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 (±)-1 -hydroxyethyl 2-ethoxy-1 -[p-(o-1 H-tetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate, 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 such as polyvinyl alcohol, maltodextrin, xanthan gum.

WO 2006/079496 discloses composition comprising candesartan and carragenan.

WO 2007/147514 discloses a tablet comprising candesartan cilexetil coated with tri-(CrC6) alkyl citrate, di-(Cr C6) alkyl phthalate, di-(CrC6) 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, wherein the solubilizer is selected from non-ionic, anionic, cationic or zwitterionic surfactants.

WO 2008/045006 discloses that the presence of antioxidant selected from butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodium ascorbate, calcium ascorbate, ascorbic palmitate, 2,4,5- trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenoI, erythorbic acid, gum guaiac, propyl gallate, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone and tocopherols and metal chelating agent selected from ethylenediamine tetracetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid 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 selected from waxes, polymers, block co-polymers, stabilizers, surfactants, fats, fatty acids, prevents or diminishes the candesartan decomposition.

EP 1 997 479 discloses 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 block-copolymers of polyoxypropylene (poly(propylene oxide)) and polyoxyethylene (poly(ethylene oxide)) and hydrogenated triglyceride esters of ricinoleic, oleic, and Hnoleic acids.

WO 2009/056266 discloses process for the preparation of tablet by granulating candesartan cilexetil, a sugar alcohol and a binding agent using alcohol.

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

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 starch derivatives and propylene glycol without using fatty acid esters and oily substances..

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, prepared by granulating a blend of excipients with a dispersion of candesartan, starch derivative and propylene glycol in a solvent, with the proviso that said dosage form is free of fatty acid esters or oily substances.

Detailed description of the invention

In another embodiment, the blend of excipients includes diluent, binder, disintegrant, adsorbent and glidant.

In another embodiment, starch derivatives include sodium starch glycolate, pregelatinised starch, hydroxyl alkyl starch, maize starch. Preferably sodium starch glycolate. The amount of starch derivative used in the dispersion may range from about 0.2% to 5% w/w.

In another embodiment of the present invention, the dosage form further comprises one or more pharmaceutically acceptable excipients selected from diluent, binder, disintegrant, glidant and lubricant.

In another embodiment, the dispersion used for granulation is prepared by a process comprising the steps of:

(i) separately preparing the dispersions of starch derivative and propylene glycol in a solvent

(ii) mixing the dispersions prepared in step (i),

(iii) preparing the dispersion of candesartan in a solvent,

(iv) adding the dispersion of step (iii) by continuous stirring to the dispersion of step (ii).

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% w/w.

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

When the dispersion of candesartan cilexetil is added with continuous stirring to the sodium starch glycolate dispersion, where sodium starch glycolate is present in a highly hydrated state, the swelling tendency of sodium starch glycolate may protect candesartan cilexetil in composition from undergoing degradation over a period of time by entrapping the drug particles within the gel structure. Upon granulation and drying, the drug particles will be coated with a film of dehydrated remnants of the sodium starch glycolate gel. This helps in dissipating the disorienting pressure of compression thereby making the composition stable.

The ratio of candesartan to starch derivative may range from about 1:40 to about 20:1.
In another embodiment, the dosage form further comprises diuretic such as amiloride, chlorthalidone, furosemide, hydrochlorothiazide and indapamide to achieve synergistic therapeutic efficacy in the treatment of hypertension.

Suitable diluents used according to the present invention are selected from lactose, 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 40% to 80% by weight.

Suitable binders used according to the present invention are selected from the group comprising hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pregelatinized starch and the like. The amount of binder may range from about 0.5% to 5% by weight.

Suitable disintegrants used according to the present invention are selected from crospovidone, sodium starch glycolate, carmellose calcium, croscarmellose sodium and the like. The amount of disintegrant may range from about 0.5% to 10% by weight.

The adsorbent of the present invention may be selected from fine particulate grades of magnesium aluminum 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.

In another embodiment, the present invention provides a stable oral dosage form comprising candesartan cilexetil, starch derivative and propylene glycol and one or more pharmaceutical^ acceptable excipients, with the proviso that said dosage form is free of fatty acid esters or oily substances.

In another embodiment, the present invention provides a stable oral dosage form comprising about 1% to 10% w/w of candesartan cilexetil, about 0.2% to 5% w/w of starch derivative and about 1% to 5% w/w of propylene glycol and one or more pharmaceutically acceptable excipients, with the proviso that said dosage form is free of fatty acid esters or oily substances.

In another embodiment, there is provided a stable oral dosage form comprising candesartan cilexetil, prepared by granulating blend of excipients comprising diluent, optionally disintegrant and adsorbent with a dispersion of candesartan, starch derivative and propylene glycol in a solvent, with the proviso that said dosage form is free of fatty acid esters, fatty acid esters of polyhydric alcohols, oily substances.
In another embodiment, a stable oral dosage form comprises candesartan cilexetil, prepared by granulating blend of excipients comprising about 40% to 75% w/w of diluent, optionally about 1% to 5% w/w of disintegrant and about 2% to 10% w/w of adsorbent with a dispersion of about 1% to 10% w/w of candesartan, about 0.2% to 1% w/w of sodium starch glycolate and about 1% to 5% w/w of propylene glycol in a solvent, with the proviso that said dosage form is free of fatty acid esters or oily substances is provided.

In another embodiment, the granules of candesartan are blended with one or more extra granular excipients such as diluent, disintegrant, glidant and lubricant.

