WO2022123592A1

WO2022123592A1 - Stable pharmaceutical composition of azilsartan medoxomil or pharmaceutical acceptable salt and processes for preparing thereof

Info

Publication number: WO2022123592A1
Application number: PCT/IN2021/051135
Authority: WO
Inventors: Ulhas Dhuppad; Arun Kumar Pandey; Roshal Lal SANDAL; Rajesh Kulkarni; Sagar Baheti
Original assignee: Alkem Laboratories Ltd
Priority date: 2020-12-08
Filing date: 2021-12-04
Publication date: 2022-06-16

Abstract

The present invention relates to a 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), an antioxidant and one or more other pharmaceutically acceptable excipient(s) and process of preparation of thereof.

Description

STABLE PHARMACEUTICAL COMPOSITION OF AZILSARTAN MED OXO MIL OR PHARMACEUTICAL ACCEPTABLE SALT AND PROCESSES FOR PREPARING THEREOF”

DESCRIPTION

FIELD OF THE INVENTION

This invention relates to stable pharmaceutical composition comprising azilsartan medoxomil and processes for preparing thereof.

BACKGROUND OF THE INVENTION

Azilsartan medoxomil, a prodrug, is hydrolysed to azilsartan in the gastrointestinal tract during absorption. Azilsartan is an angiotensin II receptor blocker.

The drug substance used in the drug product formulation is the potassium salt of azilsartan medoxomil, also known by the US accepted name of azilsartan kamedoxomil and is chemically described as (5MethyI-2-oxo4,3-dioxol-4-yl)methyI 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 and its structural formula is:

Azilsartan kamedoxomil is a white to nearly white powder with a molecular weight of 606.62. It is practically insoluble in water and freely soluble in methanol.

Edarbyclor is a combination of azilsartan medoxomil (angiotensin II receptor blocker; as its potassium salt) and chlorthalidone (thiazide-like diuretic).

SUBSTITUTE SHEET (RULE 26) Azilsartan medoxomil, a prodrug, is hydrolyzed to azilsartan in the gastrointestinal tract during absorption. Azilsartan is an angiotensin II receptor blocker. Chlorthalidone is a monosulfamyl thiazidelike diuretic that differs chemically from thiazide diuretics by the lack of a benzothiadiazine structure.

Chlorthalidone is chemically described as 2-chloro-5(l-hydroxy-3-oxo-1- isoindolinyl) benzenesulfonamide. Its empirical formula is C14H11C1N2O4S. The structural formula for chlorthalidone is

Chlorthalidone is a white to yellowish white powder with a molecular weight of 338.76. Chlorthalidone is practically insoluble in water, in ether, and in chloroform; soluble in methanol; slightly soluble in ethanol.

Edarbyclor is available for oral use as tablets. The tablets have a characteristic odor. Each Edarbyclor tablet contains 42.68 mg of azilsartan kamedoxomil, which is equivalent to containing azilsartan medoxomil 40 mg plus 12.5 or 25 mg of chlorthalidone. Each tablet of Edarbyclor also contains the following inactive ingredients: mannitol, microcrystalline cellulose, fumaric acid, sodium hydroxide, hydroxypropyl cellulose, crospovidone, magnesium stearate, hypromellose 2910, talc, titanium dioxide, ferric oxide red, polyethylene glycol 8000, and printing ink gray.

The angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzymes (ACE, kinase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Azilsartan medoxomil is an orally administered prodrug that is rapidly converted by esterases during absorption to the active moiety, azilsartan. Azilsartan blocks the vasoconstrictor and aldosteronesecreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the ATI receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathway for angiotensin II synthesis.

An AT2 receptor is also found in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Azilsartan has more than a 10,000-fold greater affinity for the ATI receptor than for the AT2 receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction catalyzed by ACE. Because azilsartan does not inhibit ACE (kinase II), it should not affect bradykinin levels. Whether this difference has clinical relevance is not yet known. Azilsartan does not bind to or block other receptors or ion channels known to be important in cardiovascular regulation.

