PHARMACEUTICAL FORMULATIONS FOR CARDIOVASCULAR AND ASSOCIATED DISORDERS

INTRODUCTION

Aspects of the present invention relate to pharmaceutical compositions comprising combinations of two or more active agents, for the management of cardiovascular and associated disorders. In embodiments, pharmaceutical compositions of the present invention are useful in the treatment of cardiovascular disorders. In aspects, the present invention also provides processes for preparation of such compositions.

The present invention further relates to the management of subjects having an elevated risk of cardiovascular events and other associated diseases or disorders. Aspects of the present invention provide pharmaceutical compositions comprising a combination of three drugs, particularly pharmaceutical compositions comprising a combination of at least one angiotensin inhibitor, at least one calcium channel blocker, and at least one diuretic, in a single dosage form.

Cardiovascular diseases (CVDs) are the most prevalent diseases in the world, and are among the foremost causes of death. They have become a major public health problem in many developing countries. About two-thirds of the global estimated 14.3 million annual cardiovascular disease deaths occur in the developing world. By the year 2015, cardiovascular diseases could be the most important cause of mortality in India. The prevalence of coronary artery disease in India increased from 1% in 1960 to 9.7% in 1995 in urban populations, and in rural populations it has almost doubled in the last decade. India had 6.6 million cases of this cardiovascular disease and the number in former Socialist countries was 5.8 million. For the cardiovascular disease stroke, the study indicated 9.5 million cases in Established Market Economies; China had 7.4 million cases and the sub-Saharan Africa had 1.3 million. There is an epidemiological transition from infective to degenerative diseases, increases in the prevalence of cardiovascular risk factors, and ageing of the population, which eventually leads to an increase in the absolute numbers of people with coronary heart disease (CHD) and increased health awareness and demand for health care facilities. So now there is a need for developing and implementing preventive interventions for effective management of CVDs.
Currently angiotensin II receptor blockers and calcium channel blockers are widely used as medicaments for the treatment or prophylaxis of hypertension, heart diseases, and the like. An angiotensin II receptor blocker, which is a renin angiotensin system inhibitor, is particularly effective for renin dependent hypertension and shows protective effects on cardiovascular and renal impairment. Furthermore, since calcium channel blockers possess natriuretic action in addition to vasodilative action, they are also effective on fluid retentive (renin independent) hypertension.

A combination of the angiotensin II receptor antagonist telmisartan and a diuretic, such as hydrochlorothiazide (HCTZ), in the form of a bilayer pharmaceutical tablet as a fast disintegrating tablet matrix for immediate release of the active is disclosed in European Patent No. 1467712.
International Application Publication No. WO 2009/125987 discloses pharmaceutical formulations containing an extended-release compartment having a dihydropyridine calcium channel blocker, and an immediate-release compartment having an angiotensin-2 receptor blocker, wherein the dihydropyridine calcium channel blocker and the angiotensin-2 receptor blocker are separately contained in each compartment and for which release characteristics are controlled.

European Patent No. 1272220 discloses a method for the prevention of cardiovascular disease, a formulation for the prevention of cardiovascular disease, the use of specified active principals for the manufacture of such a formulation for use in the method, and a method of preparing said formulation. The formulation comprises at least two blood pressure lowering agents, each selected from a different physiological mode of action selected from a diuretic, a beta blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, and a calcium channel blocker, and an active principle from at least two of the following three categories: i) at least one lipid-regulating agent; ii) at least one platelet function altering agent; and iii) at least one serum homocysteine lowering agent.

International Application Publication No. WO 2009/115301 discloses a solid pharmaceutical composition comprising at least two layers, wherein the first layer contains a non-peptide angiotensin II receptor antagonist in a dissolving matrix, and the second layer contains a diuretic characterized in that the second layer contains the diuretic or the pharmaceutically acceptable salt thereof in a dissolving matrix, and the pharmaceutical composition is substantially free of disintegrants.

U.S. Patent Application Publication No. 2009/0275559 discloses an anti-hypertensive composition for morning dosing, comprising a first anti-hypertensive agent, and optionally a diuretic, providing release of said first anti-hypertensive agent, and of said optional diuretic, on dosing, followed, within 4-12 hours later, by release of a second anti-hypertensive agent.

U.S. Patent No. 6294197 discloses a compressed solid dosage form comprising an effective amount of valsartan, or a pharmaceutically acceptable salt thereof, an effective amount of hydrochlorothiazide (HCTZ), and, at least one pharmaceutically acceptable additive.

U.S. Patent No. 6204281 discloses a method for the treatment or prevention of hypertension associated with diabetes, comprising administering a therapeutically effective amount of a combination consisting essentially of: (i) the AT1 -antagonist valsartan or a pharmaceutically acceptable salt thereof; (ii) the calcium channel blocker verapamil, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier; to a mammal in need thereof.

U.S. Patent Application Publication No. 2005/0187262 discloses a method of treating or managing a cardiovascular disease or disorder, comprising administering to a patient in need of such treatment a therapeutically effective amount of: enantiomerically pure (S)-amlodipine, or a pharmaceutically acceptable prodrug, salt, or solvate thereof; and an angiotensin receptor blocker, or a pharmaceutically acceptable prodrug, salt or solvate thereof; wherein the angiotensin receptor blocker is candesartan, eprosartan, telmisartan, irbesartan, pratosartan, valsartan, or olmesartan.

There remains a need for pharmaceutical formulations comprising multiple cardiovascular disease-preventive medicines that would effectively reduce the risk of cardiovascular events. In conventional therapy, patients at higher risk of cardiovascular events frequently are on multiple drug therapy, taking two or more different medications at the same time. Presenting multiple medications in a single fixed dose composition promotes patient compliance by avoiding the inconvenience of taking multiple doses of medicines in a single day, and reducing the chance of skipping doses. Therefore, there is a need for further development of combination products to achieve the desired therapeutic end-point. Further, the fixed dose combinations also need to be safe and tolerable for administration to a subject in need thereof.

The present invention provides such pharmaceutically useful pharmaceutical compositions comprising a fixed dose combination of two or more active agents and demonstrates a significant advancement in CVD therapy.

