Field of the invention

The technical field of the present invention relates to stable oral dosage forms of angiotensin II antagonists. More particularly, the present invention relates to stable oral dosage forms of candesartan cilexetil.

Background of the invention

Candesartan belongs to a class of benzimidazole-7-carboxylic acid. It is a selective ATI subtype angiotensin II receptor antagonist, used for the treatment of cardiovascular ailments such as hypertension, heart failure and post myocardial infarction as disclosed in US 5,196,444.
Candesartan is poorly absorbed after oral administration and hence, its prodrug
candesartan cilexetil was developed. Following oral administration candesartan cilexetil
under goes hydrolysis to form candesartan. Chemically, candesartan cilexetil is (±)-l-
hydroxy ethyl, 2-ethoxy-1 - [p-(o-1 H-tetrazol-5 -ylphenyl)benzyl] -7-benzimidazole
carboxylate, cyclohexyl carbonate (ester) and is commercially marketed under the trade names Atacand®, Amias® and Atacand HCT® in combination with hydrochlorothiazide. Commercially available candesartan tablets contain 2mg, 4mg, 8mg, 16mg and 32mg of candesartan cilexetil as active ingredient and excipients such as hydroxypropyl cellulose, polyethylene glycol, lactose, cornstarch, carboxymethylcellulose calcium, magnesium stearate and iron oxide.

As disclosed in US 5,534,534, benzimidazole-7-carboxylic acid and derivatives thereof, are stable against temperature, moisture and light when they are alone in the solid state. However, when prepared into tablets by incorporating other ingredients, it has been observed that lowering of the content of the active ingredient is apt to be enhanced in the course of time due to deformation of crystals caused by pressure, abrasion and heat, applied during granulation or molding under elevated pressure during preparation.

To overcome this problem, US '534 discloses that incorporating an oily substance having a low melting point into a formulation suppress the decomposition of the active component to afford a stable composition. This patent further discloses that the oily substances exerts no undesirable influence on the active component and are selected from hydrocarbons, higher fatty acids, higher alcohols, fatty acid esters of polyhydric alcohols, higher alcohol ethers of polyhydric alcohols, and polymers or copolymers of alkylene oxide.

The following patents/patent publications further disclose different ways of stabilizing and improving dissolution of candesartan:

EP 1 711 168 discloses the use of fatty substances at a concentration of 0.5 % to about 10 % w/w results in stable compositions of candesartan cilexetil.

WO 2005/070398 discloses composition comprising candesartan and cosolvent such as propylene glycol, polyethylene glycol, ethanol, glycerin and further discloses process for the preparation of tablets comprising dispersing candesartan cilexetil, fatty acid ester in a solution comprising a co-solvent in water to form a dispersion; granulating a blend of diluents and disintegrant with the dispersion; lubricating the granules and compressing the lubricated granules into tablets.

WO 2005/084648 discloses the compositions comprising candesartan cilexetil and water soluble polymers.

WO 2006/079496 discloses composition comprising candesartan and a hydrophilic substance with hydrocolloidal properties.

WO 2007/147514 discloses a tablet comprising candesartan cilexetil coated with tri-(C1- C6) alkyl citrate, di-(C1- C6) alkyl phthalate, di-(C1 -C6) alkyl sebacate and polydimethylsiloxanes.

US 2008/0058399 discloses the use of solubilizer to enhance the bioavailability of candesartan cilexetil, wherein the composition exhibit a relative bioavailability, measured as area under the curve (AUC), of more than 1.5.

WO 2008/045006 discloses that the presence of antioxidant and metal chelating agent enhances the stability of candesartan.

WO 2008/065097 discloses composition comprising candesartan and a stabilizer selected from esters of saturated fatty acids and monohydroxy alcohols, esters of hydroxycarboxylic acids and monohydroxy alcohols, ethers of C1-C4 monohydroxy alcohols and C2-C9 polyhydroxy alcohols, saturated fatty acid alkaline salts and panthenol.