In a preferred embodiment, a stable oral dosage form comprises candesartan cilexetil, with the proviso that said dosage form is free of fatty acid esters or oily substances, prepared by a process comprising the steps of:

(i) granulating blend of excipients comprising diluent selected from lactose, microcrystalline cellulose, maize starch; optionally disintegrant selected from sodium starch glycolate, crospovidone, croscarmellose sodium; optionally adsorbent; glidant selected from colloidal silicon dioxide, talc; with a dispersion of candesartan, sodium starch glycolate and propylene glycol in a solvent,

(ii) drying the granules and

(iii) blending the dried granules of step (ii) with extra granular excipients such as disintegrant selected from sodium starch glycolate, crospovidone, carmellose calcium, croscarmellose sodium; optionally diluent selected from lactose, microcrystalline cellulose; and lubricant selected from magnesium stearate, talc and sodium stearyl fumarate and

(iv) formulating the blend obtained in step (iii) 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. 80°C, which can be attributed with the presence of lower amount of impurities as shown in tables 1 and 2.

In another embodiment, the solid oral dosage forms include tablets and capsules. The tablets may be uncoated or optionally coated.

In yet another embodiment of the present invention, film coating composition comprises a solution / suspension of film coating polymers and one or more excipients such as lactose, titanium dioxide, solubilizing agent and antisticking agent.
Suitable film coating polymers used according to the present invention are selected from ethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose and the like or mixtures thereof.

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

In yet another embodiment, the present invention also provides method of treating hypertension, congestive heart failure, angina, and myocardial infarction by administering, solid dosage forms prepared according to 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

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

i) lactose, colloidal silicon dioxide and sodium starch glycolate were sifted and
blended,

ii) sodium starch glycolate and propylene glycol were separately dispersed/dissolved in water and then mixed,

iii) candesartan was dispersed in isopropyl alcohol and added to the dispersion of step (ii),

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

v) dried the granules obtained in step (iv) and blended with extragranular microcrystalline cellulose, sodium starch glycolate,

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

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

The compositions described in example 2 and 3 were prepared using the procedure similar to the one described in example 1.

Example 2


Stability Data: Tablets prepared according to examples 1 and 2 were stored at 80°C for three days and then tested by HPLC to determine the amount of impurities such as desethyl candesartan cilexetil and N-ethyl candesartan cilexetil 1 and N-ethyl candesartan cilexetil 2. The stability data is given in tables 1 and 2.

Table 1

Table 2


The dissolution profile of candesartan tablets prepared according to the present invention was carried out in 900 ml of pH 6.5 phosphate buffer solution and 0.35% Tween 20 as medium Apparatus USP II, Paddle, @ 50 rpm speed. The release profile (% of drug released in minutes) is given in table 1.

Table 1

Claims

1. A stable oral dosage form comprising candesartan cilexetil, prepared by granulating a blend of excipients with a dispersion of candesartan, starch derivative and propylene glycol in a solvent, with the proviso that said dosage form is free of fatty acid esters or oily substances.

2. The dosage form of claim 1, wherein the blend of excipients include diluent, binder, disintegrant, adsorbent and glidant.

3. The dosage form of claim I, wherein the starch derivative is selected from sodium starch glycolate, pregelatinised starch, hydroxyl alkyl starch, maize starch.

4. The dosage form of claim 1, wherein the dispersion used for granulation is prepared by a process comprising the steps of:

(i) separately preparing the dispersions of starch derivative and propylene glycol in a solvent,

(ii) mixing the dispersions prepared in step (i),

(iii) preparing the dispersion of candesartan in a solvent,

(iv) adding the dispersion of step (iii) by continuous stirring to the dispersion of
step (ii).

5. The dosage form of claim 1, further comprise diuretic such as amiloride, chlorthalidone, furosemide, hydrochlorothiazide and indapamide.

6. A stable oral dosage form comprising candesartan cilexetil, starch derivative and propylene glycol and one or more pharmaceutically acceptable excipients, with the
proviso that said dosage form is free of fatty acid esters or oily substances.

7. A stable oral dosage form comprising about 1% to 10% w/w of candesartan cilexetil, about 0.2% to 5% w/w of starch derivative and about 1% to 5% w/w of propylene glycol and one or more pharmaceutically acceptable excipients, with the proviso that said dosage form is free of fatty acid esters or oily substances.

8. A stable oral dosage form comprises candesartan cilexetil, prepared by granulating blend of excipients comprising about 40% to 75% w/w of diluent, optionally about 1% to 5% w/w of disintegrant and about 2% to 10% w/w of adsorbent with a dispersion of about 1% to 10% w/w of candesartan, about 0.2% to 1% w/w of sodium starch glycolate and about 1% to 5% w/w of propylene glycol in a solvent, with the proviso that said dosage form is free of fatty acid esters or oily substances.

9. A stable oral dosage form comprising candesartan cilexetil, with the
proviso that said dosage form is free of fatty acid esters or oily substances,
prepared by a process comprising the steps of:

(i) granulating blend of excipients comprising diluent selected from lactose, microcrystalline cellulose, maize starch; optionally disintegrant selected from sodium starch glycolate, crospovidone, croscarmellose sodium; optionally adsorbent; glidant selected from colloidal silicon dioxide, talc; with a dispersion of candesartan, sodium starch glycolate and propylene glycol in a solvent,

(ii) drying the granules and

(iii) blending the dried granules of step (ii) with extra granular excipients such as disintegrant selected from sodium starch glycolate, crospovidone, carmellose calcium, croscarmellose sodium; optionally diluent selected from lactose, microcrystalline cellulose; and lubricant selected from magnesium stearate, talc and sodium stearyl fumarate and

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

10. The dosage form of claim 1, wherein the solvents used for dispersion is selected from water or organic solvents such as acetone, alcohol, isopropyl alcohol, methylene chloride and the mixture thereof.