SUMMARY

Aspects of the present invention relate to pharmaceutical compositions comprising combinations of two or more active agents for the management of cardiovascular and associated disorders.

In aspects, the pharmaceutical compositions of the present invention are useful in the treatment of cardiovascular disorders.

Aspects of the present invention provide processes for preparation of compositions comprising combinations of two or more active agents for the management of cardiovascular and associated disorders.

In an aspect, the present invention provides pharmaceutical compositions comprising a combination of three drugs, comprising a combination of at least one angiotensin inhibitor, at least one calcium channel blocker, and at least one diuretic, in a single dosage form.

Specifically, the present invention provides a medicament for the prophylaxis, amelioration and/or treatment of hypertension or a disease caused by hypertension and/or one or more associated disorders, comprising at least one angiotensin II receptor blocker, at least one calcium channel blocker, and at least one diuretic. Specific embodiments of the present invention provide a medicament comprising telmisartan or pharmaceutically acceptable salts thereof, amlodipine or pharmaceutically acceptable salts thereof, and a thiazide diuretic, such as hydrochlorothiazide, or pharmaceutically acceptable salts thereof. In specific embodiments of this invention, amlodipine besylate is used. Pharmaceutical formulations further contain additives, such as, but not limited to, any of diluents, disintegrants, glidants, lubricants, binders, colorants, and combinations thereof, wherein dosage forms are in the form of tablets, capsules, or multiparticulates such as pellets.

In a further aspect, the present invention provides capsule dosage forms comprising compositions of one or more active agents formulated as pellets, granules, minitablets filled in a capsule, powders, or any combinations thereof.

In an aspect, the invention provides capsule dosage forms comprising compositions wherein one or more active agents are formulated as microcapsules.
The invention further provides methods for treating hypertension and a variety of other cardiovascular disorders by administration of pharmaceutical formulations comprising: (i) an angiotensin receptor blocker (ARB); (ii) a calcium channel blocker (CCB); and (Hi) a diuretic; to mammals including humans.

Further aspects of the invention relate to pharmaceutical formulations of telmisartan, amlodipine, and hydrochlorothiazide in a bilayer form, wherein a first layer comprises telmisartan in a dissolving or disintegrating matrix comprising a basic agent, and a second layer comprises amlodipine and hydrochlorothiazide in a dissolving or disintegrating matrix.

In an aspect, the present invention provides processes for preparing pharmaceutical compositions according to the present invention, particularly comprising a combination of three drugs comprising a combination of at least one angiotensin inhibitor, at least one calcium channel blocker, and at least one diuretic, in a single dosage form.

DETAILED DESCRIPTION

Aspects of the present invention provide pharmaceutical formulations comprising
combinations of two or more active agents for the management of cardiovascular and
associated disorders. In aspects, the present invention provides pharmaceutical formulationscomprising combinations of three drugs. Particular aspects provide pharmaceutical formulations comprising a combination of at least one angiotensin inhibitor, at least one calcium channel blocker, and at least one diuretic, in a single dosage form.

Embodiments of the present invention include solid pharmaceutical formulations comprising a non-peptide angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof, a calcium channel blocker or a pharmaceutically acceptable salt thereof, and a thiazide diuretic. In embodiments, pharmaceutical formulations of the present invention comprising an angiotensin II receptor blocker, a calcium channel blocker, and a diuretic, used in combination, exhibit an enhanced therapeutic or prophylactic efficacy compared to each of the active agents administered alone.
The present invention, in specific embodiments, relates to solid dosage forms which contain a combination of telmisartan, amlodipine, and hydrochlorothiazide, intended to be administered orally. Such dosage forms can be administered once, twice, or three times per day depending upon the type and severity of the disorders, the ages, and the health conditions of the patients.

The formulations of the present invention may be in the form of a single unit dosage form such as tablet, or in the form of multiparticulates such as granules, powder, pellets, minitablets, minicapsules or tablets, filled into a sachet or a capsule.

In an aspect, the present invention provides pharmaceutical formulations comprising, for example, a combination of drugs comprising at least one angiotensin inhibitor, at least one calcium channel blocker, and at least one diuretic, wherein one or more of the active agents are formulated together as one composition in the form of a tablet, minitablets or pellets, and one or more of the remaining active agents are formulated separately as another composition in the form of a tablet, minitablets or pellets, and wherein both such compositions are then made into a single dosage form.

In embodiments, a solid pharmaceutical formulation of the invention is a tablet comprising a combination of telmisartan, amlodipine, and hydrochlorothiazide, together with pharmaceutically acceptable additives suitable for the preparation of solid dosage forms. The solid dosage forms of the present invention can take the form of monolayer tablets, bilayer tablets, trilayer tablets, or tablets having two active layers separated by a non-active layer. If desired or necessary, the tablets may also comprise four or more layers. The two or more layers of the solid pharmaceutical formulations of the present invention can be in the form of adjacent parallel layers or any other configuration, for example one layer enclosing the other layer. The at least two layers and optional further layers can also be repeated for two or several times so as to form a sandwich-like structure.

Embodiments of the present invention include pharmaceutical formulations containing telmisartan, amlodipine, and hydrochlorothiazide in a bilayer form, wherein a first layer comprises telmisartan in a disintegrating matrix comprising a basic agent, and a second layer comprises amlodipine and hydrochlorothiazide in a dissolving matrix.

Embodiments of the present invention include pharmaceutical formulations containing telmisartan, amlodipine, and hydrochlorothiazide in a bilayer form, wherein a first layer comprises telmisartan in a dissolving matrix comprising a basic agent, and a second layer comprises amlodipine and hydrochlorothiazide in a disintegrating matrix.

Embodiments of the present invention include pharmaceutical formulations comprising telmisartan, amlodipine, and hydrochlorothiazide in a bilayer form wherein a first layer comprises telmisartan and amlodipine, or telmisartan and HCTZ, or amlodipine alone, or HCTZ alone.

Embodiments of the present invention include pharmaceutical formulations comprising telmisartan, amlodipine, and hydrochlorothiazide in a bilayer tablet form, wherein both layers are a disintegrating matrix.

