WO2012033983A2

WO2012033983A2 - Candesartan pharmaceutical compositions

Info

Publication number: WO2012033983A2
Application number: PCT/US2011/050938
Authority: WO
Inventors: Amarnath Suseendharnath; Venkatesh Madhavacharya Joshi; Sunil Reddy Beeram; Venkateswarlu Vobalaboina; Harshal Prabhakar Bhagwatwar; Manish Chawla
Original assignee: Dr. Reddy's Laboratories Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2010-09-09
Filing date: 2011-09-09
Publication date: 2012-03-15
Also published as: WO2012033983A3

Abstract

Oral pharmaceutical compositions comprising candesartan or its pharmaceutically acceptable salts, esters, solvates, hydrates, enantiomers, polymorphs, or their mixtures, and processes for preparing the same are described. Also described are pharmaceutical formulations comprising compositions containing candesartan or an ester thereof, processes for preparing the formulations, and methods of use, treatment, and administration involving the formulations.

Description

CANDESARTAN PHARMACEUTICAL COMPOSITIONS

INTRODUCTION

Aspects of the present application relate to pharmaceutical compositions containing candesartan, including its pharmaceutically acceptable salts, esters, solvates, hydrates, enantiomers, polymorphs, and their mixtures, and processes for preparing the compositions. Aspects of the application relate to stable oral pharmaceutical compositions comprising candesartan cilexetil, a water-soluble or water-swellable polymer, and/or a stabilizer, and to processes for the preparation thereof.

Candesartan is a selective ATi subtype angiotensin II receptor antagonist. Candesartan cilexetil is a prodrug and is hydrolyzed to candesartan during absorption from the gastrointestinal tract. It falls in the class of drugs of benzimidazole-7-carboxylic acid and derivatives thereof. These agents exhibit a strong and more effective hypotensive action and are less likely to cause coughing as a side effect, when compared to drugs in the class of angiotensin converting enzyme inhibitors.

Candesartan cilexetil has a chemical name (±)-1 -hydroxyethyl 2-ethoxy-1 - [p-(o-1 /-/-tetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexyl carbonate (ester) and has structural Formula I.

Formula I A commercial product containing candesartan is ATACAND® oral tablets, distributed by AstraZeneca in the U.S.A. Atacand tablets contain candesartan in the form of candesartan cilexetil (as a prodrug) and are available in 4, 8, 16, and 32 mg candesartan cilexetil strengths. Atacand tablets are indicated for the treatment of hypertension and for treatment of patients with heart failure and impaired left ventricle systolic function (left ventricular ejection fraction 40%) as add-on therapy to ACE inhibitors or when ACE-inhibitors are not tolerated.

Another commercially available product containing candesartan is AM IAS® oral tablets, marketed by Takeda in Europe. Amias tablets contain candesartan as a prodrug in the form of candesartan cilexetil and are available in 2, 4, 8, 16, and 32 mg candesartan cilexetil strengths. These commercial products contain the excipients hydroxypropyl cellulose, polyethylene glycol, lactose, corn starch, carboxymethylcellulose calcium, magnesium stearate, and, in colored dosage forms, iron oxide red.

Commercially available ATACAND HCT® tablets also contain the diuretic active agent hydrochlorothiazide (HCTZ), and are available in strengths of 16 mg candesartan cilexitil and 12.5 mg HCTZ, or 32 mg of candesartan cilexitil and 25 mg HCTZ. The excipient ingredients are carboxymethylcellulose calcium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, corn starch, polyethylene glycol 8000, and iron oxides. Hydrochlorothiazide has a chemical name 6-chloro-3,4-dihydro-2/-/-1 ,2,4-benzothiadiazine-7-sulfonamide 1 ,1 -dioxide and structural Formula II.

Formula II

Candesartan cilexetil is a white to off-white powder with a molecular weight of 610.67. It is practically insoluble in water and sparingly soluble in methanol. Candesartan cilexetil is a racemic mixture having one chiral center at the cyclohexyloxycarbonyloxy ethyl ester group. Following oral administration, candesartan cilexetil undergoes hydrolysis at the ester link to form the active drug, candesartan, which is achiral.

Candesartan cilexetil as an active compound in tablet form is comparatively unstable and forms undesirable by-products, especially during long-term storage. Thus, for example, desethyl-candesartan and related compounds are formed, which may reduce the content of active compound in the tablet. This

decomposition can often also be attributed to the additives and processes used in tablet manufacture.