WO 2008/068727 discloses composition comprising candesartan cilexetil and buffering agent, wherein the pH of an aqueous dispersion of the composition in water is more than 5.5 and further discloses that the pH of more than 5.5 provides a formulation with low impurity levels.

WO 2008/109170 discloses the use of amino acid to stabilize candesartan compositions.

WO 2008/118031 and EP 2 106 789 discloses that the presence of graft copolymer of polyvinyl alcohol with polyethylene glycol ensures stability of compositions comprising candesartan.

WO 2008/134013 discloses that the excipient complex comprising carrier and oily substance prevents or diminishes the candesartan decomposition.

EP 1 997 479 discloses claims composition comprising amorphous candesartan cilexetil and aminoalkylmethacrylate polymer.

WO 2009/013237 discloses the use of plasticizer such as phthalate esters, sebacates, alginates, citrate esters, polyacrylate and polymethacrylate polymers, polymers and copolymers of ethylene, vinyl and/or acetate, various sugar alcohols, triacetin, menthol to stabilize candesartan compositions.

WO 2009/017812 discloses composition comprising candesartan and nonionic surfactant.

WO 2009/056266 discloses granulates comprising candesartan cilexetil, a sugar alcohol and a binding agent, prepared by alcoholic granulation.

WO 2009/135646 A2 discloses composition comprising candesartan and stabilizer selected from light liquid paraffin or polyethylene glycol 100-400.

EP 2 165 702 Al discloses a wet granulated composition comprising candesartan cilexetil pretreated with at least one surfactant selected from the group of anionic surfactants, preferably sodium docusate and optionally at least a second surfactant, preferably sodium lauryl sulfate; and at least one excipient.

IN 1971 /MUM/2007 discloses the use of fibrous microcrystalline cellulose to stabilize pharmaceutical composition comprising candesartan.

WO 2010/146409 A2 discloses nanostructured candesartan cilexetil and co-crystals having an average particle size of less than about 500 nm.

WO 2012/033983 A2 discloses formulation comprising candesartan cilexetil, at least one water-soluble or water-swellable polymer, and a stabilizer that is at least one of a mono-, di-, or tri-glyceride or a mono- and di-ester of polyethylene glycol, glyceryl behenate, glyceryl mono- or di-stearate, glyceryl palmitostearate, stearic acid, tragacanth gum, gum arabic, locust bean gum, gum acacia, a medium chain triglyceride, glycerol, propylene glycol, stearoyl alcohol, fractionated coconut oil, polyoxylglyceryl stearate, and N-(2-hydroxyethyl) 12-hydroxystearamide.

The above prior art references disclose various means to stabilize candesartan compositions employing fatty acids or fatty acids and cosolvents, polymers, amino acids and antioxidants. None of the prior art references disclose the stabilization of candesartan using combination of adsorbent and propylene glycol without using fatty acid esters and oily substances. The inventors of the present invention have surprisingly found that composition comprising candesartan in combination with adsorbent and propylene glycol shows improved/comparable stability and bioavailability with respect to the marketed dosage form.

Objective of the invention
Accordingly, the main objective of the present invention is to provide stable oral dosage form comprising candesartan in such a way that the dosage form will comply with the reference product in terms of in vivo parameters like Cmax, Tmax and AUC and in vitro parameters like dissolution, disintegration and etc.

Summary of the invention

Accordingly, the present invention provides a stable oral dosage form comprising candesartan cilexetil, adsorbent, propylene glycol and one or more pharmaceutically acceptable excipients.

The present invention further provides a stable oral dosage form comprising candesartan cilexetil, prepared by granulating a blend of excipients comprising adsorbent with a dispersion comprising candesartan and propylene glycol in a solvent.

Detailed description of the invention

The present invention relates a stable oral dosage form comprising candesartan cilexetil, adsorbent, propylene glycol and one or more pharmaceutically acceptable excipients.

The present invention further relates to a stable oral dosage form comprising candesartan cilexetil, prepared by granulating a blend of excipients comprising adsorbent with a dispersion comprising candesartan and propylene glycol in a solvent.

