Field of the invention

The technical field of the present invention relates to stable pharmaceutical compositions of angiotensin II antagonists. More particularly, the present invention relates to stable pharmaceutical compositions of candesartan cilexetil.

Background of the invention

Candesartan belongs to a class of benzimidazole-7-carboxylic acid. It is a selective
AT1 subtype angiotensin II receptor antagonist, used for the treatment of cardiovascular ailments such as hypertension, heart failure and post myocardial infarction.

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 (±)-1 -Hydroxy ethyl 2-ethoxy-1-H-(o-1H-tetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexyl carbonate (ester) and is commercially marketed under the trade name Atacand® and Atacand HCT® in combination with hydrochlorothiazide in the United States. Commercially available candesartan tablets contain 4 mg, 8mg, 16mg and 32mg of candesartan cilexetil as active ingredient and excipients such as hydroxypropyl cellulose, polyethylene glycol, lactose, cornstarch, carboxymethyl cellulose 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 include 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 a tablets comprising dispersing candesartan cilexetil 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-(CrC6) alkyl citrate, di-(Cr C6) alkyl phthalate, di-(C]-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.

The above prior art references disclose various means to stabilize candesartan compositions employing fatty acids, cosolvents, polymers, amino acids, antioxidants, surfactants and fibrous microcrystalline cellulose. None of the prior art references disclose the stability of candesartan can be improved by minimizing the contact of candesartan with excipients and using low stress during compression.

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 bilayered tablet comprising first layer comprising candesartan cilexetil and one or more pharmaceutically acceptable excipients and second layer comprising one or more excipients.

Detailed description of the invention

In another embodiment, the excipients include diluent, binder, adsorbent, disintegrant, colorant and glidant.

In another embodiment, the first layer comprising candesartan may be in the form of granules or as powder blend. Granules can be prepared either by melt granulation or wet or dry granulation.

The first layer comprising candesartan comprises intragranular portion and extragranular portion. The intra and extra granular portion further comprises one or more excipients selected from diluent, binder, adsorbent, disintegrant, glidant, solubilizer, co solvent, colorant and lubricant.

The excipients present in second layer may be in the form of granules or as powder blend.

In another embodiment, the tablet optionally comprises diuretic which may be present either in first layer or second layer. If the diuretic is present in first layer, it may be present either in intragranular or in extragranular portion. Diuretics such as amiloride, chlorthalidone, furosemide, hydrochlorothiazide and indapamide can be used to achieve synergistic therapeutic efficacy in the treatment of hypertension.

It is observed that the stability of candesartan decreases upon compression when compared to uncompressed blend due to crystal disorientation of candesartan due to abrasive forces during compression. Candesartan cilexetil when formulated into tablets undergoes degradation to many impurities such as desethyl candesartan, ethyl candesartan, trityl candesartan. To overcome this, the inventors of the present invention have found that the stability of candesartan can be improved by reducing the quantity of excipients and minimizing the contact of candesartan with excipients and using low stress during compression. This has been achieved by developing a bilayered tablet containing candesartan with small quantity of excipients in one layer and a second placebo layer.

It is also observed that as the percentage of candesartan in the formulation increases, the stability of formulation increases. Ideally, the formulations containing 10% or more of candesartan by weight of composition exhibits stability. However, the compositions containing less than 10% of candesartan can also be stabilized by developing a bilayered tablet containing candesartan in one layer and a second placebo layer.

Candesartan cilexetil used in the present invention may be in the form of crystalline or amorphous form.

The amount of candesartan used in the present formulation may range from about 20% to 30% by weight of first layer or 30% to 40% by weight of intragranular portion.

The ratio of candesartan to excipients in the first layer may range from about 1:1 to about 1:10 and the ratio of candesartan to excipients in the intragranular portion may range from about 1: 1 to about 1:4.

Suitable diluents used according to the present invention are selected from lactose monohydrate, sucrose, dextrose, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose, dihydrated or anhydrous dibasic calcium phosphate and the like or combination thereof. The amount of diluent may range from about 20% to 80% by weight.

