FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION (See section 10 and rule 13)
1. TITLE OF THE INVENTION
ANGIOTENSIN RECEPTOR BLOCKER (ARB) COMPOSITIONS
2. APPLICANT (S)
(a) NAME : Inventia Healthcare Limited
(b) NATIONALITY: Indian
(c) ADDRESS : Unit 703 & 704, 7th floor, Hubtown Solaris,
N S Phadke Marg, Andheri (East), Mumbai - 400 069, Maharashtra, India
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of the Invention:
The present invention relates to stable, oral compositions comprising at least one angiotensin II receptor blocker (ARB), wherein the ARB is non-granulated. The present invention provides a process for the preparation of such compositions.
Background of the Invention:
Angiotensin II Receptor Antagonists or Angiotensin II Receptor Blockers (ARBs) represent a class of antihypertensive agents that offer complete angiotensin II inhibition by interacting selectively with the receptor site. Azilsartan medoxomil, Telmisartan, Olmesartan, Losartan, Valsartan, Irbesartan, Candesartan, and Eprosartan are ARBs which are used as active agents in the treatment of hypertension, either alone or in combination with other drugs.
ARBs are poorly water-soluble compounds, and are chemically susceptible to pH changes, humidity, heat and light, giving rise to impurities. The packaging needs to protect ARB compositions from both light, oxygen, and moisture, and necessitates the use of desiccants.
■ Azilsartan, in the form of ester salt kamedoxomil, is a hygroscopic, white powder which is poorly soluble in aqueous solutions, becomes slightly soluble at pH 9 and above, where it is readily susceptible to aqueous hydrolysis. Stability experiments under various stressed conditions show that azilsartan kamedoxomil is sensitive to humidity and light.
■ Telmisartan, a low solubility and high permeability drug, undergoes oxidative, thermal, and photolytic degradation, and degradation in alkali medium.
■ Olmesartan, in the form of medoxomil ester, is a white to pale yellowish white crystalline powder, practically insoluble in aqueous solution over the physiological pH range (pH 2 to 6) with increasing solubility at pH >6 and <2. During forced degradation studies,

degradation was observed during acid and alkali hydrolysis and oxidative stress conditions.
Prior art discloses various methods to improve the stability and solubility of pharmaceutical compositions comprising ARBs.
Indian Patent Application No. 3516/KOLNP/2009 relates to a solid pharmaceutical composition comprising azilsartan and a pH control agent. The said tablets are prepared by combining azilsartan, pH control agent, an excipient, and a disintegrant, and spraying an aqueous solution of a binder like hydroxypropylcellulose or polyvinylpyrrolidone to give wet granules. The azilsartan granules are dried, lubricated and compressed into tablets. The said tablets achieve the desired stability and dissolution property.
U.S. Patent Publication No. US2009/0030057 relates to pharmaceutical granulates of telmisartan comprising, at least one water insoluble diluent, a basic agent, a surfactant, and a binder.
Indian Patent Application No. 2774/DEL/2014 discloses stable pharmaceutical compositions of azilsartan kamedoxomil which are free of pH control agent, free of unpleasant odor and packaged in a pharmaceutical package free of desiccant. The tablet compositions of the said application use the process of roll compaction to dry granulate and prepare tablets.
Indian Patent Application No. 2270/MUM/2014 discloses a pharmaceutical preparation comprising actives - a diuretic and azilsartan medoxomil and salts thereof, the said actives being stabilized by granulating them together with a pH modifier, and adjusting the pH. The preparations are further stabilized by packing them along with the desiccant in the pharmaceutical package.

U.S. Patent Publication No. 2012/0115837 relates to a solid preparation comprising an angiotensin II receptor antagonist (e.g. candesartan, telmisartan, olmesartan, azilsartan) or a salt thereof, a sugar alcohol, and a calcium antagonist (e.g. amlodipine, nicardipine, nisoldipine, nifedipine, felodipine, manidipine). The said preparations are manufactured using the process of wet granulation of drug and excipients, with an aqueous solution of the binder. The said compositions optimize and appropriately control the dissolution property of both the drugs from the preparation.
U.S. Patent Publication Numbers 2006/0110450, 2006/0078615 and 2008/0113023 disclose bilayer tablets comprising a first layer formulated for instant release of the angiotensin II receptor antagonist telmisartan from a dissolving tablet matrix. The second layer is formulated for instant release from a disintegrating or eroding tablet matrix comprising the second active agent calcium channel blocker amlodipine, HMG-CoA reductase inhibitor simvastatin and diuretic respectively. The first tablet layer composition comprises telmisartan in the form of granulates, prepared by spray drying/fluid bed granulation of an aqueous solution of telmisartan, and at least one basic agent. Granulates may further contain a solubilizer, a crystallization retarder, a non-ionic surfactant and/or an emulsifier.
Japanese Patent application 2019/104726 and 2019/059706 provides wet granulated, compression-molded tablets comprising azilsartan or a salt thereof, and amlodipine or a salt thereof, to improve the stability of the drugs over time and suppress the decrease in tablet hardness.
Thus, prior art has utilized several techniques to address the problem of storage stability and dissolution of ARBs. However, there exists a need to provide a simple, easily scalable, and industrially economical technique to provide a composition that exhibits both desired storage stability and desired dissolution profile. The inventors of the present invention have

