FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1 TITLE OF THE INVENTION:
"TELMISARTAN COMPOSITIONS"
2. APPLICANT (S):
(a) NAME: FDC Limited
(b)NATIONALITY: Indian company incorporated under the Companies Act 1956
(c) ADDRESS: 142-48, S.V. Road, Jogeshwari (West), Mumbai - 400 102, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention and the manner in which it is to be performed

Related application:
This application claims priority from our earlier applications No. 1715/MUM/2009 filed on 27/07/2009 and Application No.ll43/MUM/2010 filed on 05/04/2010.
Technical field of the invention:
The present invention is directed to a solid oral pharmaceutical composition comprising the angiotensin II receptor antagonist, Telmisartan, without use of surfactant or emulsifier and yet having good disintegration and dissolution properties. The present invention further provides a solid oral pharmaceutical composition comprising telmisartan in an amount of 5% to 30%, atleast one water soluble diluent in an amount of 1% to 25%, atleast one basic agent in an amount less than 9 % of the total weight of the composition, optionally one or more water insoluble diluents, alongwith pharmaceutically acceptable excipients.
Background and prior art:
Telmisartan is a non-peptide angiotensin II receptor antagonist. Its chemical name is 4'-[2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yl)-benzimidazol-l-ylmethyl]-biphenyl'2-carboxylic acid. The molecular structure of Telmisaratan is represented as:

Telmisartan is a type of angiotensin II receptor blocker that is prescribed for the treatment of high blood pressure. The medication, which causes blood vessels to relax, has proven

to be effective in lowering both systolic and diastolic blood pressure. Telmisartan with a long duration of action, shows no evidence of drug accumulation after repeated administration. A t1/2 of approximately 24 hours for telmisartan, considerably longer than that observed with other agents in this class (all ≤15 hours), ensures that it will provide consistent and sustained reductions in blood pressure over 24 hours, with extensive clinical evidence and data from the community setting confirming this. In patients with mild-to-moderate hypertension, telmisartan monotherapy or in combination with other antihypertensive agents, provides effective antihypertensive efficacy throughout the dosage interval, with the drug being at least as effective as comparators. Telmisartan treatment resulted in greater antihypertensive efficacy than that achieved with the angiotensin II receptor antagonists losartan or vaisartan, and was shown to be superior to fixed-dose losartan/HCTZ.
Telmisartan is manufactured and supplied in the free acid form. It is characterized by very poor solubility in aqueous systems at the physiological pH range of the gastro- intestinal tract between pH 1 to 7. Crystalline telmisartan exists in two polymorphic forms having different melting points. Under the influence of heat and humidity, the lower melting polymorph B transforms irreversibly into the higher melting polymorph A. In addition telmisartan can be prepared in amorphous form, i.e as a kind of solidified solution having a glass transition temperature Tg of >50 ° C or preferably >80° C.
U.S Patent No. 5591762 describes telmisartan and pharmaceutically acceptable salt thereof useful in the treatment of hypertension. It also describes application of such compound for treating pulmonary diseases like oedema and chronic bronchitis, for preventing arterial re-stenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and also for preventing arteriosclerosis and diabetic angiopathy.
U.S Patent No, 6358986 describes mixture of polymorphic crystalline form A and form B of telmisartan, wherein form A has an endothermic maximum at 269+ 2° C and form B has an endothermic maxima at 183+ 2° C and 269+ 2° C which occurs during thermal analysis using DSC. After melting, the lower melting form B of telmisartan crystallises out again as a form A, resulting in the endothermic maximum at 183+ 2° C followed by