Suitable binders used according to the present invention are selected from the group comprising hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, propylene glycol, pregelatinized starch and the like. The amount of binder may range from about 1% to 15% by weight.

Suitable disintegrants used according to the present invention are selected from crospovidone, croscarmellose sodium, sodium starch glycolate, carmellose calcium and carmellose sodium and the like. The amount of disintegrant may range from about 5% to 15% by weight.

The alkaline adsorbent of the present invention may be selected from fine particulate grades of magnesium aluminium silicates available under the trade name Veegum® and Neusilin® or mixtures thereof.

Suitable glidants of the present invention include calcium silicate, magnesium carbonate, magnesium oxide, magnesium silicate, talc, colloidal silicon dioxide, starch and the like.

Suitable lubricants used according to the present invention are selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, vegetable oils, stearic acid, fumaric acid, glyceryl behenate and the like.

Suitable cosolvents used according to the present invention are selected from propylene glycol, polyethylene alcohol, ethanol, glycerin, propylene glycol esters and mixtures thereof.

The solubilizer of the present invention may be selected from anionic or non-ionic surfactants such as sodium lauryl sulphate, polyethylene-propylene glycol copolymer (poloxamer), cremophor-40, polyoxyethylene stearates (Macrogol-stearate), polysorbates and the like or mixtures thereof.

In another embodiment, the bilayered tablet comprises:

(a) first layer comprising intragranular portion comprising candesartan cilexetil and one or more pharmaceutically acceptable excipients, and extragranular portion comprising optionally diuretic and one or more excipients; and

(b) second layer comprising blend of excipients.
In a preferred embodiment, the bilayered tablet comprises:

(a) first layer comprising intragranular portion comprising based on the weight of first layer, about 20 to 30% of candesartan cilexetil, 15 to 35% of diluent, 1 to 8% of adsorbent, 5 to 15% of binder, 5 to 15% of disintegrant, 1 to 8% of cosolvent and extragranular portion comprising optionally 15 to 25% of diuretic and 0.5 to 5% of lubricant; and

(b) second layer comprising based on the weight of second layer, about 75 to 95% of diluent, 5 to 10% of binder, 1 to 5% of disintegrant and 0.5 to 5% of lubricant.

In another preferred embodiment, the bilayered tablet comprises: (a) first layer comprising intragranular portion comprising based on the weight of first layer, about 2 to 30% of candesartan cilexetil, 35% to 75% of diluent, 1 to 8% of adsorbent, 5 to 15% of binder, 5 to 15% of disintegrant, 1 to 8% of cosolvent and extragranular portion comprising optionally 15 to 25% of diuretic and 0.5 to 5% of lubricant; and

(b) second layer comprising based on the weight of second layer, about 50 to 95% of diluent, 5 to 10% of binder, 1 to 5% of disintegrant and 0.5 to 5% of lubricant.

In another preferred embodiment, the bilayered tablet comprises:

(a) first layer comprising intragranular portion comprising based on the weight of first layer, about 20 to 30% of candesartan cilexetil, 15 to 35% of diluent selected from lactose monohydrate and microcrystalline cellulose; 1 to 8% of adsorbent; 5 to 15% of binder selected from povidone, propylene glycol, pregelatinised starch and hydroxypropyl cellulose; 5 to 15% of disintegrant selected from carmellose calcium and sodium starch glycolate; and extragranular portion comprising optionally 15 to 25% of hydrochlorothiazide and 0.5 to 5% of lubricant selected from magnesium stearate and sodium stearyl fumarate; and

(b) second layer comprising based on the weight of second layer, about 75% to 95% of diluent selected from lactose monohydrate and microcrystalline cellulose; 5% to 10% of binder selected from povidone, pregelatinised starch and hydroxypropyl cellulose; 1% to 5% of disintegrant selected from carmellose calcium and sodium starch glycolate; and 0.5% to 5% of lubricant selected from magnesium stearate and sodium stearyl fumarate.