Embodiments of the present invention include pharmaceutical formulations comprising telmisartan, amlodipine, and hydrochlorothiazide in a bilayer tablet form, wherein both the layers are a dissolving matrix.

Embodiments of the present invention include pharmaceutical formulations comprising telmisartan, amlodipine, and hydrochlorothiazide in tablet form, wherein telmisartan is present in a first layer, and amlodipine in a second layer, with a coating of hydrochlorothiazide over the tablet.

Embodiments of the present invention include pharmaceutical formulations comprising telmisartan, amlodipine, and hydrochlorothiazide in tablet form, wherein telmisartan is present in a first layer, and HCTZ in a second layer, with a coating of amlodipine over the tablet.

Embodiments of the present invention include formulations comprising telmisartan, amlodipine, and hydrochlorothiazide in tablet form, wherein amlodipine is present in a first layer, and HCTZ in a second layer, with a coating of telmisartan over the tablet.
Embodiments of the present invention include pharmaceutical formulations comprising telmisartan, amlodipine, and hydrochlorothiazide tablets filled into capsules. Tablets can comprise telmisartan, amlodipine, and hydrochlorothiazide, present in separate tablets or in combinations.

In an aspect, the present invention comprises solid dosage forms as monolithic-matrix systems comprising telmisartan, amlodipine, and HCTZ.

In an aspect, the present invention provides capsule dosage forms comprising compositions of one or more active agents formulated as pellets, granules, minitablets, powders, or any mixtures thereof.

Telmisartan suitable for use in the present invention can be purchased from commercial sources or can be prepared according to known methods. The active ingredient telmisartan is generally supplied in its free acid form, although pharmaceutically acceptable salts such as the sodium salt or any other pharmaceutically acceptable salt may also be used.

Telmisartan is employed in an amount typically ranging from about 10 mg to about 80 mg, or about 20 mg to about 40 mg, per unit dose. The amount of telmisartan noted above refers to the amount of free telmisartan or salt thereof present in a given solid dosage form. In the present invention, in cases where an angiotensin II receptor blocker is used or the prophylaxis or treatment of hypertension, due to superior efficacy by using in combination with a calcium channel blocker and a diuretic, a lower dosage of the angiotensin II receptor blocker than the dosage ordinarily used in monotherapy can be used.

Amlodipine suitable for use in the present invention can be purchased from commercial sources or can be prepared according to known methods. Amlodipine may be used for purposes of this invention in its free form as well as in any suitable salt form; in a specific embodiment of this invention, amlodipine besylate is used.

Amlodipine is employed in an amount ranging from 0.5 mg to about 20 mg, or about 1 mg to about 10 mg, or about 2.5 mg to about 5 mg in a unit dose. The amount of amlodipine noted above refers to the amount of free amlodipine or salt thereof present in a given solid dosage form.

Hydrochlorothiazide suitable for use in the present invention can be purchased from commercial sources or can be prepared according to known methods.

Hydrochlorothiazide may be used for purposes of this invention in its free form as well as in any suitable salt form.

Hydrochlorothiazide is employed in an amount ranging from 1 mg to about 50 mg, or about 5 mg to about 25 mg, or about 6.25 mg to about 12.5 mg in a unit dose. The amount of hydrochlorothiazide noted above refers to the amount of free hydrochlorothiazide or salt thereof present in a given solid dosage form.

The percent of particles with different dimensions that exist in a powder is called the particle size distribution. It is represented in certain ways. Particle size is the maximum dimension of a particle, normally expressed in units of urn. Particle size distributions can be expressed in terms of D10, D50, and D90, The D10, D50 and Dgo represent the 10th percentile, median or 50th percentile, and the 90th percentile of the particle size distribution, respectively, as measured by volume. That is, the D10, D50, D90 are values of the distribution such that 10%, 50%, and 90% by volume of the particles have sizes of the specified value or less, or are the percentages of particles smaller than those sizes. D50 is also known as the median size of particles. It is one of the important parameters representing characteristics of particles in a powder. For a sample, if D50= 5 pm, it means that 50% by volume of the particles are smaller than 5 pm. Similarly, if D10= 5 pm, 10% by volume of the particles are less than or equal to 5 pm, and if D=5 pm, 90% by volume of the particles are less than or equal to 5 pm.

The particle sizes of the telmisartan and hydrochlorothiazide for purposes of the present invention can be obtained by any suitable process of synthesis and/or size classification or reduction equipment known in the art, for example, process such as sieving and equipment such as jet mills, pulverizers, and fluid energy mills.

In embodiments, the invention includes pharmaceutical formulations comprising telmisartan, amlodipine, and hydrochlorothiazide, wherein: the particle size distributions of telmisartan have D10 values about 50 pm or less, D50 values about 100 pm or less, and D90 values less than about 200 pm; the particle size distributions of amlodipine have D10 values about 50 pm or less, D50 values about 100 pm or less, and D90 values about 250 pm or less; and the particle size distributions of HCTZ have D90 values less than about 250 pm and D50 values less than about 125 pm.

When the terms "active agent," "pharmacologically active agent," and "drug" are used in the present invention, it is to be understood that this includes the active compound as well as any of its pharmaceutically acceptable salts, esters, amides, prodrugs, metabolites, analogs, solvates, hydrates, enantiomers, derivatives, and the like.

It has been found that telmisartan has pH-dependent solubility and is more soluble in strongly alkaline conditions. Also, hydrochlorothiazide has been observed to be sensitive to alkaline conditions. So, in the compositions comprising telmisartan and hydrochlorothiazide, if a strong alkalizing agent is present in the composition to provide stable compositions, it is required to separate telmisartan and hydrochlorothiazide distinctly in the formulation.

In all of the above embodiments, the telmisartan part of the composition is preferably associated with one or more basic agents, water soluble or insoluble diluent, and optionally other pharmaceutically acceptable excipients.

The terms "salt" or "pharmaceutically acceptable salt" as used herein refer to salts which are known to be non-toxic and are commonly used in pharmaceutical practice.
The term "excipient" or "pharmaceutically acceptable excipient" means a component of a pharmaceutical product that is not a pharmacologically active ingredient, such as fillers or diluents, basic agents, binders, lubricants, disintegrants, carriers, colorants, and any combinations thereof.