U.S. Patent No. 5,534,534 discloses that degradation of candesartan cilexetil over time can be reduced by incorporating oily substances having a low melting point. The oily substance having a lower melting point is described as being incorporated into the formulation to form a stable composition in which decomposition is minimized.

The stability of pharmaceutical compositions of candesartan cilexetil can also be characterized by measuring the levels of various degradation products including desethyl candesartan and total related substances. An increase in the levels of desethyl candesartan and total related substances is a result of an unstable or less stable formulation.

It poses a challenge for formulation scientists to develop stable dosage forms comprising candesartan that are similar to the properties of a reference formulation for both in vitro and in vivo conditions, and also for stability.

SUMMARY

Aspects of the present application relate to pharmaceutical compositions comprising candesartan or its pharmaceutically acceptable salts, esters, solvates, hydrates, enantiomers, polymorphs or their mixtures, and processes for preparing the same. Further aspects of the application relate to pharmaceutical formulations comprising compositions containing candesartan or an ester thereof, to processes for preparing the same, and to methods of use, treatment, and administration involving the formulations.

In an aspect, there are provided pharmaceutical compositions, comprising an effective amount of candesartan cilexetil, one or more water-soluble or water- swellable polymers, and one or more stabilizers. In an aspect, there are provided pharmaceutical compositions, comprising an effective amount of candesartan cilexetil, one or more water-soluble or water- swellable polymers, and one or more stabilizers, in the form a solid dispersion.

In an aspect, pharmaceutical compositions may include one or more water- soluble or water-swellable polymers, such as one or more of

polyvinylpyrrolidones, hydroxypropyl celluloses, hypromelloses, hydroxyethyl celluloses, polyvinyl alcohols, xanthan gum, sodium carboxymethylcellulose, calcium carboxymethylcellulose, methyl celluloses, gums, alginic acid, pectins, or any mixtures of two or more thereof. A water-soluble or water-swellable polymer may be present at concentrations between about 0.5% and about 99% by weight of a total solid dispersion.

In an aspect, there are provided pharmaceutical compositions comprising an effective amount of candesartan cilexetil and one or more water-insoluble or hydrophobic or lipophilic polymeric or non-polymeric substances and one or more stabilizers, together with one or more other pharmaceutically acceptable excipients.

In an aspect, there are provided pharmaceutical compositions comprising candesartan cilexetil, and processes for the preparation thereof.

In an aspect, there are provided pharmaceutical compositions comprising candesartan cilexetil along with a Gelucire® product as a stabilizer, and processes for preparation thereof.

In an aspect, there are provided processes for the preparation of solid dispersion compositions, comprising candesartan cilexetil, a water-soluble or - swellable polymer, and a stabilizing agent. In certain embodiments, processes include dispersing or dissolving candesartan cilexetil and one or more water- soluble or water-swellable polymers, optionally together with a stabilizer, in a suitable solvent to form a dispersion or solution. The solvent is then removed, such as by using a rotary evaporator, freeze dryer, spray dryer, thin-film dryer, or using any other suitable solvent removal techniques.

Embodiments of the processes include dispersing or dissolving

candesartan cilexetil and one or more water-soluble or water-swellable polymers, optionally together with a stabilizer, in a suitable solvent to form a dispersion or solution, granulating one or more fillers and optionally other pharmaceutically acceptable excipients with the dispersion or solution to form granules, drying the granules and sizing, lubricating, and compressing the granules.

In an aspect, there are provided processes for the preparation of a pharmaceutical composition of candesartan cilexetil, embodiments of processes comprising: a) dispersing candesartan cilexetil, one or more water-soluble or water-swellable polymers, and a stabilizer in a granulating fluid to form a drug dispersion; b) granulating the drug dispersion with one or more fillers and one or more disintegrants to form granules; c) drying and sizing the granules; and d) lubricating and compressing the granules.

Solid dispersion compositions of the present application may also include one or more pharmaceutically acceptable excipients. The excipients may be one or more of fillers, binders, disintegrants, lubricants, coloring agents, flavoring agents, etc.

Solid dispersion compositions of the present application may include one or more additional active ingredients. The additional active ingredients may include any of substances such as diuretics, anti-hyperlipidemics, angiotensin converting enzyme inhibitors, and other angiotensin receptor antagonists. An example of a useful diuretic is hydrochlorothiazide.