Candesartan cilexetil when formulated into tablets undergoes degradation to many impurities such as desethyl candesartan, ethyl candesartan, trityl candesartan and the like. The inventors of the present invention found that the use of combination of adsorbent and propylene glycol will stabilize candesartan in dosage form and reduce the level of impurities.

In another embodiment, the present invention provides a stable oral dosage form comprising about 1% to 40% by weight of candesartan cilexetil, about 0.5% to 15% by weight of adsorbent and about 1% to 5% by weight of propylene glycol and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention provides a stable oral dosage form comprising about 1% to 40% by weight of candesartan cilexetil, about 0.5% to 15% by weight of adsorbent and about 1% to 5% by weight of propylene glycol and one or more pharmaceutically acceptable excipients, wherein the dosage form is free of fatty acid esters or oily substances or carragenan.

In another embodiment, the present invention provides a stable oral dosage form comprising about 1% to 40% by weight of candesartan cilexetil, about 0.5% to 15% by weight of adsorbent and about 1% to 5% by weight of propylene glycol and one or more pharmaceutically acceptable excipients, wherein the dosage form is in the form of monolayered tablet.

In a preferred embodiment, the present invention provides a stable oral dosage form comprising about 1% to 40% by weight of candesartan cilexetil, about 0.5% to 15% by weight of adsorbent selected from colloidal silicon dioxide, maize starch and magnesium aluminum silicate and about 1% to 5% by weight of propylene glycol and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention provides a stable oral dosage form comprising about 1% to 40% by weight of candesartan cilexetil, about 1% to 40% by weight of hydrochlorothiazide, about 0.5% to 15% by weight of adsorbent and about 1% to 5% by weight of propylene glycol and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention provides a stable oral dosage form comprising candesartan cilexetil, prepared by granulating blend of excipients comprising diluent, binder, disintegrant and adsorbent with a dispersion of candesartan, binder and propylene glycol in a solvent, wherein the dosage form is free of fatty acid esters, fatty acid esters of polyhydric alcohols, oily substances or carragenan.

In another embodiment, the present invention provides a stable oral dosage form comprising candesartan cilexetil and a diuretic, prepared by granulating diuretic and blend of excipients comprising diluent, binder, disintegrant and adsorbent with a dispersion of candesartan, binder and propylene glycol in a solvent.

In another preferred embodiment, the present invention provides a stable oral dosage form comprising candesartan cilexetil, prepared by granulating a blend of excipients comprising about 0.5% to 15% by weight of adsorbent, about 5% to 95% by weight of diluent, about 0.5 to 40% by weight of binder, about 1% to 30% by weight of disintegrant, optionally diuretic and colorants, with a dispersion comprising about 1% to 40% by weight of candesartan, about 1% to 10% by weight of propylene glycol, about 0.5 to 40% by weight of binder and optionally one or more pharmaceutically acceptable excipients in a solvent.

In another preferred embodiment, the present invention provides a stable oral dosage form comprising candesartan cilexetil, prepared by granulating about 1% to 40% by weight of hydrochlorothiazide and a blend of excipients comprising about 0.5% to 15% by weight of adsorbent, about 5% to 95% by weight of diluent, about 0.5 to 40% by weight of binder, about 1% to 30% by weight of disintegrant, optionally colorants, with a dispersion comprising about 1% to 40% by weight of candesartan, about 1% to 10% by weight of propylene glycol, about 0.5 to 40% by weight of binder and optionally one or more pharmaceutically acceptable excipients in a solvent.

"Candesartan" according to the present invention includes, but not limited to, candesartan free base, its pharmaceutical acceptable salts, esters, ethers, solvates, hydrates, polymorphs and the like, preferably candesartan cilexetil.

Candesartan cilexetil used in the present invention may be in the form of crystalline or amorphous form. The amount of candesartan may range from about 1% to about 40% by weight of the dosage form.