In a preferred embodiment, provides bilayered tablet comprising first layer comprising candesartan cilexetil and one or more pharmaceutically acceptable excipients and second layer comprising one or more excipients prepared by a process comprising the steps of: first layer

(i) granulating candesartan and one or more excipients with a solution comprising propylene glycol and water, (ii) drying the granules and (iii) blending the dried granules of step (ii) with extragranular excipients.

Second layer

(iv) blending diluent, disintegrant, binder and colorant

(v) lubricating the blend of step (iv)

(vi) compressing the blend of first layer obtained in step (iii) and second portion obtained in step (v) using bilayer tablet compression machine.

In another preferred embodiment, provides bilayered tablet comprising first layer comprising candesartan cilexetil and one or more pharmaceutically acceptable excipients and second layer comprising one or more excipients prepared by a process comprising the steps of:

first layer

(i) granulating candesartan cilexetil, diluent selected from lactose monohydrate, microcrystalline cellulose; disintegrant selected from carmellose calcium, sodium starch glycolate, adsorbent, binder selected from povidone, pregelatinised starch and hydroxypropyl cellulose with a solution comprising propylene glycol and water,

(ii) drying the granules and

(iii) blending the dried granules of step (ii) with optionally hydrochlorothiazide and

(iv) lubricating the blend of step (iii). Second layer

(v) blending diluent selected from lactose monohydrate, microcrystalline cellulose; disintegrant selected from carmellose calcium, sodium starch glycolate, binder selected from povidone, pregelatinised starch and hydroxypropyl cellulose (vi) lubricating the blend of step (v)

(vii) compressing the blend of first layer obtained in step (iv) and second portion obtained in step (vi) using bilayer tablet compression machine.

The bilayered tablets prepared according to present invention have shown good stability when stored at accelerated conditions.

In yet another embodiment, the present invention also provides method of treating hypertension, congestive heart failure, angina, and myocardial infarction by administering bilayered tablet of the present invention.

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.

Example 1

Example 2

The processing steps involved in manufacturing candesartan tablets given in example 1 and 2 are given below:

First layer

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

ii) granulated the blended material of step (i) with a solution of propylene glycol and water

iii) dried the granules obtained in step (iii) and blended with an optional hydrochlorothiazide,

iv) lubricated the blend of step (iii) with magnesium stearate,

Second layer

(v) lactose monohydrate, carmellose calcium, hydroxypropyl cellulose and colorant were sifted and blended,

(vi) lubricated the blend of step (v) with magnesium stearate,

(vii) compressing the blend of first layer obtained in step (iv) and second portion
obtained in step (vi) using bilayer tablet compression machine.

Stability Data: Tablets prepared according to examples 1 and 2 were stored at 40°C/75% RH for six months and then tested by HPLC to determine the amount of impurities such as desethyl candesartan cilexetil and N-ethyl candesartan cilexetil 1, N-ethyl candesartan cilexetil 2 and total impurities. The stability data is given in tables 1 and 2.

Table 1

Claims:

1. A bilayered tablet comprising first layer comprising candesartan cilexetil and one or more pharmaceutical^ acceptable excipients and second layer comprising one or more excipients.

2. The bilayered tablet of claim 1, wherein the excipients include diluent, binder, adsorbent, disintegrant, colorant and glidant.

3. The bilayered tablet of claim 1, wherein the first layer comprising candesartan is in the form of granules or as powder blend.

4. The bilayered tablet of claim 1, wherein the second layer is in the form of granules or as powder blend.

5. A bilayered tablet comprises:

(a) first layer comprising intragranular portion comprising candesartan
cilexetil and one or more pharmaceutically acceptable excipients, and
extragranular portion comprising optionally diuretic and one or more excipients; and

(b) second layer comprising blend of excipients.