In accordance with the invention, the term "dissolving matrix" refers to a formulation having immediate release; when present in a testing fluid environment, the entire drug content would be readily dissolved in the fluid medium. This infers that when the dosage form is in a physiological medium, the drug readily dissolves in it and enhances systemic absorption.

In accordance with the invention, the term "disintegrating matrix" refers to a composition of the dosage form which, when present in a testing fluid environment, would disintegrate into small particles, from which the drug can be released into the fluid.
Useful pharmaceutically acceptable excipients of the present invention include, but are not limited to, diluents, basic agents, disintegrants, binders, lubricants, colorants, antioxidants, surfactants, pH modifiers, glidants, and the like, and any combinations thereof.

The excipients that are useful in preparing the pharmaceutical compositions are generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for human pharmaceutical use as well as for veterinary use. An "excipient" or "pharmaceutically acceptable excipient" as used in the specification includes both one and more than one such excipient. The amount of each additive in a solid dosage formulation may vary within ranges conventional in the art.

Suitable diluents include, without limitation thereto, water soluble and water insoluble diluents such as: microcrystalline cellulose ("MCC," e.g., cellulose MK GR); silicified MCC (e.g. PROSOLV™ HD 90); microfine cellulose; low-substituted hydroxypropyl celluloses; carbohydrates such as monosaccharides like glucose, oligosaccharides like sucrose, trehalose, anhydrous lactose and lactose monohydrate; cyclodextrins such as hydroxypropyl beta-cyclodextrin; sugar alcohols like sorbitol, mannitol (e.g. different grades of PearlitoKS)), lactitol, maltitol, erythritol.and xylitol; starches such as corn starch and pregelatinized starch; poly(ethylene) glycols (PEG); dextrates; dextrin; maltodextrin; dextrose; inorganic bases and salts such as calcium carbonate, calcium sulfate, dibasic calcium phosphate, tribasic calcium phosphate, magnesium carbonate, and magnesium oxide; and any combinations thereof.

Suitable basic agents include, without limitation thereto, ammonia, alkali or alkaline metal oxides or hydroxides such as sodium hydroxide, potassium hydroxide, magnesium oxide, magnesium hydroxide and ammonium hydroxide; basic amino acids such as arginine and lysine; meglumine (N-methyl- D-glucamine); carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate.

Suitable disintegrants include, without limitation thereto, L-hydroxypropyl celluloses, croscarmellose sodium, methylcelluloses, microcrystalline celluloses, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium (e.g. AC-DI-SOL™, PRIMELLOSE™), crospovidone (e.g. KOLLIDON™, POLYPLASDONE™), povidones, guar gum, magnesium aluminum silicate, colloidal silicon dioxide (AEROSIL™), polacrilin potassium, starches, pregelatinized starches, corn starch, maize starch, sodium starch glycolate (e.g. EXPLOTAB™), sodium alginate, and any combinations thereof.

Suitable binders include, without limitation thereto, cellulose powder, crystalline cellulose, light anhydrous silicic acid, acacia, guar gum, alginic acid, carbomers (e.g. Carbopol™), dextrin, maltodextrin, methylcelluloses, ethylcelluloses, hydroxyethyl celluloses, hydroxypropyl celluloses (e.g. KLUCEL™), hydroxypropyl methylcelluloses (e.g. METHOCEL™), carboxymethylcellulose sodium, liquid glucose, magnesium aluminum silicate, polymethacrylates, polyvinylpyrrolidones (e.g. povidone K-90 D, KOLLIDON™), vinylpyrrolidone-vinylacetate copolymers (copovidone), gelatin, pregelatinized starches, corn starch, and other starches, microcrystalline cellulose (e.g., cellulose MK GR) and any combinations thereof. Dry binders and/or wet granulation binders are used depending on the manufacturing processes chosen to prepare the pharmaceutical formulations.

Suitable glidants include, without limitation, colloidal silicon dioxide (e.g., Aerosil® 200), magnesium trisilicate, powdered cellulose, starch, talc, and any combinations thereof.

Suitable lubricants include, without limitation, magnesium stearate, calcium stearate, aluminum or calcium silicate, stearic acid, PEG 4000-8000, Pearlitol DC 300, talc, hydrogenated castor oil (e.g., CUTINA™), glyceryl behenate, and any combinations thereof.

Suitable colorants include, without limitation, pigments such as yellow, red, and black iron oxides, titanium dioxide, food and drug dyes and lakes, and any combinations thereof.

The compositions may further include additional pharmaceutically acceptable excipients such as antioxidants, surfactants, carriers, solubilizers, pH control agents, etc.

Various film-forming agents that are useful for coating dosage forms include, but are not limited to, cellulose derivatives such as soluble alkyl- or hydroalkyl-cellulose derivatives such as methyl celluloses, hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxymethylethyl celluloses, hydroxypropyl methylcelluloses, sodium carboxymethyl celluloses, etc., insoluble cellulose derivative such as ethyl celluloses and the like, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacrylic acid, polyvinyl alcohols, polyvinyl acetates, polyvinylpyrrolidones, polymethacrylates and derivatives thereof (Eudragit™ products), chitosan and derivatives thereof, shellac and derivatives thereof, waxes, and fat substances. Useful enteric coating materials include, but are not limited to, materials such as cellulosic polymers like cellulose acetate phthalates, cellulose acetate trimellitates, hydroxypropyl methylcellulose phthalates, polyvinyl acetate phthalates, etc., methacrylic acid polymers and copolymers (Eudragit™), and the like, and mixtures thereof.
Some excipients are used as adjuvants to the coating processes, including excipients such as plasticizers, opacifiers, antiadhesives, polishing agents, etc. Various useful plasticizers include, but are not limited to, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, triethyl citrate, and mixtures thereof. An opacifier like titanium dioxide may also be present in an amount ranging from about 10% (w/w) to about 20% (w/w), based on the total weight of the coating.

