FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
"NOVEL COMPOSITION FOR THE TREATMENT OF HYPERTENSION"
AJANTA PHARMA LTD.
A company incorporated under the laws of India having their office at
98, Ajanta house, Charkop, Kandivali (West)
Mumbai - 400067, Maharashtra, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION:
The present invention relates to a novel composition comprising metoprolol, telmisartan and amlodipine or salts thereof for use in the treatment of hypertension. More specifically, the present invention relates to a pharmaceutical composition comprising metoprolol, telmisartan and amlodipine or salts thereof for once daily administration. The invention also relates to a novel stable composition comprising telmisartan and amlodipine or salts thereof in a single layer and process of preparation thereof.
BACKGROUND OF THE INVENTION
Hypertension is a serious global health issue, affecting millions of patients. It is the number one health related risk factor in India, with the largest contribution to burden of disease and mortality. It contributes to an estimated 1.6 million deaths annually in India, due to ischemic heart disease and stroke. Fifty seven percent of deaths related to stroke and 24% of deaths related to coronary heart disease are related to hypertension. Hypertension is one of the commonest non-communicable diseases in India, with an overall prevalence of 29.8% and a higher prevalence in urban areas of 34% vs. rural prevalence of 28%.
Despite having various antihypertensive agents that have shown their efficacy and safety, the percentage of patients achieving the recommended therapeutic goals is unacceptably low. Although modern antihypertensive drugs are effective, approximately 50% of hypertensive patients fail to achieve the therapeutic goal of blood pressure < 140/90 mmHg with monotherapy and even less patients will be able to achieve new goal of 130/80 mmHg or lower as recommended in new American and European guidelines. Accordingly, there exists a need for new treatment avenues for hypertension that are efficacious and tolerable.
Antihypertensive drug combinations have been used in patients with inadequately controlled hypertension. These combinations are also commercially available.

Despite these available combination therapies, there is a need for newer combinations based on individual patient needs.
SUMMARY OF THE INVENTION:
The present invention provides a composition comprising metoprolol, telmisartan and amlodipine or salts thereof for use in the treatment of hypertension. More specifically, the present invention provides a pharmaceutical composition comprising metoprolol, telmisartan and amlodipine or salts thereof for once daily administration. The invention also provides a novel stable composition comprising telmisartan and amlodipine or salts thereof in a single layer and process of preparation thereof.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides a composition comprising metoprolol, telmisartan and amlodipine or salts thereof for use in the treatment of hypertension. More specifically, the present invention provides a pharmaceutical composition comprising metoprolol, telmisartan and amlodipine or salts thereof, for once daily administration.
The present inventors have found that the composition comprising combination of metoprolol, telmisartan and amlodipine or salts thereof is more effective than the antihypertensive combinations known in the prior art for the treatment of hypertension in some patients. The three drugs are known individually and have been approved for use in the treatment of hypertension. Metoprolol is commercially available as metoprolol succinate tablets or metoprolol tartrate tablets. Metoprolol is a betal-selective (cardio-selective) adreno-receptor blocking agent that works specifically on the heart to slow down the heart rate. It is available in immediate release as well as extended-release dosage forms. Toprol-XL™ tablets, containing metoprolol succinate, is available in extended release form containing either 25, 50, 100 and 200 mg of metoprolol equivalent to its base and is approved for treatment of hypertension as a once daily dose of 25 mg to 100 mg, with bi-weekly dose

