FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
COMPLETE SPECIFICATION
(SECTION 10)
PHARMACEUTICAL COMPOSITION COMPRISING TELMISARTAN
AND AMLODIPINE"
Glenmark Generics Limited
an Indian Company, registered under the Indian company's Act 1957
and having its registered office
B/2.. Mahalaxmi Chambers, 22 Bhulabhai Desai Road,
Mumbai-400 026
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF INVENTION
The present invention relates to pharmaceutical composition comprising Telmisartan and amlodipine, or pharmaceutically acceptable salts thereof, and to the process of preparation thereof.
BACKGROUND OF THE INVENTION
Telmisartan, chemically described as 4'-[(l, 4'-dimethyl-2 '-propyl [2,6'-bi-lH-benzimidazol]-l'-yl)methyl]-[1,1-biphen yl]-2-carboxylic acid, is an "angiotensin II receptor antagonist". Telmisartan and its use in treatment of hypertension is described in U.S. Patent No. 5,591,762. Amlodipine is a calcium channel blocker, and it is widely used for the treatment and prophylaxis of hypertension. Amlodipine, available as Amlodipine besylate salt is chemically described as 3-Ethyl-5-methyl(4RS)-2-[(2-aminoethoxy)methyl]-4-(2chlorophenyl)-6-methyl-l,4-dihydropyridine-3,5-dicarboxylate benzenesuiphonate. The Tablets of Telmisartan and Amlodipine, are sold under the trade names Micardis® and Norvasc® respectively, for the treatment of Hypertension. Micardis® Tablet is the first commercially available composition of Telmisartan, wherein a water insoluble Telmisartan is dispersed in an alkaline matrix comprising NaOH, Meglumine, etc.
A general treatment of hypertension includes a combination therapy, consisting of calcium channel blockers and angiotensin II receptor. Several combination products, are available for the treatment of hypertension. A recently launched combination product for the treatment of Hypertension is the fixed dose unit combination of Telmisartan and Amlodipine available in United States as TWYNSTA*, by Boehringer Ingelheim, in the form of a bilayer tablet. TWYNSTA®, tablets are formulated in four strengths with a combination of Amlodipine besylate, equivalent to 5 mg or 10 mg or Amlodipine free-base, with 40 mg, or 80 mg or Telmisartan, provided in the four combinations such as: 40/5 mg, 40/10 mg, 80/5 mg, and 80/10 mg. TWYNSTA® bilayer Tablets provides a one layer ;omprising Amlodipine and another layer comprising Telmisartan dispersed in an alkaline matr-.x comprising NaOH, Meglumine, etc.
Boerhringer's, US Patent application No. 20060110450 ('450 patent) discloses a bilayer tablet comprising, first layer consisting of Telmisartan dispersed in a dissolving tablet matrix and second layer consisting of amlodipine dispersed in a disintegrating or eroding tablet matrix. The inventors of 450 patent encountered an unusual problem of incompatibility between Amlodipine and alkaline excipient. while developing the combination product of Telmisartan and amlodipine.

Inventors of '450 patent found that amlodipine component undergoes degradation due to hydrolysis, when it is added to the telmisartan granulate, which comprises alkaline excipients such as NaOH and Meglumine. In order to overcome incompatibility between Amlodipine and alkaline excipient, inventors of '450 patent prepared separate film-coated tablets of telmisartan and amlodipine and filled into capsules. In another approach, amlodipine or its granules/pellets were film coated and mixed with conventional telmisartan matrix. Since both of the above mentioned techniques, faced a problem of either a patient compliance or degradation, inventors of '450 patent finally prepared a bilayer tablet having amlodipine in one layer and Telmisartan in another layer. Telmisartan granulate component, of the bilayer tablet was prepared by spray-drying the mixture comprising, an aqueous solution of telmisartan, a basic agent, a solubilizer and/or crystallization retarder, followed by mixing spray-dried granules with a water-soluble diluent, and other excipients. Subsequently, the telmisartan granulate and amlodipine granulate were compressed into a bilayer tablet.
The prior art teaches relatively difficult and cumbersome techniques for solving the issue of incompatibility. Spray drying of Telmisartan component, followed by the compression of Telmisartan granulate and amlodipine granulate into bilayer tablet is a complex and expensive processes in pharmaceutical industry. Therefore a stable pharmaceutical composition comprising Telmisartan and amlodipine, which are relatively easy to manufacture are highly desired.
SUMMARY OF INVENTION
Despite of the known incompatibilities between amlodipine and telmisartan granulate, inventors of present invention incorporated amlodipine and telmisartan in a single pharmaceutical composition, without compromising the stability of amlodipine.
In one of the major aspects, the present invention provides a stable pharmaceutical composition comprising telmisartan and amlodipine, or hydrates, esters, pharmaceutical^ acceptable salts thereof, substantially dispersed in the single matrix.
In one embodiment, a stable pharmaceutical composition comprises telmisartan and amlodipine, or hydrates, esters, pharmaceutically acceptable salts thereof, substantially dispersed in the single matrix, and less than 0-3% of an impurity associated with amlodipine.

