DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

PHARMACEUTICAL COMPOSITION COMPRISING AZILSARTAN MEDOXOMIL OR COMBINATION THEREOF

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
HITECH CITY, KONDAPUR,
HYDERABAD - 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION

This invention relates to solid oral pharmaceutical composition comprising azilsartan medoxomil or a pharmaceutically acceptable salt and/or combination thereof. In particular, the invention relates to stable pharmaceutical composition comprising azilsartan kamedoxomil and/or chlorthalidone with one or more suitable pharmaceutically acceptable excipients.

BACKGROUND OF THE INVENTION

Hypertension, also referred to as high blood pressure and sometimes called arterial hypertension, is a condition in which the arteries have persistently elevated blood pressure. Azilsartan medoxomil is a prodrug that is rapidly converted by esterases during absorption to the active moiety azilsartan. The potassium salt of azilsartan medoxomil is azilsartan kamedoxomil. Azilsartan blocks vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT receptor.

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. Azilsartan kamedoxomil, 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. Its empirical formula is C30H23KN4O8 and structural formula is

Chlorthalidone produces diuresis with increased excretion of sodium and chloride. 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. Chlorthalidone is chemically described as 2-chloro-5(1-hydroxy-3-oxo-1- isoindolinyl) benzenesulfonamide. Its empirical formula is C14H11CIN2O4S and structural formula is

Azilsartan Kamedoxomil tablet 40 mg and 80 mg was first approved by U.S. FDA on Feb 25, 2011 under the brand name EDARBI® to the Arbor Pharmaceuticals, indicated for the treatment of hypertension. Azilsartan kamedoxomil and chlorthalidone tablet was first approved by U.S. FDA on Dec 20, 2011 under the brand name EDARBYCLOR® to the Arbor Pharmaceuticals, indicated for treatment of hypertension, to lower blood pressure. Edarbyclor tablet contains 42.68 mg of azilsartan kamedoxomil, which is equivalent to azilsartan medoxomil 40 mg plus 12.5 or 25 mg of chlorthalidone.

U.S. Patent No. 5,354,766 discloses compound azilsartan. U.S. Patent No. 7,157,584 discloses azilsartan kamedoxomil. U.S. Patent No. 7,572,920 discloses process of preparation of the azilsartan kamedoxomil and method for treating hypertension in combination with a diuretic.

U.S. Patent No. 9,066,936 discloses a solid pharmaceutical composition comprising azilsartan kamedoxomil and a pH control agent, wherein the pH control agent has pH of about 3 to 5.

U.S. Patent No. 9,169,238 discloses a solid pharmaceutical composition comprising azilsartan kamedoxomil, chlorthalidone and a pH control agent, wherein the pH control agent has pH of about 2 to 5.

Indian Patent publication IN2013CH05882 discloses tablet composition comprising azilsartan kamedoxomil and pH regulating agent having a pH not less than 5. It also discloses that composition optionally comprising second active agent.

Azilsartan is unstable in the neutral pH range, at which the pharmaceutical preparation is generally produced hence stabilization of azilsartan composotions is very important from pharmaceutical point of view. In addition, a combination drug product composed of azilsartan and other active ingredient such as diuretic and the like cannot be easily formulated into a preparation superior in stability and dissolution property due to differences in chemical properties.

The inventors of the present invention have surprisingly found that azilsartan kamedoxomil composition or composition comprising azilsartan in combination with chlorthalidone is still stable at higher pH range values and shows enhanced stability and dissolution simultaneously, when pH agent added in extra granulation portion which is a significant advancement over the teachings of the art. Accordingly, inventors of this invention have developed stable pharmaceutical compositions comprising azilsartan kamedoxomil and/or combination with chlorthalidone and a pH regulating agent having a pH more than 5 preferably in the range of 7 to 12 with one more pharmaceutically acceptable excipient(s).

The present invention further provides a simple, stable, economical and industrially feasible process for preparing pharmaceutical composition comprising azilsartan kamedoxomil or azilsartan in combination with chlorthalidone and pH control agent with one or more suitable pharmaceutically acceptable excipients

SUMMARY OF THE INVENTION

In one aspect, there is provided a solid oral pharmaceutical composition comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof and pH control agent having pH more than 5 and one or more pharmaceutically acceptable excipients.

In another aspect, an invention provides an oral pharmaceutical composition comprising:
a) intragranular portion comprising (i) 5 to 25% w/w of azilsartan kamedoxomil; (ii) 35 to 45% w/w of microcrystalline cellulose (iii) 0.1 to 5% w/w of hydroxy propyl cellulose.
b) extragranular portion comprising (i) 0.1 to 5% w/w of magnesium aluminometasilicate; (ii) 15 to 30% w/w of mannitol (iii) 4 to 12 % w/w of croscarmellose sodium (iv) 0.1 to 3 % w/w of magnesium stearate.

In another aspect, an invention provides an oral pharmaceutical composition comprising:
a) intragranular portion comprising (i) 5 to 25% w/w of azilsartan kamedoxomil; (ii) 39 to 42% w/w of microcrystalline cellulose (iii) 0.48 to 0.50% w/w of hydroxy propyl cellulose.
b) extragranular portion comprising (i) 0.10 to 0.50% w/w of magnesium aluminometasilicate; (ii) 20 to 28% w/w of mannitol (iii) 7 to 10% w/w of croscarmellose sodium (iv) 0.57 to 0.60% w/w of magnesium stearate.

In another aspect, an invention provides an oral pharmaceutical composition comprising:
a) intragranular portion comprising (i) 23.25 % w/w of azilsartan kamedoxomil; (ii) 40.92% w/w of microcrystalline cellulose (iii) 0.49% w/w of hydroxy propyl cellulose and
b) extragranular portion comprising (i) 0.41% w/w of magnesium aluminometasilicate; (ii) 23.68% w/w of mannitol (iii) 8.71% w/w of croscarmellose sodium (iv) 0.59% w/w of magnesium stearate.