surprisingly found that when ARBs are used in a non-granulated form the said compositions exhibit desired storage stability over extended periods of time. The said compositions also exhibit the desired dissolution.
Further, when non-granulated ARB is used in compositions designed for oral co-delivery of at least one ARB and at least one other active agent, such compositions also exhibit good storage stability and desired dissolution.
OBJECTS OF THE INVENTION
The principal object of the present invention is to provide stable, oral compositions comprising at least one ARB, wherein the ARB is non-granulated.
Another object of the present invention is to provide stable, oral compositions comprising at least one ARB, wherein the ARB is non-granulated, and the average cumulative dissolution of ARB is not less than 70% at 30 minutes.
Another object of the present invention is to provide stable, oral compositions comprising at least one ARB, wherein the ARB is non-granulated, and wherein the content of total impurities in the ARB compositions is not more than 7%.
Another object of the present invention is to provide stable, oral compositions for oral co-delivery comprising at least one ARB and at least one other active agent, wherein the ARB is non-granulated.
Yet another object of the invention is to provide a process for the preparation of stable, oral compositions comprising at least one non-granulated ARB.

SUMMARY OF THE INVENTION
The present invention provides stable, oral compositions comprising at least one angiotensin II receptor blocker (ARB), wherein the ARB is non-granulated. Further, the present invention provides stable compositions for oral co-delivery comprising at least one ARB and at least one other active agent, wherein the ARB is non-granulated. The present invention provides a process for the preparation of such compositions.
DETAILED DESCRIPTION OF THE INVENTION
The invention provides stable, oral compositions comprising at least one ARB, wherein the ARB is non-granulated.
The term “ARB” as used herein include angiotensin II receptor blockers such as losartan, valsartan, irbesartan, candesartan, telmisartan, eprosartan, olmesartan, tasosartan, enoltasosartan, and azilsartan, and their pharmaceutically acceptable salts, hydrates, esters, derivatives or solvates thereof. One such example of ARB is azilsartan kamedoxomil. ARB can be in crystalline form and/or amorphous form.
The term “non-granulated”, as used herein, refers to any component that is not in the form of granules or granulates, but is in the form of a powder, the said powder capable of being further compressed into tablets and/or filled into capsules. The “non-granulated” component is not subjected to processes of wet granulation, dry granulation, fluidized bed granulation, rapid mixer granulation, high-shear mixer granulation, centrifugal wet granulation, steam granulation, spray drying granulation, melt granulation, melt extrusion, freeze-granulation, thermal adhesion granulation, foam granulation, pneumatic dry granulation, moisture-activated dry granulation, roll compaction, slug compaction, co-milling, co-crystallization, solvent evaporation, or co-precipitation.

The term “inert excipient granules” as used herein, refers to inactive and inert excipients which are in the form of granules, the said granules being free of any active agent. The inactive, inert excipients are subjected to processes of wet granulation, dry granulation, fluidized bed granulation, rapid mixer granulation, high-shear mixer granulation, centrifugal wet granulation, steam granulation, spray drying granulation, melt granulation, melt extrusion, freeze-granulation, thermal adhesion granulation, foam granulation, pneumatic dry granulation, moisture-activated dry granulation, roll compaction, slug compaction, co-milling, co-crystallization, solvent evaporation, or co-precipitation, to give inert excipient granules. The “inert excipient granules” are capable of being further compressed into tablets and/or filled into capsules.
The present invention relates to stable, oral compositions comprising at least one ARB, wherein the ARB is non-granulated.
ARBs can be selected from azilsartan, telmisartan, olmesartan, losartan, valsartan, irbesartan, candesartan, eprosartan, tasosartan, enoltasosartan, and their pharmaceutically acceptable salts, hydrates, esters, derivatives or solvates thereof. Azilsartan kamedoxomil, telmisartan, valsartan and olmesartan are the preferred ARBs.
The stable, oral compositions comprise ARB in concentrations ranging from 0.5% to about 80%, preferably from about 1% to about 60%, and more preferably from about 1% to about 50%, and most preferably from about 1% to about 40% by weight of the composition.
In one aspect, the stable, oral ARB compositions comprise at least one non-granulated ARB, and at least one non-granulated excipient.