In a preferred embodiment, present invention provides a stable pharmaceutical composition comprising telmisartan and amlodipine besylate, substantially dispersed in the single matrix, and less than 0.3% of an impurity associated with Amlodipine.
In another major aspect, the present invention provides pharmaceutical composition comprising amlodipine or pharmaceutically acceptable salts thereof, wholly encompassing a core comprising telmisartan or hydrates, esters, or pharmaceutically acceptable salts.
In one embodiment, the pharmaceutical composition comprises, amlodipine besylate and atleast one pharmaceutically acceptable excipients, coated upon a core comprising telmisartan or pharmaceutically acceptable salts thereof.
In a preferred embodiment, the pharmaceutical composition comprising, amlodipine besylate and atleast one pharmaceutically acceptable excipients, coated upon a tablet comprising telmisartan or pharmaceutically acceptable salts thereof, is stable.
In another embodiment, present invention provides a process for preparation of pharmaceutical composition comprising, Telmisartan and amlodipine, or hydrates, esters, pharmaceutically acceptable salts thereof, substantially dispersed in the single matrix.
In yet another embodiment, present invention provides a process for preparation of pharmaceutical composition comprising, amlodipine besylate and atleast one pharmaceutically acceptable excipients, coated upon a tablet comprising telmisartan or pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF INVENTION
The present invention provides stable pharmaceutical composition comprising telmisartan and amlodipine, hydrates, esters, or pharmaceutically acceptable salts thereof. The present invention, does not limit to the specific hydrates, esters, or pharmaceutically acceptable salts of telmisartan or amlodipine, however telmisartan in free acid form and amlodipine besylate are preferred for the purpose of present invention.
Preferably the pharmaceutical composition of present invention, is stable, that is, the level of degradation product of Amodipine, especially 3-ethyl 5-methyl 2-{[(2-aminoethoxy)methyl]-4-

(2-chlorophenyl)-6-methylpyridine-3,5-dicarboxylate} called as "Impurity A" is controlled. In a more preferred embodiment, the pharmaceutical composition prepared in accordance with the present invention, has Impurity A, less than 0.3 % by weight relative to amlodipine, after the storage for about 3 months at about 40 degree Celsius and 75% relative humidity.
In one embodiment, present invention provides pharmaceutical composition comprising telmisartan and amlodipine, or hydrates, esters, pharmaceutically acceptable salts thereof, substantially dispersed in the single matrix.
In a preferred embodiment, present invention provides a stable pharmaceutical composition comprising telmisartan and amlodipine besylate, substantially dispersed in the single matrix, wherein Impurity A is less than 0.3% by weight relative amlodipine.
In a preferred embodiment, the composition of present invention comprises, Telmisartan and amlodipine in ratio of about 8:0.5 to about 4:1.
In one embodiment, the present invention provides a stable pharmaceutical composition comprising Telmisartan and Amlodipine or pharmaceutically acceptable salts thereof, wherein Telmisartan and/or Amlodipine or its granules are coated with a film, preferably of a film forming material. For the purpose of present invention, the aforesaid coat is referred to as "film coat" hereinafter in the specification. In an instant case, the pharmaceutical composition comprises a single matrix comprising film coated telmisartan granules, amlodipine or granules thereof, and atleast one pharmaceutically acceptable excipient. In another embodiment, the pharmaceutical composition comprises a single matrix comprising film coated amlodipine granules, telmisartan granules and atleast one pharmaceutically acceptable excipient.
In one embodiment, present invention provides, Telmisartan Granulate comprising about 15-25% of Telmisartan, about 3-12% alkalizing agent, 2-8% of binder and 30-90% of diluents and about 5-15% of disitengrant. by weight relative to the weight of Telmisartan granulate.
The 'film coating" is done by coating either Telmisartan or Amlodipine, or its granules with a film forming polymer selected from the group comprising but not limited to Hydroxypropyl Methylcellulose, Hydroxypropyl cellulose, Hydroxyethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, ethyl cellulose, and methacrylic copolymers preferably Amino Methacrylate