In another aspect, an invention provides an oral pharmaceutical composition comprising:
a) intragranular portion comprising (i) 5 to 25% w/w of azilsartan kamedoxomil;
b) extragranular portion comprising (i) 0.10 to 0.50% w/w of magnesium aluminometasilicate.

In another aspect, an invention provides an oral pharmaceutical composition comprising
a) intragranular portion comprising (i) 42.68 to 85.36 mg of azilsartan kamedoxomil; (ii) 65 to 165 mg of microcrystalline cellulose (iii) 0.80 to 1.98 mg of hydroxy propyl cellulose and
b) extragranular portion comprising (i) 0.60 to 1.5 mg of magnesium aluminometasilicate; (ii) 35 to 95 mg of mannitol (iii) 12 to 40 mg of croscarmellose sodium (iv) 0.90 to 2.40 mg of magnesium stearate.

In another aspect, an invention provides an oral pharmaceutical composition comprising
a) intragranular portion comprising (i) 42.68 to 85.36 mg of azilsartan kamedoxomil; (ii) 75.12 to 150.24 mg of microcrystalline cellulose (iii) 0.90 to 1.80 mg of hydroxy propyl cellulose and
b) extragranular portion comprising (i) 0.75 to 1.50 mg of magnesium aluminometasilicate; (ii) 43.47 to 86.94 mg of mannitol (iii) 16 to 32 mg of croscarmellose sodium (iv) 1.08 to 2.16 mg of magnesium stearate.

In another aspect, an invention provides an oral pharmaceutical composition comprising:
a) first intragranular portion comprising (i) 5 to 25% w/w of azilsartan kamedoxomil; (ii) 20 to 40% w/w of diluent; (iii) 0.1 to 5% w/w of binder; and
b) second intragranular portion comprising (i) 2 to 10% w/w of chlorthalidone; (ii) 20 to 40% w/w of diluent; (iii) 0.1 to 5% w/w of binder; and
c) extragranular portion comprising (i) 0.1 to 5% w/w of pH control agent; (ii) 5 to 25% w/w of diluent; (iii) 3 to 12% w/w of disintegrant; (iv) 0.1 to 3% w/w of lubricant; wherein pH control agent is selected from meglumine, lysine, arginine, magnesium aluminometasilicate which provides pH in the range of 6 to 12.

In another aspect, an invention provides an oral pharmaceutical composition comprising:
a) first intragranular portion comprising 5 to 25% w/w of azilsartan kamedoxomil;
b) optionally second intragranular portion comprising 2 to 10% w/w of chlorthalidone;
c) extragranular portion comprising 0.1 to 3% w/w of pH control agent is selected from magnesium aluminometasilicate; wherein at least 75% of azilsartan kamedoxomil dissolves within 60 minutes in a 900ml of pH 6.8 phosphate buffer at a temperature of 37±0.5°C using a USP apparatus-2 at a paddle rotation of about 75 rpm.

In another aspect, an invention provides an oral pharmaceutical composition comprising:
a) first intragranular portion comprising 5 to 25% w/w of azilsartan kamedoxomil;
b) second intragranular portion comprising 2 to 10% w/w of chlorthalidone;
c) extragranular portion comprising 0.1 to 3% w/w of pH control agent; wherein compositions contains not more than 4.5% of total impurities by weight relative to azilsartan kamedoxomil and chlorthalidone when measured by HPLC after storage for 3 months at 400C/75% relative humidity.

In another aspect, an invention provides a solid oral pharmaceutical composition comprising:
a) first intragranular portion comprising (i) 5 to 25% w/w of azilsartan medoxomil or pharmaceutically acceptable salt thereof; (ii) 0.5 to 5% w/w of at least two binders selected from hydroxy propyl cellulose, carbopol;
b) second intragranular portion comprising (i) 2 to 10 % w/w of chlorthalidone; (ii) 0.5 to 5% w/w of binder selected from hydroxy propyl cellulose; and
c) extragranular portion comprising a pH control agent selected from 0.1 to 1.0% w/w of magnesium aluminometasilicate; wherein the pH control agent have a pH in the range of 7 to 12 when dissolved or suspended in water at a concentration of 1% w/v at 25?.

In another aspect, an invention provides an oral tablet composition comprising:
a) first intragranular portion comprising (i) 5 to 25% w/w of azilsartan kamedoxomil;
b) second intragranular portion comprising (i) 2 to 10 % w/w of chlorthalidone;
c) extragranular portion comprising (i) 0.1 to 1% w/w of magnesium aluminometasilicate; (ii) 5 to 15% w/w of microcrystalline cellulose; (iii) 4 to 12 % w/w of crospovidone; and (iv) 0.1 to 2% w/w of magnesium stearate;
wherein weight ratio of azilsartan kamedoxomil to magnesium aluminometasilicate is in the range of about 1:0.0170, 1:0.0175, 1:0.0180, 1:0.0185.

In another aspect, an invention provides an oral tablet composition comprising:
a) first intragranular portion comprising (i) 10.90% w/w of azilsartan kamedoxomil; (ii) 26.49% w/w of microcrystalline cellulose, mannitol or combination thereof; (iv) 2.2 % w/w of hydroxy propyl cellulose, carbopol or combination thereof; and
b) second intragranular portion comprising (i) 3.19 to 6.39 % w/w of chlorthalidone; (ii) 30.56 to 33.75 % w/w of microcrystalline cellulose, mannitol or combination thereof; (iii) 1.38 % w/w of hydroxy propyl cellulose; and
c) extragranular portion comprising (i) 0.19 % w/w of magnesium aluminometasilicate; (ii) 11.20 % w/w of microcrystalline cellulose; (iii) 7.28 % w/w of crospovidone; and (iv) 0.48 % w/w of magnesium stearate.