Antiadhesives are frequently used in film coating processes to avoid sticking effects during film formation and drying. An example of an antiadhesive for this purpose is talc.
Suitable polishing agents include polyethylene glycols of various molecular weights or mixtures thereof, talc, surfactants (e.g., glycerol monostearate and poloxamers), fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol, and myristyl alcohol), and waxes (e.g., carnauba wax, candelilla wax and white wax).

In addition to the above coating ingredients, sometimes commercially available pre-mixed coating materials such as OPADRY™ products (supplied by Colorcon) or TABCOAT™ products can be used. OPADRY™ compositions generally comprise polymer, plasticizer and, if desired, pigment in a dry concentrate. OPADRY™ products produce attractive, elegant coatings on a variety of tablet cores and can be used in both aqueous and organic coating procedures. Pre-mixed coating products generally require only dispersion in a liquid before use.

In an aspect, the present invention provides processes for making fixed dose combination formulations. The processes for manufacturing formulations of present invention are not limited to the processes described herein, and the formulations can be prepared by using any of the processes known to one skilled in the art. One, or more than one, active ingredients can be used together with, or without, directly compressible grade excipients, by granulation together or separately, using wet granulation or dry granulation with or without excipients. Further one or more than one active agent can be granulated while the others may be used without granulation. Spray drying and spray granulation techniques may also be used to prepare the compositions of the present invention.

In embodiments, the pharmaceutical formulations of the present invention can be manufactured as follows: granules of active agents are prepared by sifting at least one active agent and one or more excipients through a desired mesh size sieve and then mixing, using a rapid mixer granulator, planetary mixer, mass mixer, ribbon mixer, fluid bed processor, or any other suitable device. The blend can be granulated, such as by adding a solution with or without a binder, whether alcoholic or hydro-alcoholic or aqueous, in a low or high shear mixer, fluidized bed granulator and the like, or by dry granulation. The granules can be dried using a tray dryer, fluid bed dryer, rotary cone vacuum dryer, and the like. The sizing of the granules can be done using an oscillating granulator or comminuting mill or Quadra co-mill or colloid mill or fluid energy mill or any other conventional equipment equipped with a suitable screen. Alternatively, granules can be prepared by extrusion and spheronization, or roller compaction. Also, the manufacture of granules containing active agents can include mixing with directly compressible excipients or roller compaction.

The granules can be obtained by a dry or wet technique and can optionally be blended with one or more lubricants and/or anti-adherants. The blend can be compressed using a suitable device, such as a rotary machine to form slugs, which are passed through a mill or fluid energy mill or ball mill or Quadro co-mill or colloid mill or roller mill or hammer mill and the like, equipped with a suitable screen to obtain the milled slugs of actives.
In embodiments, the present invention provides pharmaceutical tablet dosage forms, such as bilayer tablet dosage forms.

In embodiments of the invention, small tablets (minitablets) can be made by compressing granules using dies and punches of various sizes and shapes, as desired. Optionally, a coating on the tablets can be applied, if desired, by techniques known to one skilled in the art such as spray coating, dip coating, fluidized bed coating, and the like.

In embodiments of the present invention, multiparticulates such as granules, powders or pellets can be optionally coated, if desired, by techniques known to one skilled in the art such as spray coating, dip coating, fluidized bed coating, and the like.
In embodiments of the present invention, suitable solvent systems such as alcoholic, hydroalcoholic, aqueous, and organic may be used.

In embodiments, the present invention provides small tablets (minitablets), pellets, granules, and/or powders, filled into capsules.

In embodiments, the invention includes use of packaging materials such as containers and closures composed of polyethylene and/or polypropylene and/or glass, and blisters or strips composed of aluminum or high-density polypropylene or polyethylene, or polyvinyl chloride or polyvinyl chloride coated with polyvinylidene chloride, generally termed as PVC/PVDC. Different grades of PVC/PVDC are available as PVC/PVDC 40 gsm, PVC/PVDC 60 gsm, PVC/PVDC 90 gsm, etc. PVC/PVDC 40 gsm means 40 grams of PVDC coating per square meter of PVC foil. Similarly 60 gsm means 60 grams of PVDC coating per square meter of PVC foil, and 90 gsm means 90 grams of PVDC coating per square meter of PVC foil, etc. in embodiments, aluminum foil blister packages or high density polyethylene (HDPE) containers are used.

The dosage forms can be subjected to in vitro dissolution evaluations according to Test 711 "Dissolution" in United States Pharmacopoeia 24, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 1999, ("USP") to determine the rate at which drug is released into aqueous fluids from the dosage forms, and drug concentrations can be determined in solutions using techniques such as high performance liquid chromatography (HPLC).

In embodiments, products of the present invention may be produced as bilayer tablets, or tablets filled into capsules, as explained below, but the scope of the present invention should not be limited to these techniques.

Certain specific aspects and embodiments of the present invention are described in the following examples, provided only for purposes of illustration and not to be considered as limiting the scope of the invention in any manner.

EXAMPLES EXAMPLE 1: Telmisartan, Amlodipine Besylate, and Hydrochlorothiazide (40/5/12.5) mg and (20/2.5/6.25) mg Bi-layer Tablets.

A) Composition of Telmisartan Layer:

* Evaporates during processing. Manufacturing process:

1. Sodium hydroxide, meglumine, povidone, telmisartan, and polysorbate 80 were
dissolved in water to prepare binder solution.

2. Pearlitol SD 200 was sifted through a #40 mesh sieve.

3. Pearlitol SD 200 was granulated with step 1 solution, using top spray fluid bed processor maintaining the granulation parameters as follows: inlet temperature:
60°C±5°C; product temperature: 40°C±5°C; atomization: 2.0 - 2.5 bar; spray rate: 60-120 g/min; CFM: 300-750.,

4. The obtained granules were dried to achieve a desired loss on drying (LOD) less than 2% w/w, determined using a halogen moisture balance (HMB) at 105°C.

5. The obtained dried granules were sifted through a #30 mesh sieve.

6. The extragranular ingredients Pearlitol SD 200 and Pearlitol DC 300 were sifted
through a #30 mesh sieve and blended for 10 minutes in a double cone blender
(DCB), together with sifted granules obtained above. Then magnesium stearate was
sifted through a #60 mesh sieve, added, and blended for 5 minutes.