In an aspect, there are provided pharmaceutical compositions comprising effective amounts of candesartan cilexetil and hydrochlorothiazide, a water- soluble or water-swellable polymer, and a stabilizing agent.

In embodiments, there are provided pharmaceutical compositions in the form of tablets comprising candesartan cilexetil, a water-soluble or water- swellable polymer, a stabilizing agent, and one or more other pharmaceutically acceptable excipients, wherein particle sizes of the blends used to prepare tablets are such about 20% to about 80% of particles are retained on a 100 mesh sieve, and about 10% to about 60% of the particles are retained on an 80 mesh sieve.

Pharmaceutical formulations of the present application may be in the form of tablets or capsules that may optionally be coated with one or more functional and/or non-functional coating layers.

In an aspect, there are provided methods of treating hypertension and cardiac diseases in patients in need thereof. The methods include administering a pharmaceutical formulation comprising an effective amount of candesartan cilexetil. In embodiments, the present application provides candesartan

compositions containing candesartan or any of its pharmaceutically acceptable salts, esters, solvates, hydrates, enantiomers, polymorphs, including any mixtures of two or more thereof, and/or candesartan complexes, having particle size distributions wherein 90% of the particles have sizes less than about 600 μιη, or less than about 100 μιη, or less than about 20 μιη.

In embodiments, the present application provides stable compositions comprising candesartan cilexetil, which are substantially free of degradation impurities during manufacturing and after commercially relevant storage periods.

In embodiments, formulations of the present application may contain any one or more of the impurities 1 , 2, 3, 4, 5, 6, 7, triphenyl methanol, tnphenylmethyl methyl ether, 1 N-ethyl oxo candesartan cilexetil, 2N-ethyl oxo candesartan cilexetil and 2N ethyl impurity as described in Figs. 1 -3, or any other drug-related impurities, in amounts such that the impurities do not substantially adversely affect the safety and efficacy of the formulation.

In embodiments, the application provides stable formulations comprising candesartan cilexetil or its pharmaceutically acceptable salts, wherein levels of one or more of the impurities 1 , 2, 3, 4, 5, 6, 7, triphenyl methanol, tnphenylmethyl methyl ether, 1 N-ethyl oxo candesartan cilexetil, 2N-ethyl oxo candesartan cilexetil and 2N ethyl impurity, or any other drug-related impurities, are present in amounts less than about 5%, or less than about 2%, or less than about 1 %, or less than about 0.5% by weight of the label candesartan cilexetil content.

In embodiments, the application relates to stable formulations wherein total drug-related impurities, as determined using high performance liquid

chromatography (HPLC), are less than about 5% by weight of the label candesartan cilexetil content.

In embodiments, the application provides processes for producing stable candesartan-containing granules, wherein the granules have losses on drying (LOD) in the range of about 0.25-10%, or about 0.5-5%, or about 1 -3%, by weight.

Various polymorphic structures of candesartan cilexetil are known. The present application is applicable to all of these structures. BRIEF DESCRIPTION OF THE DRAWINGS Figs. 1 -3 show the structures of various impurities related to candesartan cilexetil, one or more of which can be present in the bulk drug substance, can be produced during manufacturing of pharmaceutical formulations, and/or can form during storage of a pharmaceutical product.

DETAILED DESCRIPTION

The term "candesartan cilexetil" as used herein refers to a prodrug that is hydrolyzed to candesartan for absorption from the gastrointestinal tract. The concentration of candesartan cilexetil may be between about 2% to about 35% of the total weight of a formulation or, it may be between about 3% to about 30% of the total weight of a formulation. Although much of the discussion herein uses candesartan cilexetil as a representative of the active agents that can be used, the scope of the disclosure is not to be limited to use of this particular compound.

The term "stable" relates to a formulation capable of maintaining commercially acceptable stability with respect to the levels of drug-related impurities, particularly desethyl candesartan and other drug-related substances. Such stability is required for commercially relevant periods, for example about 6, 12, 18, or 24 months after manufacturing, during which times a product is stored in its original packaging at common ambient temperatures. Storage stability can be predicted by the impurity formation observed during storage for shorter times under "accelerated" stability testing conditions, such as at 40°C and 75% relative humidity, or at 60°C.

The term "water soluble" means solubility in an aqueous fluid at 20°C of at least about 10 g per 100 ml_, or at least about 30 g per 100 ml_, or at least about 40 g per 100 mL.