In another aspect, an invention provides an oral tablet composition comprising:
a) first intragranular portion comprising (i) 10.90% w/w of azilsartan kamedoxomil; (ii) 2.2 % w/w of hydroxy propyl cellulose, carbopol or combination thereof; and
b) second intragranular portion comprising 3.19 to 6.39 % w/w of chlorthalidone;
c) extragranular portion comprising 0.19 % w/w of magnesium aluminometasilicate; wherein the weight ratio of two binders i.e. carbopol to hydroxy propyl cellulose in first portion is in the range of about 1:15 to about 1:17, preferably 1:16.

In another aspect, an invention provides an oral tablet composition comprising:
a) first intragranular portion comprising (i) 40 to 60 mg of azilsartan kamedoxomil; (ii) 93 to 114 mg of microcrystalline cellulose, mannitol or combination thereof; (iii) 6 to 10 mg of hydroxy propyl cellulose, carbopol or combination thereof; and
b) second intragranular portion comprising (i) 8 to 40 mg of chlorthalidone; (ii) 107 to 145 mg of microcrystalline cellulose, mannitol or combination thereof; (iii) 4 to 7 mg of hydroxy propyl cellulose; and
c) extragranular portion comprising (i) 0.2 to 2 mg of magnesium aluminometasilicate; (ii) 39 to 48 mg of microcrystalline cellulose; (iii) 25 to 31 mg of crospovidone; and (iv) 1.7 to 2.1 mg magnesium stearate.

In another aspect, an invention provides a solid oral pharmaceutical composition comprising:
a) first intragranular portion comprising (i) 40 to 60 mg of azilsartan medoxomil or pharmaceutically acceptable salt thereof; (ii) 6 to 10 mg of at least two binders selected from hydroxy propyl cellulose, carbopol;
b) second intragranular portion comprising (i) 12.5 to 25 mg of chlorthalidone; (ii) 4 to 7 mg of binder selected from hydroxy propyl cellulose;
c) extragranular portion comprising a pH control agent selected from 0.2 to 2 mg of magnesium aluminometasilicate; wherein the pH control agent have a pH in the range of 7 to 12 when dissolved or suspended in water at a concentration of 1% w/v at 25?.

In another aspect, an invention provides an oral tablet composition comprising:
a) first intragranular portion comprising (i) 40 to 60 mg of azilsartan medoxomil or a pharmaceutically acceptable salt thereof; (ii) 6 to 10 mg of hydroxy propyl cellulose, carbopol or combination thereof; and
b) second intragranular portion comprising (i) 12.5 to 25 mg of chlorthalidone; (ii) 4 to 7 mg of hydroxy propyl cellulose;
c) extragranular portion comprising 0.2 to 2 mg of magnesium aluminometasilicate; wherein weight ratio of hydroxy propyl cellulose as a binder in first portion and second portion is in the range of about 1: 0.54, 1: 0.67, 1: 0.83.

In another aspect, an invention provides an oral tablet composition comprising:
a) first intragranular portion comprising (i) 42.68 mg of azilsartan kamedoxomil; (ii) 103.72 mg of microcrystalline cellulose, mannitol or combination thereof; (iii) 8.6 mg of hydroxy propyl cellulose, carbopol or combination thereof;
b) second intragranular portion comprising (i) 12.5 to 25 mg of chlorthalidone; (ii) 119.6 to 132.1 mg of microcrystalline cellulose, mannitol or combination thereof; (iii) 5.40 mg of hydroxy propyl cellulose;
c) extragranular portion comprising (i) 0.75 mg of magnesium aluminometasilicate; (ii) 43.85 mg of microcrystalline cellulose; (iii) 28.50 mg of crospovidone; and (iv) 1.9 mg of magnesium stearate.

In another aspect, the present invention relates to method of using pharmaceutical composition comprising of effective amount of azilsartan kamedoxomil, chlorthalidone and pH control agent with one or more pharmaceutically acceptable excipients in the treatment of hypertension.

DETAILED DESCRIPTION OF THE INVENTION

The term “pharmaceutical composition” or "composition" or "solid oral pharmaceutical composition" as used herein refers to a solid dosage form comprising effective amount of azilsartan medoxomil or a pharmaceutically acceptable salts thereof and or chlorthalidone and one or more pharmaceutically acceptable excipients suitable for administration, such as a tablet, capsule, caplets, mini-tablets, granules and the like.

The term “active” or “active ingredient” or “drug” used interchangeably, is defined to mean active drug (e.g. azilsartan kamedoxomil or chlorthalidone). In accordance with the present invention, the term "azilsartan" unless indicated otherwise in the entire specification refers to azilsartan in the form of free base or its pharmaceutically acceptable salt, amorphous, crystalline or any isomer or derivative, hydrate or solvate, prodrug or combinations thereof. Preferably azilsartan is in the form of azilsartan kamedoxomil, which is potassium salt of azilsartan medoxomil. Said composition also contains combination of Azilsartan with other drugs such as diuretics.

Examples of the diuretic in the present invention include thiazide preparations (e.g., hydrochlorothiazide, hydroflumethiazide etc.), chlorobenzenesulfonamide agents (e.g., chlorthalidone, mefruside, indapamide etc.), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like, especially, chlorthalidone is preferable.

The term ‘‘stable’’ refers to formulations that substantially retain the labelled amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.

The term “therapeutically effective amount” is defined to mean the amount or quantity of the active drug is sufficient to elicit an appreciable pharmacological response when administered to the patient.

The term “about” is used herein to mean approximately, roughly, around, or in the regions of. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 10 percent.

The term ‘‘portion’’ refers to a part of whole composition which can be either Intragranular or Extragranular and which is formulated separately from other parts of composition before forming into final composition. As per present invention there may be several portions and composition can comprises first portion or second portion or both.

The term ‘‘w/w’’ refers to total weight of substance/excipients with respect to total composition weight or the proportion of a particular substance within a mixture, as measured by weight or mass.

The term “impurity” refers to undesired contents present or produced in a pharmaceutical composition.