exothermic maximum, which reflects the crystallisation of melt of form B into high melting form A.
U.S Patent application No. 20040110813 describes solid Telmisartan pharmaceutical formulations. Telmisartan exists in 2 polymorphic forms Form A and Form B. Both the polymorphs have solubility in pH range of 1 to 7. This patent application further describes pharmaceutical composition comprising 3% to 50% telmisartan dispersed in dissolving matrix comprising a basic agent in molar ratio of basic agent: Telmisartan of 1:1 to 10: [1|, a surfactant or emulsifier in an amount of about 1 to 20 wt % of the final composition, 25 to 70 wt % of a water soluble diluent, and optionally 0 to 20 wt. % of further excipients and/or adjuvants,
U.S Patent application No 2009/0030057 describes pharmaceutical compositions of Telmisartan comprising at least one water insoluble diluent, a basic agent, a surfactant, and a binder, wherein the amount of water insoluble diluents in the pharmaceutical granulate is about 40% to about 70% by weight of the pharmaceutical granulate. The composition further comprises one or more diluents, wherein the amount of water soluble diluents is less than 25% of the pharmaceutical granulate. Telmisartan in the composition amounts from about 12.5% to about 15 % of the total weight of the composition.
WO2009004064 describes process for the preparation of telmisartan intermediate and further converting such intermediate to telmisartan and/or salts thereof. It further describes pharmaceutical composition containg telmisartan or a derivative thereof, a basic agent and water soluble diluent, in an amount greater than 70% per weight of the total composition, wherein the formulation does neither comprise a surfactant nor a water insoluble diluent.
The above prior arts suffer from one or more drawbacks. Most of the prior art mentions preparation of composition by either spray drying or fluidized bed processing for granulating wet mass. Although both these processes are sophisticated and advanced, they call for more stringent control over critical process parameters and optimization of such process for the composition containing high portion of water soluble diluent like sorbitol

is difficult. Also composition which uses high portion of water soluble diluent has tendency to become hygroscopic.
The above constraints have been overcome by the present invention. Accordingly, the present invention provides a solid oral pharmaceutical composition comprising telmisartan in an amount of 5% to 30%, atleast one water soluble diluent in an amount of 1% to 25%, atleast one basic agent in an amount less than 9 % of the total weight of the composition, optionally one or more water insoluble diluents and other pharmaceutically acceptable excipients.
Further it has been surprisingly found in the present invention that such solid oral pharmaceutical compositions of telmisartan can be prepared without use of surfactant or emulsifier, and yet have good disintegration and dissolution properties which give immediate and complete drug release.
Object of the invention:
The primary objective of the present invention is to provide a bioavailable solid oral pharmaceutical composition of telmisartan, which is free of surfactant or emulsifier.
Another object of the present invention is to provide a solid oral pharmaceutical composition of telmisartan having good disintegration and dissolution properties which further provides rapid and complete drug release.
Yet another objective of the invention is to provide a process for preparing solid oral pharmaceutical composition of Telmisartan using simple granulation process, thereby offering cost effective technology.
It is another object of the invention to prepare composition of telmisartan using lesser amount of basic agent.
Summary of the invention:

In accordance with the above objectives, the present invention is directed to a solid oral pharmaceutical composition of Telmisartan without use of surfactant or emulsifier, and yet having good disintegration and dissolution properties. The present invention further provides a solid oral pharmaceutical composition comprising telmisartan in an amount of 5% to 30%, atleast one water soluble diluent in an amount of 1% to 25%, atleast one basic agent in an amount less than 9 % of the total weight of the composition, optionally one or more water insoluble diluents, and other pharmaceutically acceptable excipients. The present invention also provides process for manufacturing such compositions using simple granulation process.
Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and
optional embodiments, so that various aspects thereof may be more fully understood and
appreciated
Accordingly, the present invention provides a solid oral pharmaceutical composition
comprising
A) an active ingredient
B) diluent(s)
C) basic agent(s)
D) other pharmaceutically acceptable excipients
The active ingredient for the purpose of the present invention is telmisartan prepared through a synthetic process. The amount of telmisartan in the compositions of the invention varies in an amount of 5% to 30% by weight of total formulation.
Telmisartan is a white to slightly yellowish, odorless crystalline powder. It is practically insoluble in water and in the pH range of 3 to 9, and is sparingly soluble in a strong acid except hydrochloric acid. Telmisartan is soluble in a strong base.
A basic agent is added to the pharmaceutical composition to solublize telmisartan, and the resulting solution is used for granulating a mixture of diluent(s) and disintegrant(s) in the manufacturing process, as well as for controlling the pH of composition. Basic agent used