In another aspect, the stable, oral ARB compositions comprise at least one non-granulated ARB, and inert excipient granules.
The stable, oral compositions, comprising at least one non-granulated ARB, can be in the form of powder, powder blends, single layered compressed tablets, layered compressed tablets such as bi-layered compressed tablets and multi-layered compressed tablets, capsules or a combination thereof. The compositions may further be coated with a film-coating.
In an aspect, stable, oral compositions comprising at least one non-
granulated ARB, provides ARB in the form of rapid release, extended-
release, sustained-release, controlled-release, prolonged release,
delayed-release, enteric-release, timed-release, pulsed-release, or a
combination thereof.
In yet another aspect, the stable, oral compositions provide co-delivery of at least one ARB as the first active agent, and at least one other active agent, wherein the said compositions comprise ARB in a non-granulated form.
In one aspect, the stable, oral compositions for co-delivery comprise at least one non-granulated ARB, at least one non-granulated excipient, and at least one other active agent.
In another aspect, the stable, oral compositions for co-delivery comprise at least one non-granulated ARB, inert excipient granules, and at least one other active agent.
The stable, oral compositions for co-delivery, comprising at least one non-granulated ARB, and at least one other active agent, can be in the form of

powder, powder blends, single layered compressed tablets, layered compressed tablets such as bi-layered compressed tablets and multi-layered compressed tablets, capsules or a combination thereof. The compositions may further be coated with a film-coating.
In an aspect, stable, oral compositions for co-delivery, comprising at least one non-granulated ARB, and at least one other active agent, provide ARB or the other active agent, in the form of rapid release, extended-release, sustained-release, controlled-release, prolonged release, delayed-release, enteric-release, timed-release, pulsed-release, or a combination thereof.
Another embodiment of the invention provides stable, oral compositions for co-delivery, in the form of layered compressed tablets, comprising at least one non-granulated ARB in a first layer, and at least one other active agent in a second layer.
In one aspect, the layered tablet compositions for oral co-delivery comprise at least one non-granulated ARB, and at least one non-granulated excipient in the first layer, and at least one other active agent in the second layer.
In another aspect, the layered tablet compositions for oral co-delivery comprise at least one non-granulated ARB and inert excipient granules in the first layer, and at least one other active agent in the second layer.
In another aspect, the weight of the first layer of the layered tablet compositions for oral co-delivery, comprising at least one non-granulated ARB, is about 30% to about 90%, preferably from about 40% to about 80% by weight of the composition.

The other active agent can be selected from antihypertensive agents and hypoglycemic agents.
Antihypertensive agents can be diuretics, calcium channel blockers (CCB), and ACE inhibitors.
■ Diuretics include chlorothalidone, chlorothiazide, hydrochlorothiazide, indapamide, methylclothiazide, and pharmaceutically acceptable salts thereof.
■ Calcium channel blockers include amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, nivaldipine, flunarizine, prenylamine, diltiazam, fendiline, gallopamil, mibefradil, anipamil, tiapamil, and verapamil, and pharmaceutically acceptable salts thereof.
■ ACE inhibitors include alacepril, benazepril, benazeprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enaprilat, fosinopril, imidapril, lisinopril, moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril, and trandolapril, and pharmaceutically acceptable salts, esters, solvates, and hydrates thereof.
Hypoglycemic agents include repaglinide, nateglinide, glimepiride, glibenclamide, gliclazide, glipizide, metformin, miglitol, acarbose, muraglitazar, pioglitazone, rosiglitazone, tesaglitazar, saroglitazar, sitagliptin, vildagliptin, alogliptin, saxagliptin, dapagliflozin, empagliflozin, canagliflozin, and their pharmaceutically acceptable salts, esters, solvates, and hydrates thereof.
The at least one other active agent in the stable, oral ARB compositions for co-delivery maybe in a non-granulated form, or in the form of granules or granulates.

In an aspect, the stable, oral compositions for co-delivery comprise at least one non-granulated ARB, and at least one other active agent, wherein the other active agent is present in concentrations ranging from about 0.5% to about 80%, preferably from about 1% to about 60%, more preferably from about 1% to about 50%, and most preferably from about 1% to about 40% by weight of the composition.
In another aspect, stable, oral compositions are in the form of layered compressed tablets, comprising at least one non-granulated ARB in a first layer, and at least one other active agent in a second layer, wherein the ARB is present in concentrations ranging from about 0.5% to about 80%, preferably from about 1% to about 60%, more preferably from about 1% to about 50%, and most preferably from about 1% to about 40% by weight of the layer.
In another aspect, stable, oral compositions are in the form of layered compressed tablets, comprising at least one non-granulated ARB in a first layer, and at least one other active agent in a second layer, wherein the other active agent is present in concentrations ranging from about 0.5% to about 80%, preferably from about 1% to about 60%, more preferably from about 1% to about 50%, and most preferably from about 1% to about 40% by weight of the layer.
The stable, oral compositions for co-delivery comprising at least one non-granulated ARB, and at least one other active agent, comprise one or more excipients selected from the group of diluents, binders, disintegrants, antioxidants, pH modifying agents, surfactants, lubricants, and glidants.
Diluent(s) are present in concentrations ranging from about 20% to about 99% by weight of the ARB composition, and are selected from those known in the art such as microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, carboxymethylcellulose