adjustment, until optimum blood pressure reduction is achieved. Amlodipine is commercially available as maleate and besylate (benzenesulfonate) salt in the dosage strengths of 2.5 mg, 5 mg and 10 mg equivalent to amlodipine base, sold under the brand name Norvasc™. Amlodipine is a calcium channel blocker approved for the treatment of high blood pressure and coronary artery disease. Telmisartan is an angiotensin II receptor antagonist, which works by blocking the hormone angiotensin II that further relaxes the blood vessels. Telmisartan is generally available in its free acid form, although pharmaceutically acceptable salts such as the sodium or potassium salt may also be used. Telmisartan is commercially available under the brand name Micardis™, in the dosage strengths of 20 mg, 40 mg and 80 mg for the treatment of hypertension and cardiovascular risk reduction. A combination of amlodipine Besylate and telmisartan is also commercially available, as Tywnsta™ in various dosage strengths of 5mg/40mg, 5mg/80mg, 10mg/40mg and 10mg/80mg equivalent to amlodipine base/telmisartan.
The present inventors have found that the composition comprising a combination of metoprolol, telmisartan and amlodipine or salts thereof, fulfils the unmet need of reducing high blood pressure in some patients. Also, as the three drugs are provided in a single dosage form, there is an ease of administration and better patient compliance. In addition, the composition allows for once daily administration at lower approved dosages than those used alone and therefore has lower side effect profile.
The composition may be formulated as a tablet. The tablet may be in the form of a monolayer tablet, with all the active ingredients in one single layer. The tablet may also be formulated in the form of bilayer tablet with two active ingredients in single layer. Each of the three drugs, metoprolol, telmisartan and amlodipine, or salts thereof are present in single layer, or bilayer. Each of these can be in immediate release or in extended-release forms. Preferably, the composition according to the present invention may be formulated as a bilayer tablet, wherein the bilayer tablet comprises a first layer comprising Metoprolol or salts thereof in extended-release

form and a second layer comprising telmisartan and amlodipine or salts thereof in immediate release form.
In another embodiment, the present invention provides a stable pharmaceutical composition comprising an immediate release composition comprising telmisartan or salts thereof, amlodipine or salts thereof, one or more stabilizing agent, at least one polymer and optionally other pharmaceutically acceptable excipients, wherein the immediate release composition is in a single layer. The present inventors have found a way to formulate telmisartan and amlodipine or salts thereof in a single layer so as to obtain a composition which is physically and chemically stable and is feasible for large scale production. Such a composition was not known in the prior art.
In the prior art, the composition of amlodipine and telmisartan was formulated in separate layers. For e.g., even the commercial product, Twynsta®, marketed since 2009, is a bilayer tablet containing amlodipine besylate and telmisartan, wherein amlodipine and telmisartan are present in separate layers. It was known that amlodipine or its salts and telmisartan are not compatible to be formulated as a single layer or could not be combined in a common blend to obtain a stable product. Telmisartan is known to have poor solubility in aqueous systems at the gastrointestinal pH range of 1 to 7 and is therefore formulated with alkaline excipients, for example, Sodium hydroxide and meglumine to meet in vitro and in vivo bioavailability. On the other hand, amlodipine is not stable enough when it gets in direct contact with alkaline excipients used in a telmisartan formulation, as the ester bond in amlodipine molecule is subject to hydrolysis when exposed to alkaline medium. Therefore, since the conditions of stability of both the drugs are different, the conventional approach of directly mixing the active components of combination with the necessary excipients and compressing as a single layer tablet could not be applied to a fixed dose combination of telmisartan and amlodipine or salts thereof.

There were attempts in the art to develop a composition wherein telmisartan and amlodipine or salts thereof were formulated in a single layer. For e.g. CN102008469 discloses single layer tablet composition comprising telmisartan and amlodipine. The reference discloses making telmisartan granules and amlodipine granules separately, then mixing the granules with excipients, and tableting to prepare the single layer tablets. The data at the end of the document gives stability and dissolution results of only 10 days and it can be seen from the tables 1, 2 and 3 that the tablets changes its appearance, indicating instability, within 10 days when subjected to stability studies in 60°C /75% RH and when subjected to light (4500Lx) conditions. KR101883664 discloses single-layer combination tablet containing telmisartan and amlodipine, wherein telmisartan is adsorbed to calcium silicate and granulated, the telmisartan granules are then mixed with a separate admixture of amlodipine with d-mannitol, sodium bicarbonate, and then other excipients are added to this mixture and the composition is tableted. As with other prior art references, the composition disclosed in this patent reference also shows lower dissolution of amlodipine as compared to the commercial product Twynsta®. Further, the process uses calcium silicate and sodium bicarbonate in high amounts, which may increase the size of the tablet, reducing patient compliance. Further, Kim et al discloses single-layered tablet comprising telmisartan and amlodipine, wherein 99.5% anhydrous ethanol is used for granulation of telmisartan potassium; amlodipine is then added in admixture with colloidal silicon dioxide. The use of absolute ethanol makes the process and the composition of the invention not feasible for large scale production and distribution.
The present inventors have developed a composition comprising telmisartan and amlodipine formulated in single layer that is physically and chemically stable and is feasible for large scale production and commercialization.
In a more specific embodiment the invention provides an immediate release composition comprising telmisartan and amlodipine and salts thereof, wherein the