in the formulation is selected from group consisting of but not limited to alkali metal hydroxides, alkaline hydroxide, alkaline phosphates, alkaline carbonates, meglumine, veegum and basic amino acids such as arginine. Total basic agent used in the formulation is less than 9% preferably less than 7% by weight of the total composition.
Accordingly, in one embodiment, the composition of the present invention comprises telmisartan in an amount of 5% to 30% w/w; preferably 7% to 25% w/w; more preferably 8% to 20% w/w; still more preferably 9% to 16% w/w of the formulation.
The term 'diluent(s)' herein below refers to water-soluble and water-insoluble diluents. Suitable water soluble diluent (s) used in the pharmaceutical composition of the present invention is selected from the group consisting of sugars including lactose, sucrose, glucose, lactulose and dextrose and polyols including mannitol, xylitol, erythritol, dulcitol, ribitol, lactitol and sorbitol in the range 1% to 25% preferably 2% to 20% by weight of the total composition.
Suitable water insoluble diluent (s) used in the pharmaceutical composition of the present invention is selected from group consisting of but not limited to cellulose or cellulose derivatives such as microcrystalline cellulose, powdered cellulose, pregelatinized starch, starch, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium oxide and magnesium carbonate in the range of about 0% to 75% preferably 0% to 60% by weight of the total composition.
The compositions of the present invention further comprise excipients such as lubricants, disintegrants and optionally colorants.
Lubricant is at least one component selected from a group consisting of magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitosteartae, stearic acid, talc, zinc stearate, hydrogenated vegetable oil, glyceryl behenate and colloidal silicon dioxide, in the range of about 0.5 to about 2% preferably 0.5% to 1.5% of total weight of the composition.

Disintegrants is at least one component selected from group consisting of but not limited to cellulose, croscarmellose sodium, crospovidone, starch, sodium starch glycolate, in the range of about 0.5 to about 60% preferably 2% to 50% of total weight of the composition.
The pharmaceutical composition of the invention is in solid oral dosage form containing telmisartan in conventional pharmaceutical dosages. According to the present invention an oral solid formulation of telmisartan is prepared by simple granulation method, wherein the inactive excipients are granulated using the solution of active agent. The compositions of the invention are having remarkable dissolution pattern thereby enabling complete drug release.
Accordingly, in another embodiment, the invention provides process for manufacturing pharmaceutical compositions of the present invention which comprises the following
steps:
a) dissolving Telmisartan in solution of one or more basic agents;
b) sifting and granulating mixture of diluent(s) and disintegrant(s) using the drug solution;
c) drying the wet mass, sizing the dried granules;
d) sifting disintegrant and optionally a diluent, and mixing with dried granules in step (c);
e) sifting lubricant(s) and blending with the blend in step (d); and
f) filling the blend of step (e) into capsules/ sachets or compressing into tablets using suitable tooling as per requirement.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples: Example 1

Ingredients mg/unit
Binder solution
Telmisartan 80.0
Meglumine 24.0
Sodium hydroxide 6.0
Water q.S.
Dry mix
Mannitol 112.0
Microcrystalline Cellulose 218.0
Crospovidone 70.0
Extragranular
Crospovidone 50.0
Microcrystalline Cellulose 35.0
Magnesium Stearate 5.0
Total 600.0
Procedure:
Telmisartan is dissolved in a solution of Meglumine and sodium hydroxide. Mannitol, Microcrystalline Cellulose, Crospovidone were sifted through sieve No. 30 ASTM and granulated using drug solution. The wet mass is dried and sifted. The dried granules are passed through Sieve No. 25 ASTM. Crospovidone and Microcrystalline Cellulose were sifted through sieve No. 30 ASTM and mixed with dried granules. The dried granules are lubricated with Magnesium Stearate which was sifted through sieve No. 40 ASTM and the same is compressed into tablets using suitable punches.
Dissolution profile in pH 7.5 Phosphate buffer. 900 ml. 75 rpm, paddle is given below:

Time (min) % drug release
10 73
15 93
20 94
30 93
45 94
60 94

Example 2

Ingredients nig/unit
Binder solution
Telmisartan 80.0
Meglumine 24.0
Sodium hydroxide 6.0
Water q.s.
Dry mix
Mannitol 66.0
Microcrystalline Cellulose 500.0
Crospovidone 8.0
Extragranular
Microcrystalline Cellulose 100.0
Crospovidone 8.0
Magnesium Stearate 8.0
Total 800.0
Telmisartan is dissolved in a solution of Meglumine and sodium hydroxide. Mannitol, Microcrystalline Cellulose, Crospovidone were sifted through sieve No. 30 ASTM and granulateed using drug solution. The wet mass is dried and sifted the dried granules through Sieve No. 25 ASTM. Crospovidone and Microcrystalline Cellulose were sifted through sieve No. 30 ASTM and mixed with dried granules. Magnesium Stearate was sifted through sieve No. 40 ASTM and the blend was lubricated with the same.
Example 3