Copolymer like Eudragit E. However for the purpose of present invention the film coating polymer such as Hydroxypropyl Methylcellulose, hereinafter HPMC or Polyvinyl pyrollidone hereinafter PVP, is preferred but HPMC is more preferred. The solution or dispersion of film coating polymer such as HPMC or PVP is sprayed on the Telmisartan or Amlodipine, or its granules, to form a film that partly or completely covers the particles or granules. The solution or dispersion comprising film forming polymers optionally contains plasticizers such as polyethylene glycol.
Preferably the film coated Telmisartan or Telmisartan granules comprises, about 1 to 10%, preferably 3-6%, more preferably about 4.5 % by weight, of film coating material, relative to the weight of Telmisartan or its granule.
In a another preferred embodiment, wherein telmisartan and amlodipine besylate, are substantially dispersed in the single matrix, the telmisartan granules are coated with the film coating materials and further amlodipine powder or its granules mixed with the film coated Telmisartan Granules. Telmisartan granules can be prepared by the methods such as spray drying, wet granulation, and dry granulation methods, however wet granulation is particularly preferred. Preferably Telmisartan granule are prepared by dissolving Telmisartan, an alkalizing agent such as NaOH, meglumine, and PVP in purified water and further spraying the solution over the bed comprising diluents and disintegrant. Further the granules are dried and dried granules are coated a film coating materials such as HPMC. The film coated granules of Telmisartan are then mixed with Amlodipine besylate optionally admixed with diluents, and disintegrant. The mixture thus obtained is lubricated by using the Lubricant such as Magnesium stearate and compressed into a Tablet, that comprises Telmisartan and Amlodipine besylate dispersed in a single matrix.
The final composition prepared in accordance of present invention comprises I to 40 % telmisartan, 1 to 30 % binder, I to 10 % alkalizing agents, 1 to 50 % diluent, 1 to 20 % disintegrant and 0.1 to 10 % of film coating polymer and 1 to 40 % of amlodipine besylate, 0.1 to 10 % lubricant, by weight relative to the total weight of pharmaceutical composition.
The pharmaceutical composition of the present invention can be provided in the form of a tablet, capsule, granules or pellets, however a tablet is more preferred.
In one embodiment, the pharmaceutical composition of present invention, on storage for about three months, at 40 Deg C Temperature and at 70% Relative humidity, contains impurity A, less

than 0.3%. preferably less than 0.2%, more preferably less than 0.1%, by weight relative to the amlodipine.
In another embodiment, the pharmaceutical composition of present invention, releases not less than 70 % of telmisartan and not less than 70 % of amlodipine, within 30 minutes, after an exposure to the 0.01 N HC1, at 500 RPM in USP type II Apparatus.
In another major aspect, the present invention provides pharmaceutical composition comprising amlodipine hydrates, esters, or pharmaceutically acceptable salts thereof, with or without pharmaceutically acceptable excipients, wholly encompassing a core of telmisartan or hydrates, esters, or pharmaceutically acceptable salts. In an alternative option a Telmisartan wholly encompass the core comprising Amlodipine.
In the present aspect of this invention, amlodipine layer completely encircles the Telmisartan core. The core of present invention may be a Telmisartan alone or the granules, pellets, tablets, minitablets, microtablet comprising Telmisartan. However tablet or a mini-tablet is more . preferred.
In a preferred embodiment, present invention provides a stable pharmaceutical composition comprising, amlodipine preferably amlodipine besylate, with or without pharmaceutically acceptable excipients, wholly encompassing a tablet comprising telmisartan or pharmaceutically acceptable salts thereof.
In a yet another embodiment, a stable pharmaceutical composition comprises, amlodipine preferably amlodipine besylate, with atleast one pharmaceutically acceptable excipients, wholly encompassing a tablet comprising telmisartan or pharmaceutically acceptable salts thereof, wherein the amount of impurity A associated with amlodipine is less than 0.3 % by weight, relative to amlodipine.
In yet another embodiment, a stable pharmaceutical composition comprises, telmisartan, with or without pharmaceutically acceptable excipients, wholly encompassing a core or tablet comprising amlodipine or pharmaceutically acceptable salts thereof.
In one embodiment, a core comprising Telmisartan, is coated with a solution or a dispersion comprising Amlodipine, optionally containing a binder and plasticizer. The composition of