immediate release composition comprises telmisartan granules and amlodipine granules.
In a specific embodiment, the immediate release composition comprises telmisartan granules and amlodipine granules, wherein the telmisartan granules comprises telmisartan or salts thereof, one or more basic agent, at least one polymer and optionally other pharmaceutically acceptable excipients and the amlodipine granules comprises amlodipine or salts thereof, one or more stabilizing agent, at least one polymer and optionally other pharmaceutically acceptable excipients.
In yet another specific embodiment, the immediate release composition comprises telmisartan granules and amlodipine granules, wherein the telmisartan granules comprises telmisartan or salts thereof, one or more stabilizing agent, at least one polymer and optionally other pharmaceutically acceptable excipients and the amlodipine granules comprises amlodipine or salts thereof and optionally other pharmaceutically acceptable excipients.
Specific examples of suitable basic agent that may be used according to the present invention are one or more selected from alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, meglumine (N-methyl-D-glucamine), basic amino acids such as arginine and lysine. Preferred basic agents are sodium hydroxide and meglumine. Examples of suitable polymers that may be used in the composition include, but are not limited to, cellulose and cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose. Presently, preferred polymer is low viscosity grade hydroxypropylcellulose and hydroxypropylmethylcellulose. One or more stabilizing agent is selected from organic acid and polysaccharide. Exemplary organic acids include, but are not limited to, citric acid, ascorbic acid, fumaric acid, lactic acid, maleic acid, malic acid, sorbic acid, tartaric acid and their salts, hydrates or solvates thereof. Preferred organic acid is citric acid. Examples of suitable polysaccharide include but is not limited to pullulan, chitosan, and dextran. More

preferably a suitable polysaccharide is pharmaceutical grade pullulan. Stabilizing agent can be added intragranularly or extragranularly.
Other pharmaceutically acceptable excipients that may be used in the composition include diluents, binders and/or carriers, disintegrating agent, glidant, lubricant and colouring agent. Specific example of suitable diluent that may be used according to the present invention include but is not limited to microcrystalline Cellulose, mannitol, sorbitol, dibasic calcium phosphate and pregelatinized starch etc. Examples of suitable binders are polyvinylpyrrolidone, copolymers of vinyl pyrrolidone with other vinyl derivatives, microcrystalline cellulose, pregelatinized starch, celluloses, cellulose derivatives and gums. Preferred disintegrating agents are selected from croscarmellose sodium (crosslinked carboxymethylcellulose Sodium), Sodium starch glycolate, crospovidone (crosslinked polyvinylpyrrolidone), corn starch, pregelatinized starch, low-substituted hydroxypropylcellulose, microcrystalline cellulose or mixtures thereof. Particularly preferred are sodium starch glycolate and crospovidone. Specific examples of glidants include colloidal silicon dioxide and talc. Particularly preferred glidant is hydrophobic colloidal silicon dioxide. Preferred lubricants are sodium stearyl fumarate and magnesium Stearate. Particularly preferred is magnesium Stearate. In addition, other excipients and adjuvants that may be used are for example HPMC, PEG or PVA based film coating agents, colouring agent including dyes and pigments such as iron oxides.
The immediate release composition according to the invention may comprise may comprise about 0.1 to about 20% wt.%, preferably about 1 to about 15 wt.%, of telmisartan or salts thereof; about 0.1 to about 10 wt.%, preferably about 0.5 to about 5 wt.%, of amlodipine equivalent to its base; about 0 to about 20 wt.%, preferably about 0.1 to about 10 wt.%, of one or more basic agent; about 0.1 to about 20 wt.%, preferably about 0.1 to about 10 wt.%, of polymer; about 0.1 to about 20 wt.%), preferably about 0.1 to about 15 wt.% of stabilizing agent; and optionally include one or more of the following excipients and/or adjuvants in the