6. A bilayered tablet comprises:

(a) first layer comprising intragranular portion comprising based on the weight of first layer, about 20 to 30% of candesartan cilexetil, 15 to 35% of diluent, 1 to 8% of adsorbent, 5 to 15% of binder, 5 to 15% of disintegrant, 1 to 8% of cosolvent and extragranular portion comprising optionally 15 to 25% of diuretic and 0.5 to 5% of lubricant; and

(b) second layer comprising based on the weight of second layer, about 75 to 95% of diluent, 5 to 10% of binder, 1 to 5% of disintegrant and 0.5 to 5% of lubricant.

7. A bilayered tablet comprises:

(a) first layer comprising intragranular portion comprising based on the weight of first layer, about 2 to 30% of candesartan cilexetil, 35% to 75% of diluent, 1 to 8% of adsorbent, 5 to 15% of binder, 5 to 15% of disintegrant, 1 to 8% of cosolvent and extragranular portion comprising optionally 15 to 25% of diuretic and 0.5 to 5% of lubricant; and

(b) second layer comprising based on the weight of second layer, about 50 to 95% of diluent, 5 to 10% of binder, 1 to 5% of disintegrant and 0.5 to 5% of lubricant.

8. A bilayered tablet comprises:

(a) first layer comprising intragranular portion comprising based on the weight of first layer, about 20 to 30% of candesartan cilexetil, 15 to 35% of diluent selected from lactose monohydrate and microcrystalline cellulose; 1 to 8% of adsorbent; 5 to 15% of binder selected from povidone, propylene glycol, pregelatinised starch and hydroxypropyl cellulose; 5 to 15% of disintegrant selected from carmellose calcium and sodium starch glycolate; and extragranular portion comprising optionally 15 to 25% of hydrochlorothiazide and 0.5 to 5% of lubricant selected from magnesium stearate and sodium stearyl fumarate; and

(b) second layer comprising based on the weight of second layer, about 75% to 95% of diluent selected from lactose monohydrate and microcrystalline cellulose; 5% to 10% of binder selected from povidone, pregelatinised starch and hydroxypropyl cellulose; 1% to 5% of disintegrant selected from carmellose calcium and sodium starch glycolate; and 0.5% to 5% of lubricant selected from magnesium stearate and sodium stearyl fumarate.

9. A bilayered tablet comprising first layer comprising candesartan cilexetil and one or more pharmaceutically acceptable excipients and second layer comprising one or more excipients prepared by a process comprising the steps of:

first layer

(i) granulating candesartan and one or more excipients with a solution comprising propylene glycol and water,

(ii) drying the granules and

(iii) blending the dried granules of step (ii) with extragranular excipients.

Second layer

(iv) blending diluent, disintegrant, binder and colorant

(v) lubricating the blend of step (iv)

(vi) compressing the blend of first layer obtained in step (iii) and second portion
obtained in step (v) using bilayer tablet compression machine.

10. A bilayered tablet comprising first layer comprising candesartan cilexetil and one or more pharmaceutically acceptable excipients and second layer comprising one or more excipients prepared by a process comprising the steps of:

first layer

(i) granulating candesartan cilexetil, diluent selected from lactose monohydrate, microcrystalline cellulose; disintegrant selected from carmellose calcium, sodium starch glycolate, adsorbent, binder selected from povidone, pregelatinised starch and hydroxypropyl cellulose with a solution comprising propylene glycol and water,

(ii) drying the granules and

(iii) blending the dried granules of step (ii) with optionally hydrochlorothiazide and

(iv) lubricating the blend of step (iii).

Second layer

(v) blending diluent selected from lactose monohydrate, microcrystalline
cellulose; disintegrant selected from carmellose calcium, sodium starch glycolate,
binder selected from povidone, pregelatinised starch and hydroxypropyl cellulose

(vi) lubricating the blend of step (v)

(vii) compressing the blend of first layer obtained in step (iv) and second portion obtained in step (vi) using bilayer tablet compression machine.