sodium, carboxymethylcellulose calcium, microfine cellulose, starch, modified starch, pregelatinized starch, starch 1500, dextrin, dextran, maltodextrin, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, cyclodextrins, or mixtures thereof. Diluents may also be selected from glucose, lactose, mannitol, sucrose, dextrose, sorbitol, fructose, sorbitol, compressible sugar, or mixtures thereof.
In an aspect, stable, oral compositions in the form of layered compressed tablets, comprising at least one non-granulated ARB in a first layer, and at least one other active agent in a second layer, comprise diluent(s) in concentrations ranging from about 20% to about 99% by weight of the layer.
Binder(s) are present in concentrations ranging from about 0.1% to about
40% by weight of the ARB composition and are selected from those known
in the art such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl
cellulose (HPC), methylcellulose, ethylcellulose, hydroxyethyl cellulose,
polyvinylpyrrolidone (PVP), polyvinyl alcohol, gelatin, waxes, fatty alcohols
(such as stearyl alcohol, cetyl alcohol), waxes, polyethylene glycol, gelatin,
carbomer, gums (such as xanthan gum, guar gum, acacia, locust bean
gum), magnesium aluminium silicate (veegum), alginates,
polymethacrylates or mixtures thereof.
In an aspect, stable, oral compositions in the form of layered compressed tablets, comprising at least one non-granulated ARB in a first layer, and at least one other active agent in a second layer, comprise binder(s) in concentrations ranging from about 0.1% to about 40% by weight of the layer.
Disintegrant(s) are present in concentrations ranging from about 1% to about 25% by weight of the ARB composition and are selected from those

known in the art such as sodium starch glycolate, crospovidone, croscarmellose sodium, and croscarmellose calcium.
In an aspect, stable, oral compositions in the form of layered compressed tablets, comprising at least one non-granulated ARB in a first layer, and at least one other active agent in a second layer, comprise disintegrant(s) in concentrations ranging from about 1% to about 25% by weight of the layer.
Antioxidant(s) are present in concentrations ranging from 0.05% to 3% by weight of the ARB composition and are selected from those known in the art. Preferably antioxidant(s) are selected from butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, sodium metabisulfite, sodium sulfite, sodium bisulfite, citric acid, ascorbic acid and mixtures thereof.
In an aspect, stable, oral compositions in the form of layered compressed tablets, comprising at least one non-granulated ARB in a first layer, and at least one other active agent in a second layer, comprise antioxidant(s) in concentrations ranging from about 0.05% to about 3% by weight of the layer.
pH modifying agent pH modifying agent(s) are present in concentrations from 0.1% to 20% by weight of the ARB composition and are selected from those known in the art. The pH modifying agent(s) can be acidic or basic in nature. Preferable basic pH modifying agent(s) is selected from metal oxides (such as calcium oxide, magnesium oxide), hydroxides (such as sodium hydroxide, potassium hydroxide, calcium hydroxide), carbonates can be sodium carbonate, sodium bicarbonates, potassium bicarbonates, acetates (such as sodium acetate, sodium acetate trihydrate, potassium acetate), silicates (such as sodium silicate), quaternary ammonium salts and N-methyl-D-glucamine. Preferable acidic pH modifying agents are selected from mineral acid and organic acids such as hydrochloric, nitric, phosphoric, acetic, citric, succinic, sulfuric,

fumaric, maleic, malic, benzoic, tartaric, methanesulfonic,
naphthalenesulfonic, p-toluenesulfonic, lactic, and ascorbic acid, and glycine hydrochloride. The pH modifying agent can be a buffering agent like Tris buffer, tris-(hydroxymethyl) methyl ammonium chloride.
In an aspect, stable, oral compositions in the form of layered compressed tablets, comprising at least one non-granulated ARB in a first layer, and at least one other active agent in a second layer, comprise pH modifying agent(s) in concentrations ranging from about 0.1% to about 20% by weight of the layer.
Surfactant(s) may be present in concentrations ranging from about 0.05%
to about 5% by weight of the ARB composition and are selected from
those known in the art. Preferable surfactants are selected from ionic
surfactants, such as sodium lauryl sulphate, or non-ionic surfactants such
as poloxamers, lecithins, esters of sorbitan and fatty acids (such as
Span®), esters of polyoxyethylenesorbitan and fatty acids (such as
Tween®), polyoxyethylated hydrogenated castor oil (such as
Cremophor®), polyoxyethylene stearates (such as Brij®),
dimethylpolysiloxane or any combination of the above mentioned surfactants.
In an aspect, stable, oral compositions in the form of layered compressed tablets, comprising at least one non-granulated ARB in a first layer, and at least one other active agent in a second layer, comprise surfactant(s) in concentrations ranging from about 0.05% to about 5% by weight of the layer.
Lubricant(s) may be present in concentrations from 0.25% to 5% by weight of the ARB composition and are selected from those known in the art. Preferably lubricants are selected from magnesium stearate, calcium