Telmisartan core is same as that of explained above. The binder is selected from the group comprising HPMC, PVP, HPC, HEC. The amlodipine layer of present invention is 0.1 to 10%, more preferably about 3% by weight relative to total composition.
In a preferred embodiment, the telmisartan core is coated with a coating solution or dispersion consisting of amlodipine, preferably amlodipine besylate, and HPMC of viscosity 3 Cps. The said composition contains an Impurity A. less than 0.2%, preferably less than 0.1%, by weight, relative to the weight of amlodipine, after subjecting to the temperature of about 40 Deg C and Relative humidity of 75 RH, for about three months.
The pharmaceutical composition of present invention comprises diluents, alkalizing agents, binders, disintegrants, lubricants. The suitable diluents can be selected from lactose monohydrate, lactose, sugar, starches, modified starches, mannitol, sorbitol, inorganic salts, cellulose and cellulose derivatives (e.g. microcrystalline cellulose), calcium hydrogen phosphate, calcium sulfate, xylitol and lactitol, preferably lactose.
The suitable alkalizing agent is selected from alkali metal hydroxides, such as sodium or potassium hydroxide; sodium or potassium bicarbonate, sodium or potassium carbonate, sodium or potassium biphosphate, basic amino acids such as arginine, and meglumine (N-methyl-D-glucamine), preferably sodium hydroxide and/or meglumine.
The suitable binders may include polyvinylpyrrolidone, lactose, starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, copolyvidone, gelatin and sodium alginate, preferably polyvinylpyrrolidone.
The suitable disintegrants may include crospovidone. crosscaramellose sodium, polyvinylpyrrolidone, sodium starch glycolate, corn starch, potato starch, microcrystalline cellulose; low substituted hydroxypropyl cellulose, preferably crospovidone.
The suitable lubricants may be selected from magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, silica, carnauba wax, hydrogenated vegetable oils, mineral oil, PEG and sodium stearyl fumarate. preferably magnesium stearate.

The pharmaceutical composition may in addition comprise-of additional excipients like flavoring. coloring and sweetening agents, preservatives, stabilizers, anti-oxidants, anti-adherents or glidants as appropriate.
The present invention provides a process for the preparation of pharmaceutical composition comprising telmisartan and amlodipine besylate substantially dispersed in the single matrix, which includes, (a) preparing telmisartan granules by wet granulation, (b) seal coating the telmisartan granules with film coating polymers (c) dry processing amlodipine besylate (d) subsequently mixing (b) & (c) and filling then in to capsules or compressing them in to a single layered tablet.
In another preferred embodiment, the present invention provides a process for preparing a stable pharmaceutical composition comprising telmisartan and amlodipine dispersed in a single matrix, comprising the following steps:
1. Dissolving basic agent and binder in weighed purified water and stirring.
2. Adding Telmisartan to the solution of step 1 under continuous stirring.
3. Co-sifting disintegrant and filler and transferring this blend to fluidized bed granulator.
4. Spraying solution of step 2 over the blend of step 3 and drying the obtained granules.
5. Passing the dried granules obtained from step 4 through a suitable mesh to get desired size of the telmisartan granules.
6. Optionally seal coating the telmisartan granules and drying.
7. Blending telmisartan granules from step 5 or 6, extragranular lubricant and amlodipine and compressing the blend in to tablet.
In a preferred embodiment, the telmisartan granules may be seal coated with HPMC 3 cps.
In another embodiment, present invention provides a process for the preparation of pharmaceutical composition comprising, amlodipine besylate coat wholly encompassing, a tablet comprising of telmisartan that includes (a) preparing tablet comprising telmisartan granules prepared by wet granulation, (b) optionally applying a seal coating the telmisartan tablet with a film forming polymers (d) preparing a coating solution containing amlodipine and optionally a binder and applying it on Telmisartan tablet.