The blend prepared according to Example 1 was subjected to physical evaluations such as bulk density, tapped density and particle size distribution of the blend. Results are summarized in Tables 1 and 2.

Table 1: Physical Characteristics of Telmisartan Blend

Table 2: Particle Size Distribution of Telmisartan Blend

B) Composition of HCTZ and Amlodipine Besylate Layer:

* Evaporates during processing. Manufacturing process:

1. Hydrochlorothiazide, mannitol and amlodipine besilate were sifted through a #30 mesh sieve in geometrical proportions.

2. Iron oxide red was sifted through a #60 mesh sieve.

3. The sifted material of steps 1 and 2 were co-sifted through a #30 mesh sieve.

4. Povidone (PVP 29/32) was dissolved in a sufficient quantity of water to prepare a binder solution.

5. The material of step 3 was granulated using the binder solution of step 4 in a rapid mixer-granulator (RMG), maintaining the following granulation parameters: Dry mixing time: 20 minutes, impeller fast 200 rpm and chopper off; Binder solution addition: 1 minute, impeller fast 200 rpm and chopper off; Racking: 1 minute; Remaining binder solution addition: 1 minute impeller fast (200 rpm) and chopper off; Racking: 1 minute; and Kneading: 15 seconds, impeller fast 200 rpm and chopper slow (1400 rpm).

6. The wet granules were milled using a Quadro co-mill with a 2 mm screen at 250 RPM.

7. The wet granules were dried in a rapid dryer at an inlet temperature 60°C±5°C, to achieve a desired LOD less than 2% w/w.

8. The dried granules and Pearlitol SD 200 were separately sifted through a #30 mesh sieve.
9. The dried granules and Pearlitol SD 200 of step 8 were loaded into a double cone blender and blended for 10 minutes.

10. Magnesium stearate was sifted through a #60 mesh sieve and blended with the dried granules of step 9 for 5 minutes.

C) Preparation of Bilayer Tablet 1. White blend and pink blends (telmisartan blend, and amlodipine and HCTZ blend) were compressed into tablets, using 14*7mm oval shaped punches for (40/5/12.5) mg strength.

The blend of amlodipine and HCTZ prepared according to Example 1 is subjected to physical evaluations such as bulk density, tapped density and particle size distribution of the blend. Results are summarized in Tables 3 and 4.

Table 3: Physical Characteristics of Amlodipine Besylate and Hydrochlorothiazide Blend

Table 4: Particle Size Distribution of Amlodipine Besylate and Hydrochlorothiazide Blend

Tablets prepared according to Example 1 were subjected to physical evaluations such as color, hardness, friability, etc. Results are summarized in Tables 5 and 6. Table 5:

Compression parameters for (40/5/12.5)mg

Telmisartan, Amlodipine and Hydrochlorothiazide (20/2.5/6.25) mg bilayer tablets are dose proportional w.r.t (40/5/12.5) mg bilayer tablets.

Table 6: Compression parameters for (20/2.5/6.25)mg


Tablets prepared according to Example 1 are subjected to dissolution testing. The dissolution profiles are summarized in Tables 7.

Table 7: Dissolution profile for telmisartan, in different dissolution media at 100 RPM in USP type I apparatus.

Tablets of Example 1 (40/5/12.5 mg tablet) were packaged in closed HDPE containers with two 1 g molecular sieve pillow pouches and stored at accelerated stability testing conditions (40°C and 75% RH) for 3 months. Samples of the initial product and stored product were analyzed for drug assay and impurities (each expressed as % of label drug content), and percentage of drug dissolved at following conditions: Telmisartan - In 900ml of pH 7.5 phosphate buffer in USP type I apparatus at 100 RPM. HCTZ - In 900ml of pH 7.5 phosphate buffer in USP type I apparatus at 100 RPM. Amlodipine - In 500ml of pH 0.01 N HCI in USP type I apparatus at 100 RPM. Time point: 60 minutes.
Label Claim: Each Bilayer tablet contains Telmisartan 40mg, Amlodipine 5mg and HCTZ 12.5mg. The results are summarized in Table 8.

Table 8: Stability Test Results

ND = Not detected

Impurity A: 4-methyl6-(1-methyl-1 H-benzimidazole-2-yl)-2-propyl-1 H-benzimidazole Impurity D: 3-ethyl-5-methyl-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methylpyridine-3,5-dicarboxylate

DSA: 4-amino-6-chloro-1,3-benzenedisulfonamide CTZ: chlorothiazide

EXAMPLE 2: Tablets in Capsule.

A) Composition of Telmisartan Tablet



* Evaporates during processing.

Manufacturing Process:

1. Telmisartan blend was prepared by following the same manufacturing process as described in Example 1 for the preparation of telmisartan layer.

2. The blend obtained from Step 1 was compressed into tablets with capsule shaped punches of 11.4x5.5 mm.

B) Composition for Amlodipine and Hydrochlorothiazide Tablets

* Evaporates during processing.

Manufacturing Process:

1. Hydrochlorothiazide, mannitol, microcrystalline cellulose (Avicel PH 112), and pregelatinised starch (Starch 1500) were sifted through a #30 mesh sieve, and iron oxide red was sifted through a #60 mesh sieve.

2. Starch was dissolved in sufficient quantity of water to prepare a binder solution.

3. Granulation of step 1 ingredients with the binder solution was done in a RMG with the following granulation parameters: Dry mixing time: 20 minutes, impeller slow rpm and chopper off; Binder solution addition: 3 minutes, impeller fast 200 rpm and chopper off; Racking: 1 minute; Kneading: 30 seconds at impeller slow and chopper slow.

4. The wet granules were dried in a rapid dryer at an inlet temperature 60°C±5°C, to achieve a desired LOD less than 2% w/w.

5. The dried granules, amlodipine besylate, and Avicel PH112 (extragranular) were sifted through a #30 mesh sieve.

6. The dried granules were mixed in a double cone blender for 10 minutes.

Magnesium stearate was sifted through a #60 mesh sieve and blended for 5 minutes with the above blend.

7. The obtained blend was compressed into tablets with a capsule shaped punch of 9.4x4.7 mm, for (40/5/12.5) mg strength.