stearate, stearic acid, sodium stearyl fumarate, sodium benzoate, palmitic acid, talc, and glyceryl behenate.
In an aspect, stable, oral compositions in the form of layered compressed tablets, comprising at least one non-granulated ARB in a first layer, and at least one other active agent in a second layer, comprise lubricant(s) in concentrations ranging from about 0.25% to about 5% by weight of the layer.
Glidant(s) may be present in concentrations from about 0.1% to about 10% by weight of the composition and are selected from those known in the art such as colloidal silicon dioxide, hydrated silicon dioxide, light anhydrous silicic acid, aluminum silicate, titanium oxide, stearic acid, and talc.
In an aspect, stable, oral compositions in the form of layered compressed tablets, comprising at least one non-granulated ARB in a first layer, and at least one other active agent in a second layer, comprise glidant(s) in concentrations ranging from about 0.1% to about 10% by weight of the layer.
In an embodiment, stable, oral compositions of the present invention, comprising at least one non-granulated ARB, may optionally be film-coated with a film-coating layer comprising film-coating materials and optionally one or more pharmaceutically acceptable excipients selected from plasticizers, colorants, pigments, glidants, lubricants or mixtures thereof.
The film-coating materials are selected from those known in the art such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethylcellulose, polymethacrylates, polyvinyl alcohol, Surelease®, Opadry®, Opadry® AMB, Aquacoat®, polyvinyl acetate or mixtures thereof.

The process of preparing non-granulated ARB and/or non-granulated excipient, comprises one or more of steps selected from sifting and blending. The non-granulated ARB and/or non-granulated excipient can further be compressed into tablets, or filled into capsules.
The process for preparing ‘inert excipient granules’ comprises one or more of steps selected from sifting, blending, granulation (wet granulation, dry granulation, fluidized bed granulation, rapid mixer granulation, high-shear mixer granulation, centrifugal wet granulation, steam granulation, spray drying granulation, melt granulation, melt extrusion, freeze-granulation, thermal adhesion granulation, foam granulation, pneumatic dry granulation, moisture-activated dry granulation, roll compaction, slug compaction, co-milling, co-crystallization, solvent evaporation, or co-precipitation), milling, screening, and drying. The ‘inert excipient granules’ can further be compressed into tablets, or filled into capsules.
ARB compositions of the present invention can be packed in suitable packs such as aluminum blisters and PVC-PVDC bottle packs, with or without desiccants.
ARB compositions comprising non-granulated ARBs are evaluated in terms of ARB content (assay), average cumulative % dissolution of ARB, and total impurities.
ARB content in the ARB compositions comprising non-granulated ARBs, as determined by liquid chromatography, ranges from about 90% to about 110%, preferably from about 95% to about 105% of the label claim.
Dissolution of ARB from the ARB compositions comprising non-granulated ARBs, was studied in the required dissolution media, and dissolution

calculated in terms of average cumulative percentage dissolution of ARB at various time periods.
Dissolution of ARB from the ARB compositions, comprising non-granulated ARBs, is not less than 70%, preferably not less than 75%, and more preferably not less than 85% of the label claim of ARB at 30 minutes of the dissolution study.
Total impurities content in ARB compositions comprising non-granulated ARBs, as determined by liquid chromatography, is not more than 7%, preferably not more than 6%, more preferably not more than 5.5%, and most preferably not more than 5%.
Storage stability of ARB compositions comprising non-granulated ARBs
was studied in one or more of the following conditions:
Accelerated Storage Conditions:
i) 400C ± 20C and 75% ± 5 % relative humidity (400C/75%RH)
Room Temperature Storage Conditions:
ii) 300C ± 20C and 75% ± 5 % relative humidity (300C/75%RH) iii) 300C ± 20C and 65% ± 5 % relative humidity (300C/75%RH) iv) 250C ± 20C and 60% ± 5 % relative humidity (250C/60%RH)
After specific time periods of storage, the compositions were analyzed for % ARB content, % total impurities and average cumulative % dissolution of ARB.
The invention is now illustrated with non – limiting examples.
Example 1: Azilsartan kamedoxomil Composition (containing non-granulated azilsartan kamedoxomil and inert excipient granules)