amounts indicated: 0.1 to about 50 wt.% of diluents, binders and/or carriers; about 0.1 to about 20 wt.%, of disintegrating agent; 0 to about 5 wt.%, of glidant; 0.1 to about 10 wt.%, of lubricant; and 0 to about 10 wt.%, of colouring agent.
In yet another embodiment, the present invention provides a bilayer tablet comprising a first layer comprising metoprolol or salts thereof in extended-release form and a second layer comprising telmisartan and amlodipine or salts thereof in an immediate release form.
In a preferred embodiment, the present invention provides a bilayer tablet
comprising
a first layer comprising metoprolol or salts thereof, one or more release retarding
agent and optionally other pharmaceutically acceptable excipients, and
a second layer comprising an immediate release composition comprising
telmisartan or salts thereof, amlodipine or salts thereof, one or more stabilizing
agent, at least one polymer and optionally other pharmaceutically acceptable
excipients. The immediate release composition comprising telmisartan or salts
thereof, amlodipine or salts thereof, one or more stabilizing agent, at least one
polymer and optionally other pharmaceutically acceptable excipients, has been
discussed in detail above. Similar immediate release composition can be used in
this embodiment. The pharmaceutically acceptable excipients are as discussed
above.
The release retarding agent may be one or more hydrophilic or hydrophobic
polymers or combination thereof. The hydrophilic polymers that may be used as
release retarding agent according to the present invention may include, but are not
limited to, cellulosic polymers such as methylcellulose, hydroxymethylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose,
hydroxyethylmethylcellulose, hydroxypropylmethylcellulose and acrylic acid polymers such as carbomers. Preferred hydrophilic polymers are hydroxypropylmethylcellulose and carbomer homopolymer. The hydrophobic

polymers that may be used a release retarding agent according to the present invention may include, but are not limited to, ethyl cellulose, glyceryl behenate, hydrogenated castor oil and polymethacrylates. Preferred hydrophobic polymer is ethyl cellulose.
Metoprolol or its salt, one or more release retarding agent and other (optional) pharmaceutically acceptable excipients may be granulated to form a matrix. The metoprolol granules thus prepared may be compressed with the telmisartan composition and amlodipine composition of the second layer to form a bilayer tablet. The first layer comprising metoprolol may be in the form of matrix tablets wherein metoprolol is dispersed with a release retarding agent in a matrix. Alternatively, the extended-release layer may comprise an inert core coated with a layer comprising metoprolol, a release retarding agent and other pharmaceutically acceptable excipient. Such general extended-release compositions are known in the art.
The bilayer tablet composition may comprise about 1 to about 20% wt.%, preferably about 3 to about 10 wt.%, of metoprolol or salts thereof; 0.1 to about 20% wt.%, preferably about 0.1 to about 10 wt.%, of telmisartan or salts thereof; about 0.1 to about 10 wt.%, preferably about 0.5 to about 5 wt.%, of amlodipine equivalent to its base; and about 1 to about 50 wt.%, preferably about 10 to about 30 wt.%, of a release retarding agent; about 0.1 to about 20 wt.%, preferably about 0.1 to about 10 wt.%, of one or more basic agent; and about 0.1 to about 20 wt.%, preferably about 0.1 to about 10 wt.%, of polymer; about 0.1 to about 10 wt.%, preferably about 0.1 to about 5 wt.% of stabilizing agent; The Other pharmaceutically acceptable excipients that may be used include one or more of the following excipients and/or adjuvants in the amounts indicated: 0.1 to about 50 wt.% of diluents, binders and/or carriers; about 0.1 to about 10 wt.%, of disintegrating agent; 0.1 to about 5 wt.%, of glidant; 0.1 to about 5 wt.%, of lubricant; and 0 to about 5 wt.%, of colouring agent.