The term "water-swellable" is applied to excipients that are characterized by the pronounced affinity of their chemical structures for aqueous solutions, in which they swell rather than dissolve. Some hydrophilic polymers exhibiting considerable swelling in water are described in the literature as being soluble, as their dispersions have properties of solutions.

A "composition" is a combination of drug and one or more pharmaceutical excipients, such as a powder mixture or a solid dispersion, used in the preparation of finished pharmaceutical dosage forms. The term "formulation" means a pharmaceutical dosage form containing an active pharmaceutical ingredient (optionally in the form of a solid dispersion), and optionally comprising one or more pharmaceutically acceptable excipients, that is intended for therapeutic use. Formulations include finished dosage forms such as tablets, capsules, and powders for preparing solutions or suspensions.

"Stabilizers" are sometimes also referred to as "stabilizing agents" in the present application.

Suitable pharmaceutically acceptable excipients include, without limitation thereto, one or more of fillers, binders, disintegrants, lubricants, glidants, flavors, and colorants.

Suitable fillers or diluents include, but are not limited to, one or more of starches, pregelatinized starches, corn starch, lactose, sucrose, microcrystalline cellulose, powdered cellulose, mannitol, sorbitol, glucose, compressible sugar, confectioner's sugar, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, silicified microcrystalline cellulose, dextrates, dextrins, dextrose, fructose, kaolin, and lactitol.

Suitable binders include, but are not limited to, one or more of methyl celluloses, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, hydroxyethyl celluloses, polyvinylpyrrolidones, gelatin, gum arabic, ethyl celluloses, polyvinyl alcohols, pullulan, pregelatinized starches, agar, tragacanth, sodium alginate, and propylene glycol.

Suitable disintegrants include, but are not limited to, one or more of calcium carboxymethyl cellulose, colloidal silicon dioxide, starch, carmellose sodium, carmellose calcium, crospovidones, sodium starch glycolate, and crosscarmellose sodium.

Suitable lubricants include, but are not limited to, one or more of colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, and white beeswax.

Suitable coloring agents for the present application include any regulatory agency-approved colorants that are safe for human use, such as dyes, lakes, pigments, etc.

Suitable water-soluble polymers used in the present application include, but are not limited to, polyvinyl alcohols, maltodextrin, xanthan gum, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, hydroxyethyl celluloses, sodium carboxymethylcelluloses, calcium

carboxymethylcelluloses, methyl celluloses, tragacanth gum, agar, gellan gum, karaya gum, alginic acids, pectins, pregelatinized starches, and any mixtures thereof. A water-soluble polymer may be present at between about 0.1 % to about 40% of the total weight of the composition, or it may be present at between about 1 % to about 20% of the total weight of the composition.

Suitable water-swellable polymers used in the present application include, but are not limited to, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, hydroxyethyl celluloses, sodium carboxymethylcelluloses, calcium

carboxymethylcelluloses, methyl celluloses, pregelatinized starches, and any mixtures thereof.

Pharmaceutical compositions may include one or more additional excipients functioning as stabilizers, including amphiphilic mono-, di-, and tri- glycerides and mono- and di-esters of polyethylene glycol (PEG). Of this type, the commercially available GELUCIRE® products include Gelucire 33/01 , Gelucire 37/02, Gelucire 39/01 , Gelucire 43/01 , Gelucire 44/14, Gelucire 50/02, Gelucire 50/13, Gelucire 53/10, and Gelucire 62/02, where the numbers after the name refer to the melting points in degrees Celsius and the hydrophilic-lipophilic balance (HLB) values, respectively. Gelucire products are PEG-ylated with PEG 1500 (polyethylene glycol of weight average molecular weight 1500 Da). These

Gelucire products have melting points about 33°C to 62°C, so they can melt and absorb pressure during processing steps involving compression and thereby help to prevent the degradation of candesartan cilexetil. Some have HLB values that make them act as surfactants and enhance absorption of the poorly water soluble drug. Gelucire products form dispersions with warm water, and organic solvents are optional for making the formulations of the present application.

The chemical nature of various Gelucire products is shown in Table 1 .