The dissolution is performed as per conditions mentioned or provided in office of generic drugs dissolution database and as determined by the USP. The dissolution profile of tablets dosage form was measured in 900ml of phosphate buffer, pH 6.8 plus 1.0% tween 80 using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 75 revolutions per minute.

Pharmaceutically acceptable excipient(s) are components that are added to the pharmaceutical composition other than the active ingredient azilsartan kamedoxomil and chlorthalidone selected from but not limited to diluent, disintegrant, binder, lubricant and optionally other excipients.

Diluents provide bulk, also aid processing, for example, by providing improved physical properties such as flow, hardness and compressibility. The present invention comprise pharmaceutically acceptable diluents that include but are not limited to mannitol, microcrystalline cellulose, other powdered celluloses and the like and combinations thereof. Preferably diluent is used in the composition is microcrystalline cellulose, mannitol or a combination thereof.

Disintegrant are employed to facilitate breakup or disintegration of the formulation after administration. Examples of disintegrant suitable for use in the present invention include, but are not limited to croscarmellose sodium, crospovidone, sodium starch glycolate. Disintegrants are present in an amount from 3 to 12% w/w. Preferred disintegrants according to the present is crospovidone.

Binder according to the present invention include but are not limited to hydroxypropyl cellulose, starch, guar gum, powdered acacia, carbomers and the like, and combinations thereof. Binder is present in an amount from 0.1% to 5% w/w. Preferred binder according to the present invention is hydroxypropyl cellulose, carbopol or a combination thereof. Binder can be present in first intragranular portion or second intragranular portion or in both portion and wherein weight ratio of two binders i.e. carbopol to hydroxy propyl cellulose in first portion is in the range of about 1:15 to about 1:17, preferably 1:16 and weight ratio of hydroxy propyl cellulose as a binder in first portion and second portion is in the range of about 1: 0.54, 1: 0.67, 1: 0.83.

Lubricant according to the present invention include but are not limited to magnesium stearate, aluminum stearate, stearic acid, fumaric acid and combinations thereof. Lubricant is present in an amount from 0.1% to 5% w/w. Preferred lubricant according to the present invention is magnesium stearate.

The pH control agent to be used in the present invention may be any as long as it simultaneously achieves stability and dissolution of the active from the preparation. The pH control agent used in the present invention provides the pH in the range of 6 to 12. Preferably 8 to 11, more preferably 8 to 10. The pH of the pH control agent is measured under the following conditions. To be specific, it is the pH of a solution or suspension obtained by dissolving or suspending a pH control agent in water at 25° C. at a concentration of 1 w/v %.

The pH control agent is selected from but not limited to group comprising basic amino acids selected from meglumine, lysine, arginine, and the like; alkaline amino silicates such as magnesium aluminometasilicate and the like used either alone or in combinations thereof. The pH control agent is present in an amount from 0.1% to 2% w/w preferably 0.1%, 0.2%, 0.3%, 0.4%, 0.5%. Preferred pH control agent according to the present invention is magnesium aluminometasilicate. pH control agent is present in a concentration of 0.30mg, 0.50mg, 0.75mg, 0.90mg per tablet and ratio of azilsartan kamedoxomil to magnesium aluminometasilicate is in the range of about 1:0.0170, 1:0.0175, 1:0.0180, 1:0.0185.

‘‘Tablet coating’’ refers to the phenomenon of application of coating to the tablet. Film coating refers to the process of polymeric solution to bring a uniform film. Examples include polyvinyl alcohol, hydroxypropyl cellulose, Hypromellose, polyethylene glycol.

The pharmaceutical composition of the present invention can be prepared by direct compression, dry granulation or wet granulation process. Wherein, preferred methods is wet granulation. Wet granulation can be performed using Rapid mixer granulator, Fluid bed granulator, planetary mixer and the like.

Any pharmaceutically acceptable granulating solvent or mixture of granulating solvents can be used for wet granulation. Preferably, the granulating solvent used during wet granulation is water and Isopropyl Alcohol.

The pharmaceutical composition is formulated into solid oral pharmaceutical dosage forms. Solid oral pharmaceutical dosage forms include, but are not limited to, tablets, capsules, powders and granules. Preferably, the solid oral pharmaceutical dosage form is a tablet.

In one embodiment, present invention relates to a solid oral pharmaceutical composition comprising azilsartan medoxomil or a pharmaceutically acceptable salt thereof and pH control agent having pH more than 5 and one or more pharmaceutically acceptable excipients. The invention also relates to process of preparation of such composition and use thereof for the treatment of hypertension.

In another embodiment, an invention relates to an oral pharmaceutical composition comprising:
a) intragranular portion comprising (i) 5 to 25% w/w of azilsartan kamedoxomil; (ii) 35 to 45% w/w of microcrystalline cellulose (iii) 0.1 to 5% w/w of hydroxy propyl cellulose and
b) extragranular portion comprising (i) 0.1 to 5% w/w of magnesium aluminometasilicate; (ii) 15 to 30% w/w of mannitol (iii) 4 to 12 % w/w of croscarmellose sodium (iv) 0.1 to 3 % w/w of magnesium stearate.

In another embodiment, an invention relates to oral pharmaceutical composition comprising:
a) intragranular portion comprising (i) 5 to 25% w/w of azilsartan kamedoxomil; (ii) 39 to 42% w/w of microcrystalline cellulose (iii) 0.48 to 0.50% w/w of hydroxy propyl cellulose and
b) extragranular portion comprising (i) 0.10 to 0.50% w/w of magnesium aluminometasilicate; (ii) 20 to 28% w/w of mannitol (iii) 7 to 10% w/w of croscarmellose sodium (iv) 0.57 to 0.60% w/w of magnesium stearate.