Microcrystalline cellulose (67.7%w/w), mannitol (4.35%w/w) and
croscarmellose sodium (4.30%w/w) were sifted through 30 mesh ASTM and blended for about 10 minutes to form an excipient blend. A solution of fumaric acid (0.64%w/w) and sodium hydroxide (0.22%w/w) in water was added to the excipient blend. The resulting mixture was granulated with a solution of hypromellose (5cps) (3%w/w) in water to give inert excipient granules. The inert excipient granules were dried at about 400C, co-milled and sifted through 20 mesh ASTM. Azilsartan Kamedoxomil (17.07%w/w) and colloidal anhydrous silica (1.0%w/w) were sifted through 30 mesh ASTM and geometrically mixed with the dried and sifted ‘inert excipient granules’ for about 5 minutes. The resulting mix was blended with magnesium stearate (1.75%w/w) (sifted through 60 mesh ASTM) for about 5 minutes to give non-granulated azilsartan kamedoxomil composition. The composition can be compressed into single layer tablets or filled into capsules, to provide a dose equivalent to 20mg, 40mg or 80mg of azilsartan medoxomil.
Example 2: Layered Tablet Composition of Azilsartan kamedoxomil and Amlodipine besylate (containing non-granulated azilsartan kamedoxomil and inert excipient granules)
Non-granulated Azilsartan kamedoxomil layer mix (with inert excipient granules) (percentages calculated by weight of layer):
Microcrystalline cellulose (67.67%w/w), mannitol (4.35%w/w) and croscarmellose sodium (4.30%w/w) were sifted through 30 mesh ASTM and blended for about 10 minutes to form an excipient blend. A solution of fumaric acid (0.64%w/w) and sodium hydroxide (0.22%w/w) in water was added to the excipient blend. The resulting mixture was granulated with a solution of hypromellose (5cps) (3%w/w) in water to give ‘inert excipient granules’. The ‘inert excipient granules’ were dried at about 400C, co-milled and sifted through 20 mesh ASTM. Azilsartan kamedoxomil (17.07%w/w) and colloidal anhydrous silica (1.0%w/w) were sifted through

30 mesh ASTM and geometrically mixed with the dried ‘inert excipient granules’ for about 5 minutes. The resulting mix was blended with magnesium stearate (1.75%w/w) (sifted through 60 mesh ASTM) for about 5 minutes to give non-granulated azilsartan kamedoxomil layer mix.
Amlodipine Besylate Layer Mix (percentages calculated by weight of layer):
Amlodipine besylate (3.86% w/w), microcrystalline cellulose (27.78% w/w), mannitol (25.17% w/w), dibasic calcium phosphate anhydrous (23.98% w/w) and sodium starch glycolate (5% w/w) were sifted through 30 mesh ASTM and blended for about 5 minutes to give a drug mixture. Povidone (2% w/w) was added to sufficient quantity of isopropyl alcohol, and stirred till dissolved, to obtain the granulating solution. The drug mixture was granulated with the granulating solution to obtain drug granules. The granules were dried at about 450C, and co-milled to obtain dried drug granules. The dried drug granules were sifted through 20 mesh ASTM. Microcrystalline cellulose (5.91% w/w), sodium starch glycolate (5%w/w), colloidal anhydrous silica (0.25% w/w), and ferric oxide red (0.06%w/w), were sifted through 40 mesh ASTM and mixed with the dried drug granules for about 5 minutes. Magnesium stearate (1%w/w) was sifted through 60 mesh ASTM and blended with the resultant granules for about 3 minutes to give amlodipine besylate layer mix.
Non-granulated azilsartan kamedoxomil layer mix, and amlodipine besylate layer mix were compressed as bi-layered tablets using 11.5 mm round punches to provide a dose equivalent to 80 mg of azilsartan medoxomil and 5 mg of amlodipine.
Example 3: Layered Tablet Composition of Azilsartan kamedoxomil and Amlodipine besylate (containing non-granulated azilsartan kamedoxomil)

Non-Granulated Azilsartan kamedoxomil Layer Mix (percentages calculated by weight of layer):
Microcrystalline cellulose (52.82%w/w), mannitol (26.36%w/w) and
croscarmellose sodium (4.62%w/w), sodium acetate trihydrate
(0.31%w/w), fumaric acid (0.49%w/w) and propyl gallate (0.15%w/w) were sifted through 30 mesh ASTM and blended for about 10 minutes to obtain an excipient blend. Azilsartan kamedoxomil (13.13%w/w) and colloidal anhydrous silica (0.77%w/w) were sifted through 30 mesh ASTM and blended together for about 10 minutes to obtain the drug blend. The drug blend was geometrically mixed with the excipient blend and further blended for about 15 minutes. The resulting mixture was blended with magnesium stearate (1.35%w/w) (sifted through 30 mesh ASTM) for about 5 minutes to give non-granulated azilsartan kamedoxomil layer mix.
Amlodipine Besylate Layer Mix:
Amlodipine Besylate layer mix was prepared in the same way as provided
in Example 2.
Non-granulated azilsartan kamedoxomil layer mix and amlodipine besylate layer mix were compressed as bi-layered tablets using 12 mm round punches to provide a dose equivalent to 80 mg of azilsartan medoxomil and 5 mg of amlodipine.
Example 4 (Comparative Example): Layered Tablet Composition of Azilsartan Kamedoxomil and Amlodipine Besylate (containing granulated Azilsartan Kamedoxomil)
In contrast to the present invention, in the comparative example, granules of ARB were prepared using the wet granulation method.