Table 1

Product Chemical Nature

33/01 Glycerol esters of saturated C₈-is fatty acids

37/02 Saturated polyglycolized glycerides

39/01 Glycerol esters of saturated C12-18 fatty acids 43/01 Glycerol esters of saturated C12-18 fatty acids

44/14 PEG-32 glyceryl laurate

50/02 Saturated polyglycolized glycerides

50/13 PEG-32 glyceryl palmitostearate

53/10 PEG-32 glyceryl stearate

62/02 Saturated polyglycolized glycerides

Other excipients that function as stabilizers may be used, such as glyceryl behenate, glyceryl mono- and di-stearates, glyceryl palmitostearate, stearic acid, tragacanth gum, gum Arabic, locust bean gum, gum acacia, medium chain triglycerides (e.g., a Labrafac® product), glycerol, propylene glycol, stearoyl alcohol, fractionated coconut oil (e.g., a Miglyol® product), polyoxyl glyceryl stearate, N-(2-hydroxyethyl) 12-hydroxystearamide (e.g., Paricin® 220), and any mixtures of two or more thereof.

A granulating fluid according to the present application includes an aqueous or non-aqueous solvent, or can include any mixtures thereof.

The pharmaceutical compositions may include one or more additional active agents. Additional active agents include, but are not limited to, one or more of diuretics, sympathoplegic agents, vasodilators, angiotensin-converting enzyme inhibitors, and other angiotensin receptor antagonists, in each case being in the free form or in the form of a pharmaceutically acceptable salt, ester, etc., thereof.

It has been discovered that the use of water-soluble or water-swellable polymers and one or more stabilizers to form pharmaceutical compositions with candesartan cilexetil results in improved stability, with respect to the levels of impurities, in particular, desethyl candesartan, 1 N-ethyl oxo candesartan cilexetil, 2N-ethyl oxo candesartan cilexetil, 2N-ethyl impurity, and other drug-related substances, that are likely to form during storage.

In embodiments, candesartan cilexetil formulations may be prepared by dispersing candesartan cilexetil and one or more water-soluble or water-swellable polymers, together with one or more stabilizing agents, in a granulating fluid, granulating one or more fillers and one or more disintegrants with the dispersion, drying the granules, sizing, lubricating the granules, and optionally compressing the granules into tablets or filling into capsules. Pharmaceutical formulations can be prepared using any of the process steps known in the art, such as wet granulation, dry granulation, and direct compression. The final dosage forms may be in the form of tablets or capsules. The tablets can optionally be coated.

In embodiments, there are provided pharmaceutical compositions in the form of tablets comprising candesartan cilexetil, a water-soluble or water- swellable polymer, a stabilizing agent, and one or more other pharmaceutically acceptable excipients, wherein the particle sizes of the blends used to prepare the tablets are such that about 20% to about 80% of the particles are retained on a 100 mesh sieve, and about 10% to about 60% of the particles are retained on an 80 mesh sieve. The particle sizes of the blends can be determined using particle size measuring techniques that are well known to those skilled in the art. Such techniques include, for example, sieve analysis using an electromagnetic sieve shaker (e.g., with the amplitudes 20-40 and times of 10-20 minutes). Equipment such as a laser light scattering particle size analyzer, a Coulter® Counter, or an optical microscope also is useful.

Tablets may be coated with one or more coating layers, including film- forming agents and/or other pharmaceutically acceptable excipients. The coating layers over the tablet may be applied as solutions or dispersions of coating ingredients, using any conventional techniques known in the art, such as spray coating in coating pans or fluidized bed processors, dip coating, and the like. Suitable solvents used for preparing a solution or dispersion of the coating ingredients include, but are not limited to, one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, and water.

Suitable film-forming coating agents include one or more of ethyl celluloses, hydroxypropyl methylcelluloses, hydroxypropyl celluloses, methyl celluloses, carboxymethylcelluloses, hydroxymethylcelluloses,

hydroxyethylcelluloses, hydroxypropyl methylcellulose phthalates, cellulose acetates, cellulose acetate trimelliatates, cellulose acetate phthalates, waxes, polyethylene glycols, methacrylic acid polymers, such as Eudragit™ RL and RS products, and any mixtures thereof. Alternatively, commercially available pre- formulated coating products comprising film-forming polymers and marketed under various trade names, such as Opadry®, may also be used; such products are typically dispersed in water or an organic solvent prior to use.

The foregoing lists of excipient substances and solvents are representative of materials that can be used, and are not intended to be exhaustive. Also, other excipient material types are known to be useful for pharmaceutical formulations. Those skilled in the art will be aware of materials other than those mentioned herein that can be used in various embodiments, and their use is specifically contemplated by this disclosure.