In another embodiment, an invention relates to oral pharmaceutical composition comprising:
a) intragranular portion comprising (i) 23.25 % w/w of azilsartan kamedoxomil; (ii) 40.92% w/w of microcrystalline cellulose (iii) 0.49% w/w of hydroxy propyl cellulose and
b) extragranular portion comprising (i) 0.41% w/w of magnesium aluminometasilicate; (ii) 23.68% w/w of mannitol (iii) 8.71% w/w of croscarmellose sodium (iv) 0.59% w/w of magnesium stearate.
In another embodiment, an invention relates to oral pharmaceutical composition comprising:
a) intragranular portion comprising (i) 5 to 25% w/w of azilsartan kamedoxomil;
b) extragranular portion comprising (i) 0.10 to 0.50% w/w of magnesium aluminometasilicate.

In another embodiment, an invention relates to oral pharmaceutical composition comprising
a) intragranular portion comprising (i) 42.68 to 85.36 mg of azilsartan kamedoxomil; (ii) 65 to 165 mg of microcrystalline cellulose (iii) 0.80 to 1.98 mg of hydroxy propyl cellulose and
b) extragranular portion comprising (i) 0.60 to 1.5 mg of magnesium aluminometasilicate; (ii) 35 to 95 mg of mannitol (iii) 12 to 40 mg of croscarmellose sodium (iv) 0.90 to 2.40 mg of magnesium stearate.

In another embodiment, an invention relates to oral pharmaceutical composition comprising
a) intragranular portion comprising (i) 42.68 to 85.36 mg of azilsartan kamedoxomil; (ii) 75.12 to 150.24 mg of microcrystalline cellulose (iii) 0.90 to 1.80 mg of hydroxy propyl cellulose and
b) extragranular portion comprising (i) 0.75 to 1.50 mg of magnesium aluminometasilicate; (ii) 43.47 to 86.94 mg of mannitol (iii) 16 to 32 mg of croscarmellose sodium (iv) 1.08 to 2.16 mg of magnesium stearate.

In another embodiment, an invention relates to oral pharmaceutical composition comprising:
a) first intragranular portion comprising 5 to 25% w/w of azilsartan kamedoxomil;
b) optionally second intragranular portion comprising 2 to 10% w/w of chlorthalidone;
c) extragranular portion comprising 0.1 to 5% w/w of pH control agent; wherein compositions contains not more than 4.5% of total impurities by weight relative to azilsartan kamedoxomil and chlorthalidone when measured by HPLC after storage for 3 months at 400C/75% relative humidity.

In another embodiment, an invention relates to solid oral pharmaceutical composition comprising:
a) first intragranular portion comprising (i) 5 to 25% w/w of azilsartan medoxomil or pharmaceutically acceptable salt thereof; (ii) 0.5 to 5% w/w of at least two binders selected from hydroxy propyl cellulose, carbopol;
b) second intragranular portion comprising (i) 2 to 10 % w/w of chlorthalidone; (ii) 0.5 to 5% w/w of binder selected from hydroxy propyl cellulose; and
c) extragranular portion comprising a pH control agent selected from 0.1 to 1.0% w/w of magnesium aluminometasilicate; wherein the pH control agent have a pH in the range of 7 to 12 when dissolved or suspended in water at a concentration of 1% w/v at 25?.

In another embodiment, an invention relates to oral tablet composition comprising:
a) first intragranular portion comprising (i) 5 to 25% w/w of azilsartan kamedoxomil;
b) second intragranular portion comprising (i) 2 to 10 % w/w of chlorthalidone;
c) extragranular portion comprising (i) 0.1 to 1% w/w of magnesium aluminometasilicate; (ii) 5 to 15% w/w of microcrystalline cellulose; (iii) 4 to 12 % w/w of crospovidone; and (iv) 0.1 to 2% w/w of magnesium stearate;
wherein weight ratio of azilsartan kamedoxomil to magnesium aluminometasilicate is in the range of about 1:0.0170, 1:0.0175, 1:0.0180, 1:0.0185.

In another embodiment, an invention relates to oral tablet composition comprising:
a) first intragranular portion comprising (i) 10.90% w/w of azilsartan kamedoxomil; (ii) 26.49% w/w of microcrystalline cellulose, mannitol or combination thereof; (iv) 2.2 % w/w of hydroxy propyl cellulose, carbopol or combination thereof; and
b) second intragranular portion comprising (i) 3.19 to 6.39 % w/w of chlorthalidone; (ii) 30.56 to 33.75 % w/w of microcrystalline cellulose, mannitol or combination thereof; (iii) 1.38 % w/w of hydroxy propyl cellulose; and
c) extragranular portion comprising (i) 0.19 % w/w of magnesium aluminometasilicate; (ii) 11.20 % w/w of microcrystalline cellulose; (iii) 7.28 % w/w of crospovidone; and (iv) 0.48 % w/w of magnesium stearate.

In another embodiment, an invention relates to oral tablet composition comprising:
a) first intragranular portion comprising (i) 10.90% w/w of azilsartan kamedoxomil; (ii) 2.2 % w/w of hydroxy propyl cellulose, carbopol or combination thereof; and
b) second intragranular portion comprising 3.19 to 6.39 % w/w of chlorthalidone;
c) c) extragranular portion comprising 0.19 % w/w of magnesium aluminometasilicate; wherein the weight ratio of two binders i.e. carbopol to hydroxy propyl cellulose in first portion is in the range of about 1:15 to about 1:17, preferably 1:16.

In another embodiment, an invention relates to oral tablet composition comprising:
a) first intragranular portion comprising (i) 40 to 60 mg of azilsartan kamedoxomil; (ii) 93 to 114 mg of microcrystalline cellulose, mannitol or combination thereof; (iii) 6 to 10 mg of hydroxy propyl cellulose, carbopol or combination thereof; and
b) second intragranular portion comprising (i) 8 to 40 mg of chlorthalidone; (ii) 107 to 145 mg of microcrystalline cellulose, mannitol or combination thereof; (iii) 4 to 7 mg of hydroxy propyl cellulose; and
c) extragranular portion comprising (i) 0.2 to 2 mg of magnesium aluminometasilicate; (ii) 39 to 48 mg of microcrystalline cellulose; (iii) 25 to 31 mg of crospovidone; and (iv) 1.7 to 2.1 mg magnesium stearate.