In another embodiment, the stable oral dosage form of the present invention further comprises diuretic such as amiloride, chlorthalidone, furosemide, hydrochlorothiazide and indapamide to achieve synergistic therapeutic efficacy in the treatment of hypertension. The amount of diuretic may range from about 1% to about 40% by weight of the dosage form, preferably 1 to 10% by weight of the dosage form and is present in an amount of 5-40 mg.

Adsorbents according to the present invention include but not limited to colloidal silicon dioxide, silicates such as magnesium silicate, calcium silicate, aluminum silicate, magnesium trisilicate, magnesium aluminum silicate/magnesium aluminum metasilicate available under the trade name Veegum® and Neusilin®; maize starch, kaolin, bentonite and the like or combinations thereof. The amount of adsorbent may range from about 0.5% to 15% by weight of the dosage form.

In another embodiment of the present invention, the stable oral dosage form comprising candesartan may be in the form of tablet, capsule, powder and granules, preferably in the form of tablets.

In another embodiment, the stable oral dosage form is in the form of a monolayered tablet.

In another embodiment of the present invention, the stable oral dosage form comprising candesartan may be prepared by any method known in the art such as wet granulation, dry granulation and direct compression, preferably wet granulation.

In another embodiment, the stable oral dosage form is free of fatty acid esters or oily substances or carragenan.

In another embodiment, the dispersion comprising candesartan may further comprise one or more excipients selected from binder, disintegrant; with the proviso that said dispersion is free of starch derivative such as sodium starch glycolate.

"Pharmaceutically acceptable excipient/s" are the components added to pharmaceutical formulation to facilitate manufacture, enhance stability, control release, enhance product characteristics, enhance bioavailability, enhance patient acceptability, etc. Pharmaceutically acceptable excipients includes, but not limited to, diluents/fillers, binders, disintegrants, sugars, lubricants, glidants, compression aids, colors, sweeteners, preservatives, colorants, surfactants, suspending agents, dispersing agents, film formers, flavors, printing inks, etc.

Binders hold the ingredients in the composition together. Exemplary binders include, but not limited to, cellulose and its derivatives including, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose and hydroxyethyl cellulose, carboxymethyl cellulose and its salts; starch and its derivatives; hydrocolloids; sugars; polyvinyl pyrrolidone, copovidone, methacrylic acid copolymers and combinations comprising one or more of the foregoing binders. The binder may be used in the range of 0.5-40% by weight of the dosage form.

Diluents increase the bulk of the composition. Diluents according to the present invention include, but not limited to, sugars such as lactose, sucrose, dextrose; sugar alcohols such as mannitol, sorbitol, xylitol, lactitol; Starlac® (co-processed mixture of Starch and lactose), Microcelac® (co-processed mixture of microcrystalline cellulose and lactose), starch, corn starch, modified starches, pregelatinized starch, dibasic calcium phosphate, tribasic calcium phosphate, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose and the like or combinations thereof. The diluent may be used in the range of 5-95% by weight of the dosage form.

Disintegrants according to the present invention include, but not limited to, water swellable substances, for example, cellulose and its derivatives including low-substituted hydroxypropyl cellulose; cross-linked polyvinylpyrrolidone; cross-linked sodium carboxymethylcellulose, cross-linked calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxy methylcellulose, microcrystalline cellulose; sodium starch glycolate; ion-exchange resins; starch and modified starches including pregelatinized starch; formalin-casein; alginates, gums, and combinations comprising one or more of the foregoing water swellable substances. The disintegrant may be used in the range of 1 -30% by weight of the dosage form.

Surfactants are compounds which are capable of improving the wetting of the drug and/or enhancing the dissolution. The surfactants can be selected from hydrophilic surfactants or lipophilic surfactants or mixtures thereof. The surfactants can be anionic, nonionic, cationic, and zwitterionic surfactants. The surfactant may be used in the range of 0.001-5% by weight of the dosage form.