Azilsartan kamedoxomil is available in the United States of America as EDARBI® (azilsartan medoxomil) tablets and Edarbyclor® (Azilsartan Kamedoxomil; Chlorthalidone) immediate-release oral tablets and indicated for the treatment of hypertension to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. Edarbi is available in strengths i.e. 40 mg and 80mg and Edarbyclor is approved in the form of 40/12.5 mg and 40/25 mg (azilsartan/chlorthalidone) tablets.

Edarbi and Edarbyclor are indicated for the treatment of hypertension to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including the class to which this drug principally belongs.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Edarbi may be used alone or in combination with other antihypertensive agents.

The blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of azilsartan on blood pressure.

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 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.

US 9169238 patent further discloses a solid preparation containing a first part containing azilsartan or a salt thereof and a pH control agent, and a second part containing a diuretic, which is obtained by separately granulating the first part and the second part. This patent teaches separately granulating a first part comprising the azilsartan or a salt thereof and a pH control agent and a second part comprising chlorthalidone to give the solid preparation comprising the first part and the second part. The objective of this patent was to simultaneously achieve the stability and solubility of azilsartan or a salt thereof 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.

WO 2019130277A1 patent application provides pharmaceutical composition and process for the preparation of stable oral pharmaceutical compositions of azilsartan medoxomil or a pharmaceutically acceptable salt thereof, a cyclodextrin and optionally one or more pharmaceutically acceptable excipient(s).wherein the process comprises of the following steps: i) blending azilsartan medoxomil, a cyclodextrin and one or more pharmaceutically acceptable excipients, ii) dissolving 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.

Despite the above mentioned prior art solid pharmaceutical formulations of azilsartan medoxomil, there still exists a need for an oral pharmaceutical composition of azilsartan medoxomil, which is capable of stabilising the composition.

It has now been found, surprisingly, that the pharmaceutical composition, from which the active ingredients remains stable throughout the pH from about 2 to 5 without the use of pH controlling agents and the cyclodextrin or betacyclodextrin and The compositions of the present invention simultaneously achieve desired stability characteristics and dissolution profile.

OBJECT OF THE INVENTION

It is an object of the present invention to provide a stable pharmaceutical composition comprising therapeutically effective amount of azilsartan medoxomil, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients optionally with second active ingredient.

It is an another object of the present invention to provide a stable pharmaceutical composition comprising therapeutically effective amount of azilsartan medoxomil, or a pharmaceutically acceptable salt thereof and an antioxidant and one or more pharmaceutically acceptable excipients optionally with second active ingredient. 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), an antioxidant and one or more other pharmaceutically acceptable excipient(s).

It is yet another object of the present invention to provide a solid stable pharmaceutical composition of abuse-proofed, extended release pharmaceutical composition comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof, which uses a new and different beneficial formulation but is still bioequivalent to the commercially available compositions in the United States of America i.e ED ARBI® (azilsartan medoxomil) tablets and/ or EDARBYCLOR® (Azilsartan Kamedoxomil; Chlorthalidone)

SUMMARY OF THE INVENTION

A. A stable pharmaceutical composition comprising therapeutically effective amount of azilsartan medoxomil, or a pharmaceutically acceptable salt thereof and an antioxidant and one or more pharmaceutically acceptable excipients.

B. A pharmaceutical composition according as in A, wherein the composition does not comprise any pH control agent(s).

C. A pharmaceutical composition according as in A, wherein the composition is prepared by wet granulation process. D. A pharmaceutical composition according as in A, wherein the antioxidant is selected from the Sodium or Potassium Metabisulfite or combination thereof.

E. A process for the preparation of the stable pharmaceutical composition, wherein the process comprises: i) granulating azilsartan medoxomil, antioxidant and one or more pharmaceutically acceptable excipients; ii) dissolving 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.

F. A pharmaceutical composition according as in E, wherein the antioxidant is selected from the Sodium or Potassium Metabisulfite or combination thereof.