In another embodiment, an invention relates to solid oral pharmaceutical composition comprising:
a) first intragranular portion comprising (i) 40 to 60 mg of azilsartan medoxomil or pharmaceutically acceptable salt thereof; (ii) 6 to 10 mg of at least two binders selected from hydroxy propyl cellulose, carbopol;
b) second intragranular portion comprising (i) 12.5 to 25 mg of chlorthalidone; (ii) 4 to 7 mg of binder selected from hydroxy propyl cellulose;
c) extragranular portion comprising a pH control agent selected from 0.2 to 2 mg of magnesium aluminometasilicate; wherein the pH control agent have a pH in the range of 7 to 12 when dissolved or suspended in water at a concentration of 1% w/v at 25?.

In another embodiment, an invention relates to oral tablet composition comprising:
a) first intragranular portion comprising (i) 40 to 60 mg of azilsartan medoxomil or a pharmaceutically acceptable salt thereof; (ii) 6 to 10 mg of hydroxy propyl cellulose, carbopol or combination thereof; and
b) second intragranular portion comprising (i) 12.5 to 25 mg of chlorthalidone; (ii) 4 to 7 mg of hydroxy propyl cellulose;
c) extragranular portion comprising 0.2 to 2 mg of magnesium aluminometasilicate; wherein weight ratio of hydroxy propyl cellulose as a binder in first portion and second portion is in the range of about 1: 0.54, 1: 0.67, 1: 0.83.

In another embodiment, an invention relates to oral tablet composition comprising:
a) first intragranular portion comprising (i) 42.68 mg of azilsartan kamedoxomil; (ii) 103.72 mg of microcrystalline cellulose, mannitol or combination thereof; (iii) 8.6 mg of hydroxy propyl cellulose, carbopol or combination thereof;
b) second intragranular portion comprising (i) 12.5 to 25 mg of chlorthalidone; (ii) 119.6 to 132.1 mg of microcrystalline cellulose, mannitol or combination thereof; (iii) 5.40 mg of hydroxy propyl cellulose;
c) extragranular portion comprising (i) 0.75 mg of magnesium aluminometasilicate; (ii) 43.85 mg of microcrystalline cellulose; (iii) 28.50 mg of crospovidone; and (iv) 1.9 mg of magnesium stearate.

In another embodiment, an invention relates to method of using pharmaceutical composition comprising of effective amount of azilsartan kamedoxomil, chlorthalidone and pH control agent with one or more pharmaceutically acceptable excipients in the treatment of hypertension.

In another embodiment, an invention relates to the process for preparation of tablet composition wherein process comprising:
a) co-sifting azilsartan kamedoxomil and excipients through suitable sieve and mix to form a blend and prepare granules with binder solution and make granules which forms a first portion;
b) co-sifting excipients through suitable sieve and mix to form a blend and prepare granules with binder solution comprising binder & chlorthalidone which forms a second portion;
c) co-sifting extragranular excipients to through suitable sieve and mix to form a blend which forms extragranular portion.
d) sifting the lubricant and blending it with blend of step a, b and c; and
e) compressing the blend of step (d) to form tablets;
wherein the tablet is optionally film coated.

Surprisingly, it has been found that the pharmaceutical composition of the present invention has been found to have improved stability and dissolution profile coupled with simple manufacturing process at industrial scale and it is bioequivalent to commercially available counterpart tablets EDARBYCLOR®.

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

Example – 1
No Ingredients 40/12.5mg 40/25mg
Mg/tab %w/w Mg/tab %w/w
Intra-granular portion - I
1 Azilsartan Kamedoxomil 42.68 10.79 42.68 10.79
2 Mannitol 10.00 2.53 10.00 2.53
3 Microcrystalline cellulose 93.47 23.65 93.47 23.65
4 Hydroxy Propyl Cellulose 8.10 2.04 8.10 2.04
6 Carbopol 0.75 0.19 0.75 0.19
7 Isopropyl alcohol Q.S. -- Q.S. --
Intra-granular portion - II
8 Mannitol 121.00 30.62 108.50 27.45
9 Microcrystalline cellulose 9.00 2.27 9.00 2.27
10 Chlorthalidone 12.50 3.16 25.00 6.32
11 Hydroxy Propyl Cellulose 7.50 1.89 7.50 1.89
12 Water Q.S. -- Q.S. --
Extra-granular portion - III
13 Crospovidone 28.50 7.23 28.50 7.23
14 Microcrystalline Cellulose 43.85 11.09 43.85 11.09
15 Magnesium aluminometasilicate 0.75 0.18 0.75 0.18
16 Magnesium stearate 1.90 0.45 1.90 0.45
Film coating material 15.20 3.85 15.20 3.85
Coated tablet weight % 395.20 100 395.20 100
Q.S: Quantity sufficient
Azilsartan Kamedoxomil 42.68 mg is eq. to Azilsartan Medoxomil 40mg).
Film coating material: Hypromellose, Titanium dioxide, Macrogol, talc, Iron oxide yellow and Iron oxide red.