Granulated Azilsartan Layer Mix:
Azilsartan kamedoxomil (17.07% w/w), microcrystalline cellulose (61.49% w/w), mannitol (4.35% w/w) and croscarmellose sodium (2.15% w/w) were sifted through 30 mesh ASTM and blended for about 10 minutes to give an excipient blend. The drug blend was granulated with a solution of fumaric acid (0.64%w/w) and sodium hydroxide (0.22% w/w), in water. The drug blend was further granulated with a solution of hypromellose (6cps) (3% w/w) in water to give drug granules. The inert excipient granules were dried at about 400C, and co-milled. The dried drug granules were sifted through 30 mesh ASTM. Microcrystalline cellulose (9.0% w/w), and croscarmellose sodium (2.15% w/w) were sifted through 40 mesh ASTM and blended with the dried drug granules for about 10 minutes. Magnesium stearate (1.29% w/w) was sifted through 60 mesh ASTM and blended with the drug-inert excipient granules mixture to give the granulated azilsartan kamedoxomil layer mix.
Amlodipine Besylate Layer Mix:
Amlodipine besylate layer mix was prepared in the same way as provided
in Example 2.
The granulated azilsartan kamedoxomil layer mix and amlodipine besylate layer mix were compressed as bi-layered tablets using 11.5 mm round, punches to provide a dose equivalent to 80 mg of azilsartan medoxomil and 5 mg of amlodipine.
Evaluation of Compositions Dissolution Study:
Compositions prepared in accordance with Example 2 and Example 3 were analyzed for dissolution of azilsartan kamedoxomil. The dissolution was conducted using the following conditions:

■ Dissolution of azilsartan kamedoxomil was analyzed in 900ml of pH 7.8 phosphate buffer with 1% polysorbate 80, using USP Type II (paddle) apparatus at 50-100rpm and 370C ± 0.50C.
■ Dissolution of amlodipine besylate was analyzed in 500ml of 0.01 N hydrochloric acid, using USP Type II (paddle) at 75prm and 370C ± 0.50C.
Dissolution of azilsartan kamedoxomil and amlodipine is expressed in terms of average cumulative % dissolution at 30 minutes. Table 1 provides the dissolution of azilsartan kamedoxomil and amlodipine from compositions prepared in accordance with Examples 2 and 3.
Table 1: Dissolution study of example 2 and example 3

Composition Average Cumulative % dissolution at 30 minutes

Azilsartan medoxomil Amlodipine
Example 2 84% 96%
Example 3 79% 94%
Storage Stability Study
Compositions prepared in accordance with Example 2 and Comparative Example 4 were packed in aluminum blisters with and without desiccants, and subjected to accelerated and room temperature storage conditions. The compositions were analyzed for impurities, dissolution and % content (assay) of azilsartan kamedoxomil and amlodipine.
a) Impurities: The compositions were analyzed for impurities at various time periods. Limits of the acceptance criteria are:
• % Azilsartan acid impurity A is not more than 5%, preferably not more than 2.5%
• % Single maximum unknown impurity with respect to Azilsartan is not more than 0.5%, preferably not more than 0.2%

• Total impurities (total impurities with respect to azilsartan and amlodipine, both known and unknown) not more than 6%, preferably not more than 5%
Table 2 provides the impurity results of the storage stability study of ARB compositions of example 2 (packed in aluminum blisters without desiccant) and example 4 (packed in aluminum blisters with desiccant) when stored at 300C/75% RH.
Table 3 provides the impurity results of the storage stability study of ARB compositions of example 2 (packed in aluminum blisters without desiccant) and example 4 (packed in aluminum blisters with desiccant) when stored at 250C/60% RH.
Table 2: % Impurities in compositions of examples 2 and 4, when stored at 300C/75% RH

Condition / Time Period % Azilsartan Acid impurity A % Azilsartan - Single
Maximum Unknown
Impurity % Total Impurities
Example 2 / Pack: Aluminum Blisters without Desiccant
Initial 0.68 0.06 1.30
1 Month 1.29 0.07 2.05
3 Months 1.27 0.10 2.07
6 Months 1.52 0.18 3.0
Example 4 (Comparative) / Pack: Aluminum Blisters with De siccant
Initial 0.67 0.11 1.20
1 Month 2.86 0.15 4.20
3 Months 3.98 0.24 6.20

Table 3: % Impurities in compositions of examples 2 and 4, when stored at 250C/60% RH

Time Period % Azilsartan -Acid impurity A % Azilsartan -
Single Maximum
Unknown Impurity) % Total Impurities
Example 2 / Pack: Aluminum Blisters without Desiccant
Initial 0.68 0.06 1.30
1 Month 1.03 0.07 1.64
3 Months 1.28 0.08 2.05
6 Months 1.31 0.09 2.27
Example 4 (Comparative) / Pack: Aluminum Blisters with Desiccant
Initial 0.67 0.11 1.20
1 Month 2.36 0.14 3.40
3 Months 5.29 0.44 7.50
b) Dissolution: The dissolution of azilsartan medoxomil and amlodipine, from the composition of example 2, was analyzed at various time periods using the procedure provided under dissolution study. The results of the dissolution at initial and at 6 months are provided in Table 4.
Table 4: Dissolution of composition of example 2 at initial time period and at 6 months of storage at 300C/65% RH and 250C/60% RH

Condition / Time Period Average Cumulative % Dissolution at 30 minutes

Azilsartan medoxomil Amlodipine
Initial 84% 96%
300C/65% RH 6 months 84% 96%
250C/60% RH 6 months 80% 101%
ARB compositions, prepared in accordance to example 2 and scaled-up to 10,000 tablets, were packed in aluminum blisters with desiccant, and subjected to storage stability studies.