In embodiments, tablets of the present application exhibit hardnesses of about 2 to about 30 kiloponds (KP), or about 2-14 KP, and have friability less than about 2% or less than about 1 %.

In embodiments, the application provides pharmaceutical dosage forms, such as candesartan cilexetil tablets, exhibiting disintegration times of about 1 to 15 minutes in aqueous fluids, when tested according to the general method of Test 701 , Disintegration, United States Pharmacopeia 29, U.S. Pharmacopeial Convention, Inc., Rockville, Maryland, 2005, ("USP") for immediate release coated or uncoated tablets.

In embodiments, the application includes use of tamper-resistant or tamper-evident packages, and/or thermo-insulated packages, for pharmaceutical dosage forms comprising candesartan or its pharmaceutically acceptable salts. The formulations may be packaged into blisters, strips, or containers such as plastic, glass, or metal containers. The package or packaging material optionally may contain one or more oxygen absorbents or desiccants.

In embodiments, formulations of the present application can be packaged into thermo-insulated packages wherein aluminum blisters or HDPE bottle containers containing a formulation are packed into suitable thermo-insulated devices such as a thermocol or an expanded polystyrene package. In

embodiments, the container containing the composition is double-walled, wherein a hollow space between the walls is filled with air that acts as an insulator. In embodiments, either one or both of the closure and base foils used to make blisters containing a formulation contains one or more layers of a desiccant.

In embodiments, formulations of the present application exhibit appreciable chemical storage stability. Candesartan cilexetil and its impurities, including the above-mentioned impurities, can be analyzed using a high performance liquid chromatography (HPLC) method.

Drug-related impurities that can be present in candesartan cilexetil and candesartan cilexetil dispersions are shown in Table 2, and their structural formulas are shown in Figs. 1 -3. In this application, drug-related impurity amounts for product formulations are expressed as percentages of the label candesartan cilexetil content.

Table 2

Impurity Chemical Name

Impurity 1 Methyl 2-ethoxy-1 -[[(2-1 H-tetrazol-5-yl) biphenyl)-4-yl] methyl] benzimidazole-7-carboxylate

Impurity 2 2-Ethoxy-1 -[[2-(1 H-tetrazol-5-yl) biphenyl)-4-yl]methyl ] benzimidazole-7-carboxylic acid

Impurity 3 2-Ethoxy-1 -[[2-(triphenyl methyl-1 -H-tetrazol-5-yl)

biphenyl-4-yl]methyl] benzimidazole-7-carboxylate

Impurity 4 (±)-1 -Cyclohexyloxycarbonyloxy ethyl 2-ethoxy-1 -[[2-(1 - triphenyl methyl-1 H-tetrazol-5-yl) biphenyl-4- yl]methyl]benzimidazole-7-carboxylate

N-ethyl impurity (±)-1 -Cyclohexyloxycarbonyloxy ethyl 2-ethoxy-1 -[[2-(1 -

(Impurity 5) ethyl-1 H-tetrazol-5-yl) biphenyl-4-yl) methyl]

benzimidazole-7-carboxylate

Desethyl (±)-1 -Cyclohexyloxycarbonyloxy) ethyl 2-oxo-1 -[[2-(1 -H- candesartan tetrazol-5-yl) biphenyl-4-yl]methyl] benzimidazole-7-

(Impurity 6) carboxylate

Ethyl Ethyl 2 ethoxy-1 -[[(2-(1 H-tetrazol-5-yl) biphenyl-4- candesartan yl]methyl] benzimidazole-7-carboxylate

(Impurity 7)

Trityl alcohol Triphenyl methanol

MTE impurity Triphenylmethyl methyl ether

1 N-Ethyl oxo 1 -[(cyclohexyloxy)carbonyl]oxy}ethyl 2-oxo-1 -{[2'-(1 - candesartan ethyl-1 H-Tetrazol-5-yl)biphenyl-4-yl] methylj-1 H- benzimidazole-7-carboxylate.

cilexetil

2N-Ethyl oxo 1 -{[(cyclohexyloxy)carbonyl]oxy}ethyl 2-oxo-1 -{[2'-(2- candesartan ethyl-1 H- Tetrazol-5-yl)biphenyl-4-yl] methyl}-1 H- benzimidazole-7-carboxylate

cilexetil

2N-ethyl 1 -{[(cyclohexyloxy)carbonyl]oxy} ethyl 2-ethoxy-1 -{[2'-(2- impurity ethyl-1 H-tetrazol-5-yl)biphenyl-4-lyl]methyl}-1 H- benzimidazole-7-carboxylate Certain specific aspects and embodiments of the application will be described in more detail with reference to the following examples, being provided only for purposes of illustration, and it is to be understood that the scope of the present disclosure is not limited thereto.