Manufacturing process:
A. Intragranular portion - I
1. Sifting: Sift azilsartan kamedoxomil, mannitol, hydroxy propyl cellulose, carbopol and microcrystalline cellulose through # suitable mesh.
2. Preparation of binder solution: Take required quantity of isopropyl alcohol and add hydroxy propyl and stir well to get clear solution.
3. Granulation: Load sifted material of step 1 into rapid mixer granulator and add the binder solution of step 2 and dry the granules. Sift dried granules through #30 mesh.
B. Intragranular portion - II
4. Sifting: Sift mannitol and microcrystalline cellulose through #30 mesh.
5. Preparation of binder dispersion: Take required quantity of water. Add hydroxy propyl cellulose under stirring and continue stirring to get clear solution. Add chlorthalidone to under stirring and continue stirring for another 30 min.
6. Granulation: Load the sifted material of step 4 into FBP bowl and spray binder solution of step 5 and dry the granules. Sift dried granules through #40 mesh.
C. Extragranular portion - III
7. Blending: Sift crospovidone, microcrystalline cellulose, and magnesium aluminometasilicate together through #30 mesh. Load the sifted material of step 7, granules of step 3 (intragranular portion I) and granules of step 6 (intragranular portion II) in low shear blender and blend for 10min.
8. Lubrication: Sift magnesium stearate through #40 mesh and blend with materials of step 7 for 5 min.
9. Compression: Compress lubricated blend of step 8 into tablets.
10. Film Coating: Add coating material to purified water and stir for 45 min. Load the core tablets of step 9 in coating pan and pre-warm the tablets at 30? ± 5?. Coat the tablet until the target weight build up is achieved. Dry the tablets and then unload from pan coater.

Example – 2
No. Ingredients 40mg/12.5mg 40mg/25mg
Mg/tab %w/w Mg/tab %w/w
Intra-granular portion - I
1 Azilsartan Kamedoxomil 42.68 10.90 42.68 10.90
2 Mannitol 10.00 2.55 10.00 2.55
3 Microcrystalline cellulose 93.72 23.94 93.72 23.94
4 Hydroxy Propyl Cellulose 8.10 2.07 8.10 2.07
5 Carbopol 0.50 0.13 0.50 0.13
6 Isopropyl Alcohol Q.S -- Q.S --
Intra-granular portion - II
7 Mannitol 123.10 31.45 110.60 28.26
8 Microcrystalline cellulose 9.00 2.30 9.00 2.30
9 Chlorthalidone 12.50 3.19 25.00 6.39
10 Hydroxy Propyl Cellulose 5.40 1.38 5.40 1.38
11 Water Q.S -- Q.S --
Extra-granular portion - III
12 Crospovidone 28.50 7.28 28.50 7.28
13 Microcrystalline Cellulose 43.85 11.20 43.85 11.20
14 Magnesium aluminometasilicate 0.75 0.19 0.75 0.19
15 Magnesium stearate 1.90 0.48 1.90 0.48
Film coating material 14.82 3.79 14.82 3.79
Coated tablet weight 391.40 100.00 391.40 100.00
Q.S: Quantity sufficient
Manufacturing process: Manufacturing process is same as example 1.

Example – 3
No. Ingredients 40mg/12.5mg 40mg/25mg
Mg/tab %w/w Mg/tab %w/w
Intra-granular portion - I
1 Azilsartan Kamedoxomil 42.68 10.90 42.68 10.90
2 Mannitol 9.00 2.30 9.00 2.30
3 Microcrystalline cellulose 84.35 21.55 84.35 21.55
4 Hydroxy Propyl Cellulose 8.92 2.28 8.92 2.28
5 Carbopol 0.55 0.14 0.55 0.14
6 Isopropyl Alcohol Q.S -- Q.S --
Intra-granular portion - II
7 Mannitol 131.94 33.71 119.44 30.52
8 Microcrystalline cellulose 9.90 2.53 9.90 2.53
9 Chlorthalidone 12.50 3.19 25.00 6.39
10 Hydroxy Propyl Cellulose 4.86 1.24 4.86 1.24
11 Water Q.S -- Q.S --
Extra-granular portion - III
12 Crospovidone 31.35 8.01 31.35 8.01
13 Microcrystalline Cellulose 39.47 10.08 39.47 10.08
14 Magnesium aluminometasilicate 0.83 0.21 0.83 0.21
15 Magnesium stearate 1.71 0.44 1.71 0.44
Film coating material 13.34 3.41 13.34 3.41
Coated tablet weight 391.40 100.00 391.40 100.00
Q.S: Quantity sufficient
Manufacturing process: Manufacturing process is same as example 1.

Example 4
No Ingredients Mg/tab %w/w
40 mg 80 mg
Intra granular portion
1. Azilsartan kamedoxomil 42.68 85.36 23.25
2. Microcrystalline cellulose 75.12 150.24 40.92
3. Hydroxy Propyl Cellulose 0.90 1.80 0.49
4. Isopropyl Alcohol q.s. q.s. --
Extra granular portion
5. Croscarmellose sodium 16.00 32.00 8.71
6. Magnesium aluminometa silicate type I-B 0.75 1.50 0.41
7. Mannitol 43.47 86.94 23.68
8. Magnesium stearate 1.08 2.16 0.59
Film coating
9. Film coating material 4.68 9.36 2.55
Coated tablet weight 183.60 367.20 100
Q.S: Quantity sufficient
Azilsartan Kamedoxomil 42.68 mg is eq. to Azilsartan Medoxomil 40mg & Azilsartan Kamedoxomil 85.36 mg is eq. to Azilsartan Medoxomil 80mg.
Film coating material: Hypromellose, Titanium dioxide, Macrogol and Talc.

Manufacturing process:
1. Sifting: Co Sift azilsartan kamedoxomil, microcrystalline cellulose through suitable sieve.
2. Prepare binder solution by adding hydroxy propyl cellulose to required quantity of isopropyl alcohol.
3. Carry out granulation of step 1 in rapid mixer granulator, using binder solution of step 2 as granulating solution.
4. Dry the granules in a fluidized bed dryer with a desired temperature to achieve the desired LOD.
5. Sift and mill, the retain granules through suitable sieve / screen.
6. Co Sift the extra granular material (Croscarmellose sodium, Mannitol, Magnesium aluminometa silicate) through suitable sieve.
7. Load the material of step 5 in suitable blender and blend with material of step 6 for suitable time period.
8. Sift Magnesium Stearate through suitable sieve.
9. Load the sifted Magnesium stearate to the blender and lubricate the blend with suitable time period.
10. Compress the lubricated blend of step 9 by suitable punches with the target average weight.
11. Film Coating: Add coating material to Isopropyl alcohol and purified water and stir for 45 min. Load the core tablets of step 10 in coating pan and pre-warm the tablets at 30? ± 5?. Coat the tablet until the target weight build up is achieved. Dry the tablets and then unload from coating pan.