G. The composition according as in A and E, 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.

H. The composition according as in A and E 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).

I. The composition according as in A, wherein the second active agent(s) is selected from diuretics, calcium channel antagonist or ACE inhibitors. J. The composition according as in A, wherein the second active agent selected is chlorthalidone as a diuretic.

K. The Stable pharmaceutical composition comprising azilsartan medoxomil, or a pharmaceutically acceptable salt thereof as first active agent, further comprising second active agent(s), and an antioxidant and optionally one or more other pharmaceutically acceptable excipient(s), wherein the process comprises: i) Granulating azilsartan medoxomil, antioxidant and one or more pharmaceutically acceptable excipients. ii) Granulating Second active and one or more pharmaceutically acceptable excipients. iii) Granules of (i) and (ii) blended and lubricated with suitable agent and compressing or filling the granules or the blend into a suitable sized tablets or capsules.

L. The Stable pharmaceutical composition according as in K, wherein the antioxidant is selected from the Sodium or Potassium Metabisulfite or combination thereof.

M. The Stable pharmaceutical composition according as in K, wherein the second active agent(s) is selected from diuretics, calcium channel antagonist or ACE inhibitors.

N. The Stable pharmaceutical composition according as in K, wherein the second active agent selected is chlorthalidone as a diuretic.

O. The Stable pharmaceutical composition according as in K, 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.

DETAILED DESCRIPTION OF THE INVENTION

Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.

Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.

The publications discussed herein are provided solely for their availability to the applicant prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed

The term "stable" as used herein refers to chemical stability of Azilsartan in solid dosage forms wherein there is no change in assay values and dissolution and/or the total impurity remains less than 1%, when the dosage form is kept at 40°C/75% RH for 3 or 6 months. 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 or six mont 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.

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).

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, glimepiride glibenclamidum, gliclazide 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.

Film coats may be prepared from ready-to-make preparations which are available on the market. One preferred film-coat material is OPADRY®, particularly OPADRY®white, OPADRY® blue. A film coating dispersion or suspension can be prepared by using different solvents (water, alcohols, ketones, esters, chlorinated hydrocarbons), but water is preferred.

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 37°C (± 10°C), 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 37° 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 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, com 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” or solubilize 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 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. “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, com, 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 Sodium Metabisulfite, Potassium Metabisulfite, ascorbic acid, butylated hydroxyl anisole, butylated hydroxyl toluene, propyl gallate or a mixture thereof. The amount of antioxidants used in the pharmaceutical compositions of the present invention ranges from 0.01% w/w to 5% 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.

The pharmaceutical compositions of the present invention may be prepared by the conventional processes such as wet granulation, dry granulation or direct compression as known to those skilled in the art. The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.

Example 1

Manufacturing procedure:

Azilsartan Kamedoxomil and Mannitol were co-sifted through required sieve. Sodium Metabisulphite and Hydroxypropyl Cellulose were separately added in the water with constant stirring for suitable time. The sifted materials of Azilsartan Kamedoxomil and Mannitol were loaded into Fluidized bed processor and sprayed binder solution of Hydroxypropyl Cellulose was spray on the Sodium Metabisulphite onto sifted materials. Further the material were Dried in the Fluidized bed processor until desired loss on drying is achieved. After that the material sifted through required sieves. Microcrystalline cellulose and cros-carmellose sodium were passed through required sieves and added to the above blend and mix for suitable time in blender. Magnesium stearate sifted through required sieve and added to blend and lubricated for suitable time. The lubricated blend was compressed with suitable size and shape Followed by coating using opadry dispersion.

Example 2

Manufacturing procedure: Same as in example 1.

Stability data

All the initial and 6M, at 40°C /75 %RH and 25°C /60 %RH stability data were found satisfactory.

Example 3

MANUFACTURING PROCEDURE

The Azilsartan Kamedoxomil, Mannitol and Microcrystalline cellulose were sifted through suitable mesh and transferred into a fluid bed processor and Sodium Metabisulfite was dissolved into purified water. Material was granulated using the Sodium Metabisulfite solution in EBP. Dry the wet mass for suitable time. Hydroxypropyl Cellulose was dissolved into purified water. Material granulated using the Hydroxypropyl Cellulose solution. Wet granules were dried at appropriate temperature and sifted through appropriate sieve and milled through respective screen (if required) to get Azilsartan Kamedoxomil granules..

