmaceutically acceptable excipients;
ii) dissolving/dispersing granulating agent in granulating solvent;
iii) granulating the blend of step i) using granulating agent prepared in step ii);
iv) optionally adding one or more other pharmaceutically acceptable excipients to the blend in step iii);
v) compressing or filling the granules of step iii) or the blend of step iv) into a suitable sized tablets or capsules.
Claim 11: A process for the preparation of the stable pharmaceutical composition according to claim 2, wherein the process comprises:
i) blending azilsartan medoxomil, a cyclodextrin component and one or more pharmaceutically acceptable excipients;
ii) dissolving/dispersing a granulating agent in granulating solvent;
iii) granulating the blend of step i) using granulating agent prepared in step ii);
iv) optionally adding one or more other pharmaceutically acceptable excipients to the blend in step iii);
v) compressing or filling the granules of step iii) or the blend of step iv) into a suitable sized tablets or capsules.
Claim 12: A granulating solvent used according to claim 10 or claim 11, which includes anhydrous solvent, hydrous solvent or mixture of anhydrous and hydrous solvents.
Claim 13: The composition according to claim 1 or claim 2, comprising at least one desiccant, and optionally one or more pharmaceutically acceptable excipient(s).
Claim 14: The composition according to claim 1 or claim 2, comprising at least one antioxidant, and optionally one or more pharmaceutically acceptable excipient(s).
Claim 15: The composition according to claim 1 or claim 2, comprising at least one desiccant, at least one antioxidant, and optionally one or more other pharmaceutically acceptable excipient(s).
Claim 16: The composition according to any preceding claims, wherein the pharmaceutically acceptable excipient is selected from a group comprising of diluents/fillers, binders, disintegrants, lubricants, glidants, compression aids, colors, sweeteners, preservatives, suspending agents, film formers, flavors, used either alone or in combinations thereof.
Claim 17: The composition according to any preceding claims, comprising azilsartan medoxomil, or a pharmaceutically acceptable salt thereof as first active agent, further comprising second active agent(s), and optionally one or more other pharmaceutically acceptable excipient(s).
Claim 18: The composition according to claim 17, wherein the second active agent(s) is selected from diuretics, calcium channel antagonist or ACE inhibitors.
Claim 19: The composition according to claim 18, wherein the second active agent selected is chlorthalidone as a diuretic.
Claim 20: The composition according to any preceding claims, prepared in the form of tablet.
Claim 21: The composition prepared according to any preceding claims, which shows desired stability and dissolution characteristics.