Dissolution study: The dissolution profile of the tablets 40/25mg prepared using quantitative composition as mentioned in example 1 and 2 are shown in Table 1:

Table 1: Dissolution profile of commercially marketed tablets (Edarbyclor®) and Examples 1 and 2 at particular time intervals:
% Drug dissolved
Edarbyclor® Example 1 Example 2
Time (min) Azil Chlor Azil Chlor Azil Chlor
10 70 99 55 99 51 98
20 85 100 74 100 68 98
30 94 100 81 100 76 98
60 100 100 85 100 85 99
Azil: Azilsartan kamedoxomil, Chlor: Chlorthalidone

Two dissolution profiles (Edarbyclor® and Example 1 or 2) are considered similar based on f1 and f2 results of above table.

Stability studies: Tablet dosage form prepared according to Example 1 was subjected to accelerated stability testing as per the ICH guidelines at temperature 40°±2°C and relative humidity of 75%±5% for 3 months. The tablets was placed in a high density polyethylene (HDPE) bottles exposed to above mentioned condition and then evaluated for impurity profile which is shown in Table 2:

Table 2: Results of stability tests by high performance liquid chromatography:
Strength 40/12.5mg 40/25mg
Initial 3 M* Initial 3 M*
For Azilsartan medoxomil
Azilsartan 1.51 2.33 1.28 2.15
Desmethylazilsartan ND 0.06 ND 0.05
Desethylazilsartanmedoxomil 0.03 0.11 0.02 0.09
Open ringAzilsartan Medoxomil ND 0.14 ND 0.09
Azilsartan Ethyl Ester 0.01 0.06 0.01 0.05
Any other individual Impurity 0.12 0.05 0.09 ND
Total Azilsartan Medoxomil Impurities 1.68 2.7 1.4 2.43
Chlorthalodone Related Compound A 0.14 0.24 0.26 0.27
Chlorthalodone Methyl Ether 0.01 ND 0.02 ND
Chlorthalodone Impurity J ND ND ND ND
Chlorthalodone Impurity G 0.06 0.11 0.13 0.09
Impurity-1 ND 0.12 0.05 ND
Impurity-2 ND ND 0.06 ND
Impurity3 ND ND 0.05 0.11
Total Chlorthalodone Impurities 0.21 0.47 0.57 0.47
Total RS [Azilsartan medoxomil and Chlorthalidone] 1.89 3.17 1.97 2.9
NMT – Not more than; ND: Not detected; M*=months

The present formulation clearly indicates excellent chemical stability upon storage at accelerated stability conditions at 40°±2°C and 75%±5% relative humidity for three months showed no evidence of any degradation products and no reduction in the content of active substance. ,CLAIMS:Claims:
1. A solid oral pharmaceutical composition comprising:
a) first intragranular portion comprising: 40 to 85 mg of azilsartan medoxomil or pharmaceutically acceptable salt thereof;
b) optionally second intragranular portion comprising: 12.5 to 25 mg of chlorthalidone;
c) extragranular portion comprising a pH control agent selected from 0.2 to 2 mg of magnesium aluminometasilicate; wherein the pH control agent have a pH in the range of 7 to 12 when dissolved or suspended in water at a concentration of 1% w/v at 25?.

2. A solid oral pharmaceutical composition comprising:
a) first intragranular portion comprising: (i) 5 to 25% w/w of azilsartan medoxomil or pharmaceutically acceptable salt thereof; (ii) 0.5 to 5% w/w of at least two binders selected from hydroxy propyl cellulose, carbopol;
b) second intragranular portion comprising: (i) 2 to 10% w/w of chlorthalidone; (ii) 0.5 to 5% w/w of binder selected from hydroxy propyl cellulose;
c) extragranular portion comprising a pH control agent selected from 0.1 to 1.0% w/w of magnesium aluminometasilicate; wherein the pH control agent have a pH in the range of 7 to 12 when dissolved or suspended in water at a concentration of 1% w/v at 25?.

3. The solid oral pharmaceutical composition according to claim 1 and 2, wherein pharmaceutically acceptable salt of azilsartan Medoxomil is potassium salt.

4. The solid oral pharmaceutical composition according to claim 1, wherein the pH control agent magnesium aluminometasilicate is present in a concentration of 0.25mg, 0.50mg, 0.75mg, 0.90mg, 1.25mg, 1.50mg per tablet.

5. The solid oral pharmaceutical composition according to claim 1, wherein weight ratio of azilsartan kamedoxomil to magnesium aluminometasilicate is in the range of about 1:0.0170, 1:0.0175, 1:0.0180, 1:0.0185.

6. The solid oral pharmaceutical composition according to claim 1, wherein the pH control agent magnesium aluminometasilicate is present in a concentration of 0.50mg, 0.75mg, 1.0mg, 1.25mg, 1.50mg.

7. The solid pharmaceutical composition according to claim 1 and 2, wherein the solid pharmaceutical composition is a tablet or capsule, if the solid pharmaceutical composition is a tablet then it is optionally film coated.

8. The solid oral pharmaceutical composition according to claim 2, wherein the pH control agent magnesium aluminometasilicate is present in a concentration of 0.10%, 0.20%, 0.30%, 0.40%, 0.50%.

9. The solid oral pharmaceutical composition according to claim 1, wherein at least 75% of azilsartan kamedoxomil dissolves within 60 minutes in a 900ml of pH 6.8 phosphate buffer at a temperature of 37±0.5°C using a USP apparatus-2 at a paddle rotation of about 75 rpm.