In a preferred embodiment, the present invention provides a process for preparing a stable pharmaceutical composition comprising amlodipine besylale, wholly encompassing a core of telmisartan comprising the following steps:
1. Dissolving basic agent and binder in weighed purified water and stirring.
2. Adding telmisartan to the solution of step 1 under continuous stirring.
3. Co-sifting disintegrant and filler and transferring this blend to fluidized bed granulator.
4. Spraying solution of step 2 over the blend of step 3 and drying the obtained granules.
5. Passing the dried granules obtained from step 4 through a suitable mesh to get desired size of the telmisartan granules.
6. Blending the granules of step 5 with adiluent, disintegrant and lubricant and compressing the blend in to a tablet.
7. Optionally seal coating the telmisartan table of step 6 and drying.
8. Blending telmisartan granules from step 5 or 6, extragranular lubricant and amlodipine and compressing the blend in to tablet.
9. Making a polymer disf ersion of amlodipine besylate.
10. Coating the telmisartan core tablets of step 6 or 7 with the drug coating solution step 9.
In a preferred embodiment, the telmisartan core tablets may be seal coated with HPMC 3 cps.
While the present invention is disclosed by reference to the preferred embodiments and examples below, it is understood that these examples are intended in an illustrative, rather than in a limiting sense. It is contemplated that modifications and combinations will readily occur to those skilled in the art, which modifications and combinations will be within the spirit of the invention.

EXAMPLES
Example I:

Sr.
No. Ingredient Qty/Tab. (in mg)
1. Telmisartan 80.00
2. Sodium hydroxide 6.70
3. Povidone (Plasdone K 25) 24.00
4. Meglumine 24.0
4. Purified water qs
5. Lactose monohydrate (Pharmatose DCL 11) 268.5
7. Crospovidone (Polyplasdone XL l0) 35.00
8. Ferric oxide red(Sicovit Red) 0.5
Total 438.7
Seal coat
9. Hypromellose (3cps) 21.935
Extragranular
10. Amlodipine besylate 13.90
11 Magnesium stearate 4.0
Tablet Weight 479.00
Manufacturing Process:
1. Telmisartan along with Sodium Hydroxide, PVP K- 25 and meglumine were dissolved in Purified Water. This solution was used as the granulation fluid.
2. Lactose Monohydrate, PVP K-25 and Crospovidone XL 10 were sifted through ASTM mesh # 30.
3. The pre granulation blend of step no. 2 was then transferred to the bowl of Top Spray Fluid Bed Processor.

4. The blend of step no. 3 was preheated till the product bed temperature reached 28-30°C.
5. The solution of step no. 1 was sprayed to the preheated blend of step no. 4 & spraying was continued till the whole solution was completely sprayed, taking precaution that there are no lumps formed in the blend during spraying & the product temperature is maintained between 30-35°C.
6. Once the granulating fluid was completely sprayed, the granules were then dried in the same Fluid Bed Processor till the LOD (loss on drying) of the dried granules was found to be less than 2.0%w/w.
7. The dried granules of step no. 6 were then passed through ASTM mesh # 20.
8. The dried granules of step no. 7 was then seal coated with HPMC (3cps) in GLATT and then mixed extragranularly with Amlodipine besylate and sifted through ASTM mesh # 30 & blended in the Bin Blender for 10 minutes.
9. The blend of step no. 8 was then finally mixed with Magnesium Stearate sifted through ASTM mesh # 40 in the same blender for 5 minutes.
10. The blend of step no. 9 was then readily compressed into tablets.
Example II:

Sr.
No. Ingredient Qty/Tab.
(in mg)
1. Telmisartan 80.00
2. Sodium hydroxide 6.70
3. Povidone (Plasdone K 25) 24.00
4. Meglumine 24.0
5. Purified water qs
6. Lactose monohydrate (Pharmatose DCL 11) 269.0
7 Crospovidone (Polyplasdone XL l0) 35.00
Total 438.7
Seal coat
8. Hypromellose (3cps) 21.935
Extragranular