EXAMPLE 1 : Candesartan cilexetil 4 mg, 8 mg, 16 mg, and 32 mg tablets.

* Evaporates during processing.

Manufacturing procedure:

1 . Iron oxide red, lactose, corn starch and carboxymethyl cellulose calcium are sifted through a sieve and blended.

2. Hydroxypropyl cellulose and candesartan cilexetil are dispersed in water.

3. Gelucire 50/13 is dispersed in water and added to the step 2 dispersion.

4. The dispersion of step 3 is sprayed onto the ingredients of step 1 to obtain granules.

5. The granules are dried and sifted through a sieve.

6. Extragranular iron oxide red and lactose are sifted through a sieve and mixed with the granules of step 5. 7. Magnesium stearate is sifted through a sieve, added to the mixture of step 6, and blended.

8. The mixture of step 7 is compressed into tablets.

Optionally, the Gelucire 50/13 can be included as a component of step 2, and step 3 can be omitted.

Tablets prepared as above containing 32 mg of candesartan cilexetil, and a European commercial product (Amias tablets 32 mg), are stored at 60°C unpackaged for 2 weeks, and analyzed for impurity content. The results are shown in Table 3.

Table 3

ND = not detected.

EXAMPLE 2: Candesartan cilexetil 4 mg, 8 mg, 16 mg, and 32 mg tablets.

Ingredient Wt. Percent

Candesartan cilexetil 10

Lactose 55.8

Glyceryl monostearate 1

Hydroxypropyl cellulose 3 Carboxymethyl cellulose calcium 4

Iron oxide red 0.1

Water* q.s.

Extragranular

Lactose 25

Iron oxide red 0.1

Magnesium stearate 1

* Evaporates during processing.

Manufacturing procedure:

1 . Iron oxide red, lactose, carboxymethylcellulose calcium and glyceryl monostearate are sifted through a sieve and blended.

2. Hydroxypropyl cellulose and candesartan cilexetil are dispersed in water.

3. The dispersion of step 2 is sprayed onto the ingredients of step 1 , to form granules.

4. The granules are dried and sifted through a sieve.

5. Extragranular iron oxide red and lactose are sifted through a sieve and mixed with the granules.

6. Magnesium stearate is sifted through a sieve, added to the step 5 blend, and mixed.

7. The mixture is compressed into tablets.

EXAMPLE 3: Candesartan cilexetil 4 mg, 8 mg, 16 mg, and 32 mg tablets.

Ingredient Wt. Percent

Candesartan cilexetil 10

Lactose 55.8

Stearoyl alcohol 0.5

Hydroxypropyl cellulose 3

Carboxymethyl cellulose calcium 4.5

Iron oxide red 0.1

Water* q.s.

Extragranular Lactose 25

Iron oxide red 0.1

Magnesium stearate 1

* Evaporates during processing.

Manufacturing procedure:

1 . Iron oxide red, lactose, carboxymethylcellulose calcium, and stearoyi alcohol are sifted through a sieve and blended.

2. Hydroxypropyl cellulose and candesartan cilexetil are dispersed in water.

4. The granules are dried and sifted through a sieve.

7. The mixture is compressed into tablets.

EXAMPLE 4: Candesartan cilexetil 4 mg, 8 mg, 16 mg, and 32 mg tablets.

* Evaporates during processing. Manufacturing procedure:

1 . Iron oxide red, lactose, carboxymethylcellulose calcium, and stearic acid are sifted through a sieve and blended.

2. Hydroxypropyl cellulose and candesartan cilexetil are dispersed in water.

4. The granules are dried and sifted through a sieve.

5. Extragranular iron oxide red and lactose are sifted through a sieve and mixed with the granules of step 4.

7. The mixture is compressed into tablets. EXAMPLE 5: Candesartan cilexetil and hydrochlorothiazide 16/12.5 mg and 32/25 mg tablets.

* Evaporates during processing.