Lubricants and glidants aids in the processing of powder materials. Exemplary lubricants include, but not limited to, calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, fumaric acid, talc, vegetable oil, zinc stearate, and combinations comprising one or more of the foregoing lubricants. The lubricant may be used in the range of 0.01-5% by weight of the dosage form. Exemplary glidants include, but not limited to, talc, silicon dioxide, silicic acid, cornstarch, calcium silicate, magnesium carbonate, magnesium oxide, magnesium silicate and the like. The glidant may be used in the range of 0.01-5% by weight of the dosage form.

Suitable colorants according to the present invention include, but not limited to, water soluble dyes, natural colorants and water insoluble pigments such as iron oxides available under the trade name Sicovit Red® and Sicovit Yellow®.

In another embodiment, the present invention provides a stable oral dosage form comprising candesartan cilexetil, prepared by granulating candesartan, adsorbent optionally diuretic and one or more pharmaceutically acceptable excipients with a solution comprising propylene glycol, binder and optionally one or more pharmaceutically acceptable excipients in a solvent.

In another embodiment, the present invention relates to a stable oral dosage form comprising candesartan cilexetil prepared by a process comprising the steps of:

(i) granulating blend of one or more pharmaceutically acceptable excipients with a dispersion comprising candesartan, binder and propylene glycol in a solvent,

(ii) drying the granules and

(iii) blending the dried granules of step (ii) with one or more extra granular pharmaceutically acceptable excipients and

(iv) formulating the blend obtained in step (iii) into solid dosage form.

In another embodiment, the present invention relates to a stable oral dosage form comprising candesartan cilexetil prepared by a process comprising the steps of:

(i) granulating diuretic and blend of one or more pharmaceutically acceptable excipients with a dispersion comprising candesartan, binder and propylene glycol in a solvent,

(ii) drying the granules and

(iii) blending the dried granules of step (ii) with one or more extra granular pharmaceutically acceptable excipients and

(iv) formulating the blend obtained in step (iii) into solid dosage form.

In another embodiment, the present invention relates to a stable oral dosage form comprising candesartan cilexetil prepared by a process comprising the steps of:

(i) granulating blend of excipients comprising diluent, binder, disintegrant, adsorbent, glidant, colorant and optionally diuretic with a dispersion of candesartan, binder and propylene glycol in a solvent,

(ii) drying the granules and

(iii) blending the dried granules of step (ii) with extra granular excipients comprising disintegrant, lubricant, and optionally one or more pharmaceutically acceptable excipients, and

(iv) formulating the blend obtained in step (iii) into solid dosage form.

In a preferred embodiment, the present invention provides a stable oral dosage form comprising candesartan cilexetil prepared by a process comprising the steps of:

(i) preparing a blend of excipients comprising about 0.5% to 15% by weight of adsorbent, about 5% to 95% by weight of diluent, about 0.5 to 40% by weight of binder, about 1% to 30% by weight of disintegrant, optionally colorants,

(ii) optionally adding a diuretic to the blend of step (i),

(iii) granulating the blend of step (ii) with a dispersion comprising about 1% to 40% by weight of candesartan, about 1% to 10% by weight of propylene glycol, about 0.5 to 40% by weight of binder and optionally one or more pharmaceutically acceptable excipients in a solvent,

(iv) drying the granules and,

(v) blending the dried granules of step (iv) with extra granular excipients comprising about 1% to 30% by weight of disintegrant, about 0.01 to 5% by weight of lubricant, optionally about 5% to 95% by weight of diluent; and

(vi) formulating the blend obtained in step (v) into solid dosage form.

In another preferred embodiment, the present invention provides a stable oral dosage form comprising candesartan cilexetil prepared by a process comprising the steps of: (i) preparing a blend of excipients comprising about 0.5% to 15% by weight of adsorbent selected from colloidal silicon dioxide, maize starch and magnesium aluminum silicate, about 5% to 95% by weight of diluent selected from lactose, microcrystalline cellulose, maize starch, about 0.5-40% by weight of binder selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, about 1% to 30% by weight of disintegrant selected from carmellose calcium, sodium starch glycolate, crospovidone, croscarmellose sodium, optionally colorants,

(ii) optionally adding a diuretic to the blend of step (i),

(iii) granulating the blend of step (ii) with a dispersion comprising about 1% to 40% by weight of candesartan, about 1% to 10% by weight of propylene glycol, about 0.5 to 40% by weight of binder selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone and optionally one or more pharmaceutically acceptable excipients in a solvent.