Table 5 provides the storage stability results of the scale-up ARB compositions in terms of total impurities. Table 6 provides storage stability results of the scale-up ARB compositions in terms of dissolution (at 30 minutes) and % content (assay) of azilsartan and amlodipine.
Table 5: Impurities in ARB compositions prepared in accordance with Example 2 after storage at different conditions

Time Period % Azilsartan -Acid impurity A % Azilsartan -
Single Maximum
Unknown Impurity) % Total Impurities
Initial 0.79 0.10 1.44
400C/75% RH 6 Months 2.21 0.44 3.95
250C/60% RH 12 Months 2.27 0.18 3.56
300C/65% RH 6 Months 1.84 0.16 2.93
300C/75% RH 6 Months 1.59 0.14 2.57
Table 6: Dissolution and % content (assay) of azilsartan and amlodipine from ARB compositions after storage at different conditions

Condition / % Content Average Cumulative % Dissolution at 30 minutes
Time Period Azilsartan medoxomil Amlodipine besylate Azilsartan medoxomil Amlodipine besylate
Initial 103.7 98.7 105 96
400C/75% RH 6 Months 99.3 96.1 97 89
250C/60% RH 12 Months 106.2 95.2 104 91
300C/65% RH 6 Months 101.7 94.5 99 94
300C/75% RH 6 Months 107.6 96.2 101 94

As seen in Tables 2 and 3, the compositions of the present invention (Example 2), comprising non-granulated ARBs, showed significantly lower impurity levels, which were well within the limits of the acceptance criteria, when stored for 6 months in aluminum blister packs devoid of desiccants, while the composition comprising granulated ARBs (Comparative Example 4) showed significantly high levels of impurities (beyond the limits of the acceptance criteria) after just 3 months of storage, even in presence of a desiccant in the aluminum blister pack.
As seen in Table 5, the compositions of the present invention, comprising non-granulated ARBs, showed significantly lower impurity levels which were well within the acceptance criteria, even at 12 months of storage under room temperature conditions.
As seen in Tables 4 and 6, the compositions of the present invention, comprising non-granulated ARBs, showed no significant change in the dissolution of azilsartan kamedoxomil and amlodipine besylate, even at 12 months of storage under room temperature conditions.
Thus, the present invention provides simple, easily scalable, and industrially economical compositions comprising non-granulated ARB, which effectively achieve the desired dissolution as well as the desired storage stability.

WE CLAIM
1. A stable, oral composition comprising at least one angiotensin II receptor blocker (ARB) and at least one excipient, wherein the ARB is non-granulated, and wherein the excipient is selected from a non-granulated excipient and inert excipient granules.
2. The stable oral composition as claimed in claim 1 wherein the composition is in the form of powder, single layered compressed tablet, bi-layered compressed tablet, multi-layered compressed tablet, capsule, or a combination thereof.
3. The stable oral composition as claimed in claim 1 wherein the composition further comprises one or more excipients selected from diluents, binders, disintegrants, antioxidants, pH modifying agents, surfactants, lubricants, and glidants.
4. The stable oral composition as claimed in claim 3 wherein the pH modifying agent is selected from metal oxides, metal hydroxides, carbonates, acetates, silicates, quaternary ammonium salts, and N-methyl-D-glucamine.
5. The stable oral composition as claimed in claim 1 wherein the composition further comprises at least one other active agent selected from an antihypertensive agent or a hypoglycemic agent.
6. The stable oral composition as claimed in claim 5 wherein the antihypertensive agent is selected from chlorothalidone, chlorothiazide, hydrochlorothiazide, indapamide, amlodipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, diltiazam, verapamil, benazepril, captopril, delapril, enalapril, fosinopril, imidapril, lisinopril, perindopril, quinapril, ramipril, and their

pharmaceutically acceptable salts, esters, solvates, and hydrates thereof;
7. The stable oral composition as claimed in claim 5 wherein the hypoglycemic agent is selected from repaglinide, nateglinide, glimepiride, glibenclamide, gliclazide, glipizide, metformin, miglitol, acarbose, pioglitazone, rosiglitazone, sitagliptin, vildagliptin, alogliptin, saxagliptin, dapagliflozin, empagliflozin, canagliflozin, and their pharmaceutically acceptable salts, esters, solvates, and hydrates thereof .
8. The stable oral composition as claimed in claim 5 wherein the composition is in the form of a layered compressed tablet, wherein the non-granulated ARB is in a first layer, and the other active agent is in a second layer.
9. The stable oral composition as claimed in claim 8 wherein the first layer is 30% to 90% by weight of the composition.
10. The stable oral composition as claimed in claim 8 wherein the first layer comprises excipient selected from non-granulated excipient and inert excipient granules.