The present inventors have surprisingly found that the novel composition of the present invention as described above was found to be physically and chemically stable over the shelf life of the product. The present inventors found that, when the composition of telmisartan and amlodipine was prepared without the stabilizing agent and polymer, the resulting composition is not stable and further result in incomplete dissolution of the active ingredients. It is even more remarkable that the present inventors were able to develop stable telmisartan and amlodipine composition in a single layer without using any basic agent in telmisartan composition, which was thought to be essential for its bioavailability {see for e.g. WO2006048208). Further, the process used for manufacturing the composition of the invention is amenable to large scale production. The novel triple combination composition of the present invention offers advantages over monotherapy or dual therapy treatments for hypertension, such as improved adherence, dosing convenience and potentially reduced cost.
In yet another embodiment, the present invention provides process for the preparation of composition of the present invention. The composition of the present invention may be prepared by methods known in the art. The immediate release composition may be prepared by preparing telmisartan granules, amlodipine granules and then compressing the resulting granules with other pharmaceutically acceptable excipients to form a single layer of tablet.
In one embodiment, the preparation of telmisartan granules may include mixing excipients such as diluents and disintegrating agent in a granulator and granulating the mixed blend using telmisartan solution prepared by dissolving telmisartan, one or more basic agent and whole or part of polymer in a suitable solvent, drying and milling telmisartan granules to attain the desired size. Telmisartan granules may further be subjected to top spray granulation using remaining quantity of polymer solution. The preparation of amlodipine granules may include mixing excipients such as diluents and disintegrating agent and at least one stabilizing agent in a granulator, granulating the mixed blend using amlodipine solution prepared by

dissolving amlodipine besylate and polymer in a suitable solvent, drying and milling amlodipine granules to attain the desired size. The amlodipine granules may optionally be mixed with extragranular excipients including diluents and one or more stabilizing agent. In another embodiment, the preparation of telmisartan granules may comprise conventional wet granulation of telmisartan or salts thereof with pharmaceutically acceptable excipients including polymer, one or more stabilizing agent and optionally other suitable excipients. Optionally, the telmisartan granules may further subjected to granulation with polymer solution. The preparation of amlodipine granules may comprise conventional wet granulation of amlodipine or salts thereof with pharmaceutically acceptable excipients. Telmisartan granules and amlodipine granules are then mixed with the disintegrating agent and lubricant and the mixture is ready for compression.
The process of preparation of the bilayer tablet composition of the present invention, involves preparation, individually of metoprolol granules, telmisartan granules and amlodipine granules. The process of preparation of metoprolol granules includes mixing metoprolol or its salts with a release retarding agent and binder and diluent. The mixture can be granulated by for example, wet granulation, dried, milled, mixed with lubricants and other (optional) excipients to prepare metoprolol granules ready for compression. The first layer comprising metoprolol succinate and second layer comprising telmisartan and amlodipine besylate, as prepared above, may be compressed to form a bilayer tablet. The tablet may be film coated with film coating premix dispersion in water.
The composition according to the present invention may comprise from about 25 mg to 100 mg, preferably about 25 mg to 50 mg metoprolol equivalent to its base; from about 10 mg to 160 mg, preferably about 20 to 80 mg of telmisartan equivalent to its base; and from about 1 mg to 20 mg, preferably 2.5 to 10 mg amlodipine equivalent to its base. Preferred dose strengths of metoprolol equivalent to its base are 25 mg and 50 mg; preferred dose strengths of telmisartan equivalent to its are 20 mg, 40 mg, and 80 mg; and preferred dose strengths of amlodipine equivalent to

its base are 2.5 mg, 5 mg, and 10 mg. In a preferred embodiment, the composition comprises metoprolol succinate equivalent to 25 mg or 50 mg of metoprolol base, telmisartan equivalent to 40 mg telmisartan and amlodipine besylate equivalent to 5 mg of amlodipine base. The preferred salts are metoprolol succinate and amlodipine besylate.
The composition according to the present invention may be used to treat hypertension or other cardiovascular diseases such as chronic stable angina, vasospastic angina, stroke, myocardial infarction and congestive heart failure.
It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, the description above as well as the example that follow are intended to illustrate and not limit the scope of the invention.