(iv) drying the granules and

(v) blending the dried granules of step (iv) with extra granular excipients comprising about 1% to 30% by weight of disintegrant selected from carmellose calcium, sodium starch glycolate, crospovidone, croscarmellose sodium, about 0.01 to 5% by weight of lubricant selected from magnesium stearate, talc and sodium stearyl fumarate, optionally about 5% to 95% by weight of diluent selected from lactose, microcrystalline cellulose, maize starch; and

(vi) formulating the blend obtained in step (v) into solid dosage form.

In an embodiment of the present invention, the solvents used for dispersion may be selected from water or organic solvents such as acetone, alcohol, isopropyl alcohol, methylene chloride and the mixture thereof.

The dosage forms prepared according to present invention are stable at room temperature as well as accelerated conditions i.e. 40°C/75% RH, which can be attributed with the presence of lower amount of impurities.

In another embodiment, the tablets according to the present invention may be uncoated or optionally coated.

Film coating composition includes one or more polymeric carriers along with one or more pharmaceutically acceptable excipients such as plasticisers, opacifier, anti-sticking agent, colorants, sugars, pore forming agent, surfactants and the like. More particularly the film coating is Opadry.

Suitable film coating polymers according to the present invention include, but not limited to, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene oxide and the like or combinations thereof.

Suitable plasticizers according to the present invention include, but not limited to, polyethylene glycol, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, acetylated monoglycerides, glycerol, triacetin, propylene glycol, dibutyl phthalate, diethyl phthalate, isopropyl phthalate, dimethyl phthalate, dactyl phthalate, dibutyl sebacate, dimethyl sebacate, castor oil, glycerol monostearate, fractionated coconut oil and the like or combinations thereof.

Suitable opacifiers according to the present invention include, but not limited to, water insoluble pigments comprising titanium dioxide, calcium carbonate, calcium sulfate, magnesium oxide, magnesium carbonate, aluminum silicate, aluminum hydroxide, talc, iron oxide and the like or combinations thereof.

Suitable colorants include water soluble dyes, water insoluble pigments and natural colorants.

Suitable anti-sticking agents used according to the present invention are selected from talc, magnesium stearate and the like or a mixture thereof.

"% by weight" according to the present invention is calculated based on the total weight of dosage form.

In yet another embodiment, the amount of candesartan used may be in the range of about 1 to about 50 mg.

In yet another embodiment, the stable oral dosage forms prepared according to present invention can be used for treating hypertension, congestive heart failure, angina, and myocardial infarction.

The following examples further exemplify the invention and are not intended 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.

The processing steps involved in manufacturing candesartan tablets given in example 1 are given below:

i) lactose monohydrate, hydroxypropyl cellulose, magnesium aluminum silicate, carmellose calcium and sicovit red were sifted and blended,

ii) a dispersion of candesartan cilexetil, hydroxypropyl cellulose and propylene glycol in
water was prepared,

iii) granulated the blended material of step (i) with dispersion of step (ii),

iv) dried the granules obtained in step (iii) and blended with extragranular carmellose calcium,

v) lubricated the blend of step (iv) with magnesium stearate and

vi) the lubricated blend was compressed to obtain tablets, or filled into capsules.

The compositions described in examples 2 to 9 were prepared using the procedure similar to the one described in example 1.