C) Preparation of capsule

1. Telmisartan tablets, and amlodipine besylate and hydrochlorothiazide tablets, were filled into Size '0el' capsules.

EXAMPLE 3: Three tablets in a Capsule.

A) Composition for Telmisartan Tablet

* Evaporates during processing. Manufacturing Process:

1. Telmisartan blend was prepared by following the same manufacturing process as described in Example 1 for the preparation of telmisartan layer.

2. The blend obtained from Step 1 was compressed into tablets with capsule shaped punches of 11.4x5.5 mm.

B) Composition for Amlodipine Tablets

Manufacturing process:

1. Amlodipine and microcrystalline cellulose (Avicel PH 112) were sifted through a #30 mesh sieve, loaded into a double cone blender, and blended for 10 minutes.

2. Magnesium stearate was sifted through a #60 mesh sieve and blended with the blend of step 1 for 5 minutes.

3. The blend was compressed into tablets using round SC punches of 6.2 mm.

C) Composition for Hydrochlorothiazide Tablets

Manufacturing Process:

1. Hydrochlorothiazide, mannitol, microcrystalline cellulose (Avicel PH 112), povidone and dibasic calcium phosphate anhydrous (A tab) were sifted through a #30 mesh sieve.

2. Iron oxide red and zinc stearate were sifted through a #60 mesh sieve.

3. The material of step 1 was blended in a DCB for 10 minutes, then material of step 2 was added and blended for 5 minutes.

4. The blend from step 3 was compacted using a roller compactor.

5. Compacts obtained from step 4 were sifted through a #18 mesh sieve, the obtained #18 mesh passings were subjected to compaction process until satisfactory
compacts were obtained.

6. #18 mesh retains of step 5 were milled through a comminuting mill using a 4 mm screen at slow speed, knives forward, and sifted through a #18 mesh sieve.

7. #18 mesh retains of step 6 were again milled using a 2.5 mm screen at medium speed and knives forward, then milled granules were sifted through a #18 mesh sieve. The process was continued till all the material passes through #18 mesh.

8. The material from step 7 was loaded into a double cone blender and blended for 10 minutes.

9. Sodium starch glycolate and zinc stearate were sifted through a #60 mesh sieve.

10. The sifted materials of step 9 were added to the material of step 8 and blended for 5 minutes.

11. The blend was compressed into tablets using 6.2 mm, round shaped SC punches.

D) Preparation of Capsule

1. One tablet from each of A, B, and C was filled into a size 'Oel' capsule.

EXAMPLE 4: Telmisartan, Amlodipine and Hydrochlorothiazide (40/5/12.5) mg Bi-layer Tablets.

A) Composition of Telmisartan Blend

Evaporates during processing.

Manufacturing process:

1. Telmisartan blend was prepared by following the same manufacturing process as described in Example 1 for the preparation of telmisartan layer.

B) Composition of HCTZ and Amlodipine Blend

* Evaporates during processing. Manufacturing process:

1. HCTZ and amlodipine blend was prepared by following the same manufacturing process as described in Example 1 for the preparation of HCTZ and amlodipine layer.

C) Preparation of Bilayer Tablet:

1. White blend and pink blend (telmisartan blend, and amlodipine and HCTZ blend) were compressed into tablets using 14x7mm oval shaped punches for (40/5/12.5) mg strength.

EXAMPLE 5: Telmisartan, Amlodipine and Hydrochlorothiazide (40/5/12.5) mg Bi-layer Tablets.

A) Composition of Telmisartan Blend

* Evaporates during processing.

Manufacturing process:

1. Telmisartan blend was prepared by following the same manufacturing process as described in Example 1 for the preparation of telmisartan layer. B) Composition of HCTZ and Amlodipine Blend

* Evaporates during processing.

Manufacturing process:

1. Hydrochlorothiazide, microcrystalline celllulose and amlodipine besylate were sifted through a #30 mesh sieve in geometrical proportion.

2. Mannitol was sifted through a #30 mesh sieve.

3. Iron oxide red was sifted through a #60 mesh sieve.

4. The materials of steps 1,2 and 3 were co-sifted through a #30 mesh sieve.

5. Povidone (PVP 29/32) was dissolved in water to form a binder solution.

6. The material of step 4 was granulated using the binder solution of step 5 in a RMG maintaining the following granulation parameters: Dry mixing time: 20 minutes, impeller fast 200 rpm and chopper off; Binder solution addition: 1 minute, impeller fast 200 rpm and chopper off; Racking: 1 minute; Remaining binder solution addition: 1 minute, impeller fast (200 rpm) and chopper off; Racking: 1 minute; and Kneading: 15 seconds, impeller fast 200 rpm and chopper slow (1400rpm).

7. The wet granules were milled using a Quadro co-mill, through a 2 mm screen at 250 RPM.

8. Milled granules were dried in a fluid bed dryer at an inlet temperature 60°C±5°C, to achieve a desired LOD less than 2% w/w at 105° C in mettler halogen moisture analyzer.

9. Dried granules and Pearlitol SD 200 were separately sifted through a #30 mesh sieve.

10. Blending: The dried granules and Pearlitol SD 200 were loaded into a double cone blender and blended for 10 minutes.

11. Magnesium stearate was sifted through a #60 mesh sieve, added, and blended for 5 minutes.

C) Preparation of Bilayer Tablet 1. White blend and pink blend (telmisartan blend, and amlodipine and HCTZ blend) were compressed into tablets using 14*7mm oval shaped punches for (40/5/12.5) mg strength.

EXAMPLE 6: Telmisartan, Amlodipine and Hydrochlorothiazide (40/5/12.5) mg Bi-layer Tablets.

A) Composition of Telmisartan Blend

* Evaporates during processing. Manufacturing process:

1. Telmisartan blend was prepared by following the same manufacturing process as described in Example 1 for the preparation of telmisartan layer.

B) Composition of HCTZ and Amlodipine Blend

* Evaporates during processing. Manufacturing process:

1. Hydrochlorothiazide, mannitol, sorbitol, and amlodipine besylate were sifted through a #30 mesh sieve in geometrical proportion.