Examples: Bilayer tablet compositions comprising metoprolol, telmisartan and
amlodipine
Example 1:
Metoprolol succinate granules
Ingredient 25/40/5 mg
Quantity (%) per unit
Metoprolol succinate 4
Microcrystalline cellulose 4.25
Hydroxypropylmethylcellulose 20
Povidone 5
Carbomer homopolymer 4.25
Silicon dioxide 03
Magnesium stearate 0/4
Isopropyl alcohol | q.s
Telmisartan granules
Telmisartan 7
Microcrystalline cellulose 5_14
Mannitol 12
Crospovidone 3
Sodium hydroxide 0^5
Hydroxypropylcellulose (low viscosity grade) 0/7
Meglumine 3
Purified water 1 q.s
Amlodipine besylate granules
Amlodipine besylate L5
Dibasic calcium phosphate 3^5
Microcrystalline cellulose 3
Pregelatinized starch L5
Citric acid monohydrate 5
Sodium starch glycolate 215
Hydroxypropylcellulose (low viscosity grade) 0/7
Dichloromethane/ Methanol (1:3) | q.s
Common lubrication of telmisartan and amlodipine granules
Crospovidone 9
Magnesium stearate _J 0^5
Tablet compression and Film coating
Film coating premix 3
Purified Water | q.s

Manufacturing Process:
A. Preparation of metoprolol succinate granules: Sift metoprolol succinate,
hypromellose, carbomer and microcrystalline cellulose and load the sifted materials
into granulator. Dissolve povidone in isopropyl alcohol with constant stirring. Add
binder solution to the mixed blend for granulation. Pass the wet mass through mill.
Air dry the granules uniformly in the dryer and subsequently dry at 45°C to 55°C.
Mix dried granules with silicon dioxide, hypromellose, iron oxide and magnesium
stearate.
B. Preparation of telmisartan granules: Sift microcrystalline cellulose, mannitol and
crospovidone, and load the sifted materials into granulator. Prepare solution by
dissolving telmisartan, sodium hydroxide, meglumine in purified water. Add
hydroxy propyl cellulose under continuous stirring till a clear solution is obtained.
Preheat the above material at inlet temperature of 60°C± 10°C till the bed
temperature reaches to 35°C± 10°C. Granulate the mixed blend using telmisartan
solution. Dry the granules using inlet temperature of 60°C± 10°C. Sift and Mill the
granules to attain the desired size.
C. Preparation of amlodipine besylate granules: Sift microcrystalline cellulose,
pregelatinised starch, sodium starch glycolate and citric acid monohydrate, and load
the sifted materials into granulator. Take methanol: dichloromethane solvent
mixture in a vessel and dissolve citric acid monohydrate, amlodipine besylate and
hydroxypropyl cellulose. Granulate the mixed blend using amlodipine solution in
granulator. Air dry the granules uniformly in the dryer and subsequently dry at 45°C
to 55°C. Sift and mill the granules to attain the desired size.
D. Mix telmisartan and amlodipine besylate granules in blender and load
crospovidone and magnesium stearate into the blender.
E. Compress first layer comprising metoprolol succinate and second layer
comprising telmisartan and amlodipine granules. Apply final film coating over core
tablet using dispersion of film coating premix in purified water.

Example 2:
| 25/40/5 mg
Ingredient | Quantity per unit %
Metoprolol Succinate Extended Release Layer
Metoprolol Succinate 4
Microcrystalline Cellulose 43
Carbomer Homopolymer 4.25
Povidone 5_2
Hydroxypropylmethylcellulose 20
Isopropyl Alcohol g^s.
Silicon Dioxide 0.2
Magnesium Stearate | 0.5
Telmisartan IR granules
Telmisartan 7
Microcrystalline Cellulose 5^5
Mannitol 13
Crospovidone 3_J
Sodium Hydroxide (X5
Hydroxypropyl Cellulose 2
Meglumine 2
Purified Water | q.s
Amlodipine IR Granules
Amlodipine Besilate L2
Sodium Starch Glycolate 2J6
Microcrystalline Cellulose 5^5
Pregelatinized Starch 3
Hydrophobic Colloidal Silica 0.23
Pullulan 03
Hydroxypropyl Cellulose (X4
Dichloromethane qjs
Methanol qj;
Citric Acid Monohydrate | 1.72
Common lubrication of Telmisartan and amlodipine granules
Crospovidone 9
Colorant 0J
Magnesium Stearate 1 0^5
Film coating
Fiim coating premix 3^5
Isopropyl Alcohol q1s
Dichloromethane | c^s