Example 3
Example 4


Magnesium stearate 2
Examples 5-7

S.No. Ingredients Qty(mg)

Example-5 Example-6 Example-7
Intragranular
Lactose monohydrate 141.50 123.00 138.00
2 Hydroxypropyl cellulose 3.00 3.00 3.00
3 Carmellose calcium 5.50 5.50 5.50
4 Colloidal silicon dioxide 1.50 - -
5 Maize starch - 20.00 -
6 Magnesium alumino metasilicate - - 5.00
Granulating fluid
7 Candesartan cilexetil 4.00 4.00 4.00
8 Propylene glycol 5.00 5.00 5.00
9 Hydroxypropyl cellulose 2.00 2.00 2.00
10 Purified water Qs Qs Qs
Extra granular
11 Carmellose calcium 1.50 1.50 1.50
12 Magnesium stearate 1.00 1.00 1.00
Total weight 165.00 165.00 165.00
Examples 8-9

Dissolution Data: Tablets prepared according to examples 5 and 6 were subjected to dissolution studies using 900 ml of pH 6.5 Phosphate buffer containing 0.35% Tween 20 as dissolution medium in USP II apparatus at 50 rpm. The dissolution data is given in Table 1.

Tablets prepared according to Example 9 were subjected to dissolution studies using 900 ml of pH 6.5 Phosphate buffer containing 0.35% Tween 20 as dissolution medium in USP II apparatus at 50 rpm. The dissolution data is given in Table 2.

Stability Data: Tablets prepared according to Example 2 were stored at 40°C/75% RH for three months and then tested by HPLC to determine the amount of impurities. The stability data is given in Table 3.
Stability Data: Tablets prepared according to Examples 5-9 were stored at 40°C/75% RH for three months and then tested by HPLC to determine the amount of impurities. The stability data is given in Tables 4 and 5.

Table 5

We claim:

1. A stable oral dosage form comprising candesartan cilexetil, prepared by granulating a blend of excipients comprising adsorbent with a dispersion comprising candesartan and propylene glycol and one or more pharmaceutically acceptable excipients in a solvent.

2. The dosage form as claimed in claim 1, wherein the dispersion comprises candesartan, propylene glycol and a binder.

3. The dosage form as claimed in claim 1, wherein the dosage form further comprises a diuretic selected from amiloride, chlorthalidone, furosemide, hydrochlorothiazide and indapamide.

4. The dosage form as claimed in claim 1, wherein the adsorbent is selected from colloidal silicon dioxide, magnesium silicate, calcium silicate, aluminum silicate, magnesium trisilicate, magnesium aluminum metasilicate, maize starch, kaolin, bentonite and combination thereof.

5. The dosage form as claimed in claim 1, wherein one or more pharmaceutically acceptable excipients are selected from diluent, binder, disintegrant, glidant, lubricant and colorants.

6. The dosage form as claimed in claim 4, wherein the diluent is selected from lactose, sucrose, dextrose, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate and combination thereof.

7. The dosage form as claimed in claim 4, wherein the binder is selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, pregelatinized starch and combination thereof.

8. The dosage form as claimed in claim 4, wherein the disintegrant is selected from crospovidone, sodium starch glycolate, carmellose calcium, croscarmellose sodium and combination thereof.

9. A stable oral dosage form comprising candesartan cilexetil, prepared by granulating a blend of excipients comprising about 0.5 % to 15% by weight of adsorbent, about 5% to 95% by weight of diluent, about 0.5 to 40% by weight of binder, about 1% to 30% by weight of disintegrant, optionally diuretic and colorants, with a dispersion comprising about 1% to 40% by weight of candesartan, about 1% to 10% by weight of propylene glycol, about 0.5 to 40% by weight of binder and optionally one or more pharmaceutically acceptable excipients in a solvent.

10. A stable oral dosage form comprising candesartan cilexetil prepared by a process comprising the steps of:

(i) granulating blend of excipients comprising diluent, binder, disintegrant, adsorbent, glidant, colorant and optionally diuretic with a dispersion of candesartan, binder and propylene glycol in a solvent,

(ii) drying the granules and

(iii) blending the dried granules of step (ii) with extra granular excipients comprising disintegrant, lubricant, and optionally one or more pharmaceutically acceptable excipients, and

(iv) formulating the blend obtained in step (iii) into solid dosage form.