2. Iron oxide red was sifted through a #60 mesh sieve.

3. The sifted material of steps 1 and 2 were co-sifted through a #30 mesh sieve.

4. Povidone (PVP 29/32) was dissolved in water, to prepare a binder solution.

5. The material of step 3 was granulated using the binder solution of step 4 in a RMG maintaining the following granulation parameters; Dry mixing time: 20 minutes, impeller fast 200 rpm and chopper off; Binder solution addition: 1 minute, impeller fast 200 rpm and chopper off; Racking: 1 minute; Remaining binder solution addition: 1 minute, impeller fast (200 rpm) and chopper off; Racking: 1 minute; and Kneading: 15 seconds, impeller fast 200 rpm and chopper slow (1400 rpm).

6. Wet granules were milled using a Quadro co-mill, through a 2 mm screen at 250 RPM.

7. The granules were dried in a rapid dryer at an inlet temperature 60°C±5°C, to achieve a desired LOD less than 2% w/w at 105° C in mettler halogen moisture analyzer.

8. Dried granules and Pearlitol SD 200 were separately sifted through a #30 mesh sieve.

9. Sifted granules and Pearlitol SD 200 of step 8 were loaded into a double cone blender and blended for 10 minutes.

10. Magnesium stearate was sifted through a #60 mesh sieve, added, and blended for 5 minutes.

C) Preparation of Bilayer Tablet

1. White blend and pink blend (telmisartan blend, and amlodipine and HCTZ blend) were compressed into tablets, using 14*7mm oval shaped punches for (40/5/12.5) mg strength.
EXAMPLE 7: Telmisartan, Amlodipine and Hydrochlorothiazide (40/5/12.5) mg Bi-layer Tablets.

A) Composition of Telmisartan Blend

* Evaporates during processing. Manufacturing process:

1. Telmisartan blend was prepared by following the same manufacturing process as described in Example 1 for the preparation of telmisartan layer.

B) Composition of HCTZ and Amlodipine Blend

* Evaporates during processing. Manufacturing process:

1. Hydrochlorothiazide, mannitol, dicalcium phosphate, and amiodipine besylate were sifted through a #30 mesh sieve in geometrical proportion.

2. Iron oxide red was sifted through a #60 mesh sieve.

3. The sifted materials of steps 1 and 2 were co-sifted through a #30 mesh sieve.

4. Povidone (PVP 29/32) was dissolved in water, to prepare a binder solution.

5. The material of step 3 was granulated using the binder solution of step 4 in a RMG maintaining the following granulation parameters: Dry mixing time: 15 minutes, impeller fast 200 rpm and chopper off; Binder solution addition: 1 minute, impeller fast 200 rpm and chopper off; Racking: 1 minute; Remaining binder solution addition: 1 minute, impeller fast (200 rpm) and chopper off; Racking: 1 minute; and Kneading: 15 seconds, impeller fast 200 rpm and chopper slow (1400 rpm).

6. Wet granules were milled using a Quadro co-mill through a 2 mm screen at 250 RPM.
7. Milled granules were dried in a rapid dryer at an inlet temperature 60°C±5°C, to achieve a desired LOD less than 2% w/w at 105° C in mettler halogen moisture analyzer.

8. Dried granules and Pearlitol SD 200 were separately sifted through a #30 mesh sieve.

9. Sifted granules and Pearlitol SD 200 of step 8 were loaded into a double cone blender and blended for 10 minutes.
10. Magnesium stearate was sifted through a #60 mesh sieve, added, and blended for 5 minutes.

C) Preparation of Bilayer Tablet

1. White blend and pink blend (telmisartan blend, and amiodipine and HCTZ blend) were
compressed into tablets using 14*7mm oval shaped punches for (40/5/12.5) mg
strength.

CLAIMS

1. A pharmaceutical composition comprising the combination of an angiotensin receptor blocker (ARB), a calcium channel blocker (CCB), a diuretic, and one or more pharmaceutically acceptable excipients, in a single dosage form.

2. The pharmaceutical composition of claim 1, wherein an angiotensin inhibitor is telmisartan or a pharmaceutically acceptable salt thereof, a calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof, and a diuretic is hydrochlorothiazide.

3. The pharmaceutical composition of either of claims 1 or 2, in the form of a bi-layered tablet.

4. The pharmaceutical composition of claim 3, wherein telmisartan or a pharmaceutically acceptable salt thereof is present in a first layer, and amlodipine or a pharmaceutically acceptable salt thereof and hydrochlorothiazide are present in a second layer.

5. The pharmaceutical composition of claim 4, wherein a first layer is a dissolving matrix.

6. The pharmaceutical composition of either of claims 4 or 5, wherein a second layer is a dissolving matrix.

7. The pharmaceutical composition of any of claims 1-6, wherein pharmaceutically acceptable excipients comprise one or any combination of diluents, basic agents,
disintegrants, binders, lubricants, colorants, antioxidants, surfactants, pH modifiers, and glidants.

8. A process for preparing a pharmaceutical bi-layered tablet of any of claims 3-7, comprising the steps of:

a) granulating one or more diluents using a binder solution comprising telmisartan, to provide a first blend;

b) granulating hydrochlorothiazide, amlodipine, and one or more pharmaceutically acceptable excipients using a binder solution, to provide a second blend; and

c) compressing the blends of steps a) and b) to form a bi-layer tablet.

9. A process for preparing a pharmaceutical bi-layered tablet of any of claims 3-7,
comprising the steps of:

a) granulating one or more diluents using a binder solution comprising telmisartan, to provide a first blend;

b) granulating hydrochlorothiazide and one or more pharmaceutically acceptable excipients using a binder solution, to provide a second blend;

c) adding amlodipine to the blend obtained in step (b); and

d) compressing the blends of steps a) and
c) to form a bi-layer tablet.

10. A pharmaceutical composition prepared according to either of claims 8 or 9, comprising:

about 40 mg of telmisartan, about 7 mg of amlodipine besylate, and about 12.5 mg of hydrochlorothiazide; or about 20 mg of telmisartan, about 3.5 mg of amlodipine besylate, and about 6.25 mg of hydrochlorothiazide