The Chlorthalidone, Mannitol, Microcrystalline cellulose, Croscarmellose sodium and Hydroxypropyl cellulose were sifted through suitable mesh and transferred into a rapid mixer granulator and mixed in RMG for suitable time and appropriate impeller speed. Sodium Lauryl Sulfate and /or Sodium hydroxide was dissolved into purified water and sifted material was granulated using the HPC solution of in RMG. Wet granules were dried at appropriate temperature using FBD. The Dried granules were sifted through appropriate sieve and milled through respective screen (if required) to get Chlorthalidone granules.

The Granules of Azilsartan Kamedoxomil and Chlorthalidone were mixed with microcrystalline cellulose, Croscarmellose Sodium in blender with suitable time and appropriate RPM. Then Lubricated for appropriate time & RPM with Magnesium stearate. Lubricated Blend was compressed into round shaped tablet followed by coating.

Example 4

Stability Data

All the initial and 6M, at 40°C /75 %RH stability data were found satisfactory. Example 5

MANUFACTURING PROCEDURE The Azilsartan Kamedoxomil, Mannitol, Sodium metabisulfite and Microcrystalline cellulose were sifted through suitable mesh and transferred into a fluid bed processor. Hydroxypropyl Cellulose was dissolved into purified water. Material was granulated using binder solution in EBP and dried followed sifting through appropriate sieve with milling using respective screen (if required) to get Azilsartan Medoxomil granules.. The Chlorthalidone, Mannitol, Microcrystalline cellulose, Pre-gelatinized starch, Croscarmellose Sodium and Hydroxypropyl cellulose were sifted through suitable mesh and transferred into a rapid mixer granulator and mixed in RMG for suitable time and appropriate impeller speed. Sodium Lauryl Sulfate and/ or Sodium Hydroxide was dissolved into purified water. Material was granulated using binder solution in RMG and dried followed sifting through appropriate sieve with milling using respective screen (if required) to get Chlorthalidone granules.

Granules of Azilsartan Kamedoxomil and Chlorthalidone were mixed with Microcrystalline cellulose and Croscarmellose Sodium in blender bin and mixed for suitable time at appropriate RPM. Then lubricated with Magnesium stearate for appropriate time & RPM. Lubricated Blend was compressed into round shaped tablet followed by coating.

Stability Data

All the initial and IM, at 40°C /75 %RH stability data were found satisfactory.

Claims

1. A stable pharmaceutical composition comprising therapeutically effective amount of azilsartan medoxomil, or a pharmaceutically acceptable salt thereof and an antioxidant and one or more pharmaceutically acceptable excipients.

2. The Stable pharmaceutical composition as claimed in claim 1, wherein the composition does not comprise any pH control agent(s).

3. The Stable pharmaceutical composition according as claimed in claim 1, wherein the composition is prepared by wet granulation process.

4. The Stable pharmaceutical composition as claimed in claim 1, wherein the antioxidant is selected from the Sodium or Potassium Metabisulfite or combination thereof.

5. The Stable pharmaceutical composition as claimed in 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, suspending agents, film formers, flavors, used either alone or in combinations thereof.

6. A Stable pharmaceutical composition comprising azilsartan medoxomil, or a pharmaceutically acceptable salt thereof as first active agent, further comprising second active agent(s), and an antioxidant and optionally one or more other pharmaceutically acceptable excipient(s).

7. The Stable pharmaceutical composition as claimed in claim 8, wherein the second active agent(s) is selected from diuretics, calcium channel antagonist or ACE inhibitors. The Stable pharmaceutical composition as claimed in claim 8, wherein the antioxidant is selected from the Sodium or Potassium Metabisulfite or combination thereof. The Stable pharmaceutical composition as claimed in claim 8, wherein the composition is prepared by wet granulation process. The Stable pharmaceutical composition as claimed in claim 9, 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.