Manufacturing procedure:

1 . Iron oxide, lactose, and maize starch, hydrochlorothiazide, and carmellose calcium are sifted through a sieve and blended. 2. Gelucire 50/13, hydroxypropyl cellulose, and candesartan cilexetil are dispersed in water and sprayed onto the ingredients of step 1 to form granules, and the granules are dried.

3. Dried granules are sifted through a sieve.

4. Magnesium stearate is sifted through a sieve and blended with the step 3 mixture.

5. The blend of step 4 is compressed into tablets.

EXAMPLE 6: Stability testing.

Formulations prepared according to Examples 2, 3, and 4 and containing 32 mg of candesartan cilexitil are stored unpackaged at 60°C for 2 weeks, and analyzed for impurity content. The results are shown in Table 4.

Table 4

ND = not detected.

Claims

CLAIMS:

1 . A pharmaceutical 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.

2. The pharmaceutical formulation according to claim 1 , wherein the water-soluble polymer is at least one of a polyvinyl alcohol, maltodextrin, xanthan gum, a polyvinylpyrrolidone, a hydroxypropyl cellulose, a hydroxypropyl methylcellulose, a hydroxyethyl cellulose, a sodium carboxymethylcellulose, a calcium carboxymethylcellulose, a methyl cellulose, tragacanth gum, agar, gellan gum, karaya gum, alginic acid, pectin, and pregelatinized starch.

3. The pharmaceutical formulation according to claim 1 , wherein a water-swellable polymer is at least one of a hydroxypropyl cellulose, a

hydroxypropyl methylcellulose, a hydroxyethyl cellulose, a sodium

carboxymethylcellulose, a calcium carboxymethylcellulose, a methyl cellulose, and a pregelatinized starch.

4. The pharmaceutical formulation according to claim 1 , wherein the stabilizer is a mono-, di-, or tri-glyceride or a mono- or di-ester of polyethylene glycol.

5. The pharmaceutical formulation according to claim 1 , further comprising at least one additional pharmaceutically acceptable excipient that is a filler, binder, disintegrant, lubricant, or coloring or flavoring agent.

6. The pharmaceutical formulation according to claim 1 , further comprising at least one additional active ingredient that is a diuretic, anti- hyperlipidemic, angiotensin converting enzyme inhibitor, or other angiotensin receptor antagonist.

7. The pharmaceutical formulation according to claim 1 , further comprising hydrochlorothiazide as an additional active ingredient.

8. The pharmaceutical formulation according to claim 1 , in the form of a tablet.

9. The pharmaceutical formulation according to any of claims 1 -8, wherein a candesartan cilexetil ingredient has a particle size distribution where 90% of the particles have sizes less than about 20 μιη.

10. The pharmaceutical formulation according to any of claims 1 -8, in the form of a tablet comprising candesartan cilexetil, a water-soluble or water- swellable polymer, a stabilizing agent, and at least one other pharmaceutically acceptable excipient, wherein a blend used to prepare a tablet has particle sizes where about 20% to about 80% of the particles are retained on a 100 mesh sieve and about 10% to about 60% of the particles are retained on an 80 mesh sieve.

1 1 . The pharmaceutical formulation according to any of claims 1 -8, being substantially free of candesartan cilexitil degradation impurities.

12. A pharmaceutical formulation according to any of claims 1 -8, containing any one or more of 1 N-ethyl oxo candesartan cilexetil, 2N-ethyl oxo candesartan cilexetil, 2N-ethyl impurity, and any other drug-related impurities, in concentrations less than about 5% of the label candesartan cilexetil content.

13. The pharmaceutical formulation according to any of claims 1 -8, wherein the concentrations of any one or more of 1 N-ethyl oxo candesartan cilexetil, 2N-ethyl oxo candesartan cilexetil, 2N-ethyl impurity, and other drug- related impurities, are less than about 1 % of the label candesartan cilexetil content.

14. A process for preparing a pharmaceutical formulation, comprising: a) dispersing candesartan cilexetil, one or more water-soluble polymers or water-swellable polymers, and a stabilizer in a granulating fluid;

b) granulating a mixture comprising one or more fillers and one or more disintegrants to form granules with the dispersion of a);

c) drying and sizing granules; and

d) lubricating and compressing the granules into tablets.

15. A pharmaceutical formulation prepared by a process according to claim 14.

16. A method of treating hypertension and/or heart failure, comprising administering a pharmaceutical formulation according to any of claims 1 -8 or 15.