9 Amlodipine besylate 13.98
10. Microcrystalline ceiIuiose(AviceI PH 112) 115
11 Pregelatinised starch(Starch 1500) 42.39
12 Crospovidone (Polyplasdone XL 10) 35
13 DCP (Dicalcium Phosphate)(Di-Tab) 57.0
14 Sodium starch glycollate 8.0
15 Talc 10.0
16 Magnesium staearate 8.0
Tablet Weight 750.0
Manufacturing Process:
1. Telmisartan along with Sodium Hydroxide, PVP K- 25 and meglumine were dissolved in Purified Water. This solution was used as the granulation fluid.
2. Lactose Monohydrate, PVP K-25 and Crospovidone XL 10 were sifted through ASTM mesh # 30.
3. The pre granulation blend of step no. 2 was then transferred to the bowl of Top Spray Fluid Bed Processor,
4. The blend of step no. 3 was preheated till the product bed temperature reached 28-30°C.
5. The solution of step no. 1 was sprayed to the preheated blend of step no. 4 & spraying was continued till the whole solution was completely sprayed, taking precaution that there are no lumps formed in the blend during spraying & the product temperature is maintained between 30-35°C.
6. Once the granulating fluid was completely sprayed, the granules were then dried in the same Fluid Bed Processor till the LOD of the dried granules was found to be less than 2.0%w/w.
7. The dried granules of step no. 6 were then passed through ASTM mesh # 20.
8. The dried granules of step no. 7 was then seal coated with HP1V1C (3cps) at GLATT and then mixed extragranularly with Amlodipine besylate ,Avicel PH 112, Pregelatinised starch ,Crospovidone XL 10, and Di-Tab, and SSG and sifted through ASTM mesh # 30 & blended in the Bin Blender for 10 minutes.

9. The blend of step no. 8 was then finally mixed with Talc and Magnesium stearate sifted through ASTM mesh # 40 in the same blender for 5 minutes.
10. The blend of step 9 was then compressed
Example III:

Sr.
No. Ingredient Qty/Tab.
(in mg)
1 Telmisartan 80.0
2 Sodium hydroxide 6.7
3 Povidone(k-25) 24
4 Meglumine 24
5 Purified water qs
6 Lactose monohydrate(DCL-l 1) 269
7 Crospovidone XL 35
Total 438.7
Seal coat
8 HPMC( 3CPS) 2208 21.93
9 Purified water qs
'J btal 460,63
10 Crospovidone XL 35
11 Microcrystalline cellulose (Avicel PH l02) 168.29
Lubrication stage
12 Amlodipine besylate 13.98
13 Talc 12.6
14' Magnesium stearate 9.5
Total 700 mg
Manufacturing Process:
1. Telmisartan along with Sodium Hydroxide, PVP K- 25 and meglumine were dissolved in Purified Water. This solution was used as the granulation fluid

2. Lactose Monohydrate, PVP K-25 and Crospovidone XL 10 were sifted through ASTM mesh #30.
3. The pre granulation blend of step no. 2 was then transferred to the bowl of Top Spray Fluid Bed Processor.
4. The blend of step no. 3 was preheated till the product bed temperature reached 28-30°C.
5. The solution of step no. J was sprayed to the preheated blend of step no, 4 & spraying was continued till the whole solution was completely sprayed, taking precaution that there are no lumps formed in the blend during spraying & the product temperature is maintained between 30-35°C.
6. Once the granulating fluid was completely sprayed, the granules were then dried in the same Fluid Bed Processor till the LOD of the dried granules was found to be less than 2.0%w/w.
7. The dried granules of step no. 6 were then passed through ASTM mesh # 20.
8. The dried granules of step no. 7 was then seal coated with HPMC (3cps) in GLATT and then mixed extragranularly with Avicel PH 102, Crospovidone XL and sifted through ASTM mesh # 30 & blended in the Bin Blender for 10 minutes.
9. The blend of step no. 8 was then finally mixed with amlodipine besylate, Talc and Magnesium stearate sifted through ASTM mesh # 40 in the same blender for 5 minutes.
10. The blend of step 9 was then ready for compression.
Stability data:
The pharmaceutical composition prepared in example III was subjected to an accelerated stability test (3 months. 40 degree Celsius, 75 % relative humidity). The results are as shown in table I. Table I:

Tablet Condition Impurity A (% weight relative to amlodipine)
Innovator
Twynsta
80/10 tng
Tablets Initial 0.07

1 M 40/75 0.06

2 M 40/75 0.08

3 M 40/75 0.07
Example
in Initial 0.07

1 M 40/75 0.07

2 M 40/75 0.06

3 M 40/75 0.06

Dissolution data:
The pharmaceutical composition prepared in example III was subjected to dissolution testing in 0.01 N HC1, USP II, 500 rpm. The results are as shown in table II.
Table II:

Time Innovator
Twynsta
80/10 mg
Tablets Example III
Telmisartan 10 36 58

20 71 83

30 93 88

45 96 91

60 96 93
Amlodipine 10 87 52

20 91 73

30 91 77

45 91 79

60 92 81
Example IV:

Sr. No. Ingredient Qty/Tab.
(in mg)
1. Telmisartan 80.00.
2. Sodium hydroxide 6.70
3. Povidone (Plasdone K 25) 24.00
4. Meglumine 24.0
5. Purified water qs
Base Intragranular excipients

6 Crospovidone (PolyplasdoneXL l0) - 12.0
7 Lactose monohydrate (DCL-11) 269
Extragranular Excepients
8 Lactose monohydrate (DCL-11) 146.8
9 Crospovidone (PolyplasdoneXL l0) 12.0
10 Sodium starch glycollate 20.0
11 Magnesium stearate 6.0
Total 600
Seal coating
12 Hypromellose (3 cps) 18.0
13 Purified water q.s
Total 618.0
14 Amlodipine besylate 13.98
15 Hypromellose (3 cps) 12.1
16 Purified water qs
Total 644
Manufacturing Process:
1. Telmisartan along with Sodium Hydroxide, PVP K- 25 and meglumine were dissolved in Purified Water. This solution was used as the granulation fluid.
2. Lactose Monohydrate, PVP K-25 and Crospovidone XL 10 were sifted through ASTM mesh #30.
3. The. pre granulation blend of step no. 2 was then transferred to the bowl of Top Spray Fluid Bed Processor.
4. The blend of step no. 3 was preheated till the product bed temperature reached 28-30°C.
5. The solution of step no. 1 was sprayed to the preheated blend of step no. 4 & spraying was continued till the whole solution was completely sprayed, taking precaution that

there are no lumps formed in the blend during spraying & the product temperature is maintained between 30-35°C.
6. Once the granulating fluid was completely sprayed, the granules were then dried in the same Fluid Bed Processor till the LOD of the dried granules was found to be less than 2.0%w/w.
7. The dried granules of step no. 6 were then passed through ASTM mesh # 20.
8. The dried granules of step 7 were mixed with DCL-11, CROSPOVIDONE XL 10, SSG and lubricated with Magnesium stearate.
9. The blend of step no. 8 was then compressed.
10. The compressed tablets of step 9 are seal coated with HPMC (3cps).
11. Amlodipine was placed in previously prepared HPMC (3CPS) solution and stirred and it was coated to the Seal coated telmisartan tablets of step 10.
Tablets of example IV were also subjected to the stability studies, and were found to contain impurity A less than.0.2%.

Claims
1. A stable pharmaceutical composition comprising telmisartan and amlodipine besylate, wherein telmisartan and amlodipine besylate are dispersed in a single matrix.
2. A stable pharmaceutical composition comprising telmisartan and amlodipine besylate dispersed in a single matrix, wherein the impurity associated with amlodipine is less than 0.3 % weight relative to amlodipine besylate.
3. The pharmaceutical composition of claim 1, in the form of single layered tablet.
4. A stable pharmaceutical composition comprising a coat of amlodipine besylate and other pharmaceutical excipients, wholly encompassing a core comprising telmisartan and other pharmaceutical excipients.
5. A stable pharmaceutical composition comprising a coat of telmisartan and other pharmaceutical excipients, wholly encompassing a core comprising amlodipine besylate and other pharmaceutical excipients.
6. A stable pharmaceutical composition according to claim 5 or 6, wherein the impurity associated with amlodipine is less than 0.3 % weight relative to amlodipine besylate.