Manufacturing Process:
A. Prepare metoprolol granules according to example 1.
B. Preparation of telmisartan granules: Sift microcrystalline cellulose, mannitol and
crospovidone, and load the sifted materials into granulator. Prepare solution by
dissolving telmisartan, sodium hydroxide, meglumine in purified water. Add part
of hydroxy propyl cellulose under continuous stirring till a clear solution is
obtained. Preheat the above material at inlet temperature of 60°C± 10°C till the bed
temperature reaches to 35°C± 10°C. Granulate the mixed blend using telmisartan
solution. Dry the granules at product temperature of 60°C± 5°C. Sift and Mill the
granules. Perform top spray granulation of telmisartan granules with remaining
quantity of hydroxypropyl cellulose solution dissolved in water. Dry the granules
at product temperature of 60°C± 5°C, till LOD is not more than 2.5%. Sift and Mill
the granules to attain the desired size.
C. Preparation of amlodipine besylate granules: Sift microcrystalline cellulose,
pregelatinised starch, sodium starch glycolate, hydrophobic colloidal silica and
pullulan, and load the sifted materials in the granulator. Take methanol:
dichloromethane solvent mixture in a vessel and dissolve amlodipine besylate and
hydroxypropyl cellulose. Granulate the mixed blend using amlodipine solution in
granulator. Air dry the granules uniformly in the dryer and subsequently dry at 45 °C
to 55°C. Sift and mill the granules to attain the desired size. Load the dried granules
into blender. Mix Citric acid monohydrate with microcrystalline cellulose and mill
the materials, transfer this material into blender and mix with dried amlodipine
granules.
D. Mix telmisartan and amlodipine besylate granules in blender and load
crospovidone and magnesium stearate into the blender.
E. Compress first layer comprising metoprolol succinate and second layer
comprising telmisartan and amlodipine granules. Apply final film coating over core
tablet using dispersion of film coating premix in isopropyl alcohol and methylene
chloride.

Example 3:
~ I 50/40/5 mg
Ingredient 1 Quantity per unit %
Metoprolol Succinate Extended Release Layer
Metoprolol Succinate 9^4
Microcrystalline Cellulose O
Carbomer Homopolymer 7.9
Povidone 5J)
Hydroxypropylmethylcellulose 18.8
Isopropyl Alcohol qjs.
Silicon Dioxide IJO
Magnesium Stearate 1 0.5
Telmisartan IR granules
Telmisartan 7^9
Microcrystalline Cellulose L2
Mannitol 13.5
Crospovidone 31)
Citric Acid Monohydrate 018
Hydroxypropyl Cellulose (X8
Purified Water | q.s
Amlodipine IR Granules
Amlodipine Besilate L4
Sodium Starch Glycolate 0A
Microcrystalline Cellulose 4^5
Pregelatinized Starch 2J0
Dibasic calcium phosphate anhydrous 5/7
Purified water | q.s
Common lubrication of Telmisartan and amlodipine granules
Sodium Starch Glycolate 3X)
Magnesium Stearate 1 0.5
Film coating
Film coating premix 3X)
Isopropyl Alcohol q^s
Dichloromethane | q^s
Manufacturing Process:
A. Prepare metoprolol succinate granules according to example 1.
B. Preparation of telmisartan granules: Sift telmisartan, microcrystalline cellulose,
mannitol and crospovidone, and load the sifted materials into granulator. Prepare
binder solution by dissolving citric acid and hydroxypropyl cellulose in purified

water. Granulate telmisartan mixed blend using conventional granulation. Dry the granules at 55°C± 5°C.
C. Preparation of amlodipine besylate granules: Sift amlodipine besylate,
microcrystalline cellulose, dibasic calcium phosphate, pregelatinised starch and
sodium starch glycolate and load the sifted materials in the granulator. Prepare
amlodipine granules using conventional granulation. Dry the granules at at 55°C±
5°C.
D. Mix telmisartan granules and amlodipine granules and add sodium starch
glycolate and then lubricate using magnesium stearate.
E. Compress first layer comprising metoprolol succinate and second layer
comprising telmisartan and amlodipine granules. Optionally film coat the core
tablet using dispersion of film coating premix in purified water or isopropyl alcohol
and methylene chloride.
Assay: The assay results showing drug content after storage at 40°C ± 2°C and 75% ± 5% relative humidity for 6 months is given in table 1 below:
Table 1
Period (Months)
SSay Initial 01 02 I 03 06
Metoprolol 97% 96% 98% 97% 96%
Telmisartan 102% 102% 103% 103% 102%
Amlodipine 99% 100% 100% 100% 99%
Dissolution: In vitro dissolution study of the composition of example 3 was carried out after storage at 40°C ± 2°C and 75% ± 5% relative humidity for 6 months. For metoprolol dissolution study, the apparatus used was IP Apparatus 2 Paddle type at 50 RPM and dissolution medium was Phosphate Buffer pH 6.8. For amlodipine and telmisartan dissolution study, the apparatus used was IP Apparatus 2 Paddle type at 75 RPM and the dissolution mediums were 0.01 M and 0.1N hydrochloric acid. The results are given in table 2 below:
Table 2

Period (Months)
Dissolution 1 1 j 1
Initial 01 02 03 06
Metoprolol 15% 15% 15% 15% 14%
lhr
4hr 36% 37% 36% 34% 34%
8~hr 55% 55% 53% 52% 52%
24hr 89% 89% 88% 88% 88%
Telmisartan 104% 103% 102% 95% 98%
Amlodipine 91% 91% 91% 96% 94%

We Claim:
1. A pharmaceutical composition comprising metoprolol, telmisartan and amlodipine or salts thereof for, once daily administration.
2. A stable pharmaceutical composition comprising an immediate release composition comprising telmisartan or salts thereof, amlodipine or salts thereof, one or more stabilizing agent, at least one polymer and optionally other pharmaceutically acceptable excipients, wherein the immediate release composition is in a single layer.
3. The pharmaceutical composition as claimed in claim 2, wherein the immediate release composition comprises telmisartan granules and amlodipine granules.
4. The pharmaceutical composition as claimed in claim 3, wherein the telmisartan granules comprises telmisartan or salts thereof, one or more basic agent, at least one polymer and optionally other pharmaceutically acceptable excipients and the amlodipine granules comprises amlodipine or salts thereof, one or more stabilizing agent, at least one polymer and optionally other pharmaceutically acceptable excipients.
5. The pharmaceutical composition as claimed in claim 3, wherein the telmisartan granules comprises telmisartan or salts thereof, one or more stabilizing agent, at least one polymer and optionally other pharmaceutically acceptable excipients and the amlodipine granules comprises amlodipine or salts thereof and optionally other pharmaceutically acceptable excipients.
6. The pharmaceutical composition as claimed in claim 2, wherein one or more stabilizing agent is selected from organic acid and polysaccharide and the polymer is selected from low viscosity grade hydroxypropylcellulose and hydroxypropylmethylcellulose.

7. The pharmaceutical composition as claimed in claim 6, wherein the organic acid is
selected from citric acid, ascorbic acid, fumaric acid, lactic acid, maleic acid, malic
acid, sorbic acid, tartaric acid and their salts, hydrates or solvates; and the
polysaccharide is selected from pullulan, alginates, chitosan, pectin and dextran.
8. A bilayer tablet comprising
a first layer comprising metoprolol or salts thereof, one or more release retarding agent and optionally other pharmaceutically acceptable excipients, and a second layer comprising an immediate release composition comprising telmisartan or salts thereof, amlodipine or salts thereof, one or more stabilizing agent, at least one polymer and optionally other pharmaceutically acceptable excipients.
9. A bilayer tablet comprising
a first layer comprising metoprolol or salts thereof in extended-release form and a
second layer comprising telmisartan and amlodipine or salts thereof in an immediate
release form, wherein
the first layer comprises metoprolol or salts thereof, one or more release retarding
agent and optionally other pharmaceutically acceptable excipients, and
the second layer comprises telmisartan or salts thereof, amlodipine or salts thereof,
one or more stabilizing agent, at least one polymer and optionally other
pharmaceutically acceptable excipients, wherein the stabilizing agent is citric acid
and the polymer is selected from low viscosity grade hydroxypropylcellulose and
hydroxypropylmethylcellulose.