Ingredients mg/unit
Binder solution
Telmisartan 80.0
Meglumine 24.0
Sodium hydroxide 6.0
Water q.s.
Dry mix
Mannitol 44.0
Microcrystalline Cellulose 300.0
Crospovidone 6.0
Extragranular
Crospovidone 56.0
Microcrystalline Cellulose 29.0
Magnesium Stearate 5.0
Total 550.0

Procedure:
Telmisartan is dissolved in a solution of Meglumine and sodium hydroxide. Mannitol, Microcrystalline Cellulose, Crospovidone were sifted through sieve No. 30 ASTM and granulated using drug solution. The wet mass is dried and sifted the dried granules through Sieve No. 25 ASTM. Crospovidone and Microcrystalline Cellulose were sifted through sieve No. 30 ASTM and mixed with dried granules. Magnesium Stearate was sifted through sieve No. 40 ASTM and lubricated the blend and filled in the capsules.
Example 4

Procedure:

Ingredients mg/tablet
Binder solution
Telmisartan 80.0
Meglumine 24.0
Sodium hydroxide 6.0
Water q.s.
Dry mix
Lactose monohydrate 140.0
Microcrystalline Cellulose 424.0
Crospovidone 23.0
Extragranular
Crospovidone 20.0
Magnesium Stearate 7.00
Total 724.0

Telmisartan is dissolved in solution of Meglumine and sodium hydroxide. Lactose, Microcrystalline Cellulose, Crospovidone are sifted through sieve No. 30 ASTM and granulated using drug solution. Granules so obtained are dried and sifted through Sieve No. 30 ASTM. Sift Crsopovidone and Microcrystalline Cellulose through sieve No. 30 ASTM and mix with dried granules. The dried blend is lubricated with Magnesium Stearate which is sifted through sieve No. 30 ASTM and compressed.

Dissolution profile in pH 7,5 Phosphate buffer. 900 ml, 75 rpm. paddle is given below:

Time (min) % drug release
10 31
15 67
20 81
30 84
45 85
60 86
Example 5

Ingredients nig/tablet
Binder solution
Telmisartan 80.0
Meglumine 24.0
Sodium hydroxide 6.0
Water q.s.
Dry mix
Sorbitol 60 M 140.0
Microcrystalline Cellulose 424.0
Crospovidone 23.0
Extragranular
Microcrystalline Cellulose 29.0
Crospovidone 17.0
Magnesium Stearate 7.0
Total 750.0
Procedure:
Dissolve Telmisartan in solution of Meglumine and sodium hydroxide. Sift Sorbitol, Microcrystalline Cellulose, Crospovidone through sieve No. 30 ASTM and Granulate using drug solution. Dry the wet mass, and sift the dried granules through Sieve No. 30 ASTM. Sift Crsopovidone and Microcrystalline Cellulose through sieve No. 30 ASTM and mix with dried granules. Lubricate the dried granules using Magnesium Stearate which was sifted through sieve No. 30 ASTM and compress the lubricated granules. Dissolution profile in pH 7.5 Phosphate buffer, 900 ml, 75 rpm, paddle is given below:

Time (min) % drug release
10 34
15 74
20 93
30 95
45 97
60 98
Example 6

Ingredients mg/tablet
Binder solution
Telmisartan 80.0
Meglumine 24.0
Sodium hydroxide 6.0
Water q.s.
Dry mix
Mannitol 176.0
Microcrystalline Cellulose 300.0
Crospovidone 100.0
Extragranular
Microcrystalline Cellulose 46.0
Sodium Starch Glycolate 60.0
Magnesium Stearate 8.0
Total 800.0
Procedure:
Telmisartan is dissolved in solution of Meglumine and sodium hydroxide. Sift Mannitol, Microcrystalline Cellulose, Crospovidone through sieve No. 30 ASTM and granulate using drug solution. Dry the wet mass, and sift the dried granules through Sieve No. 30 ASTM. Sift Sodium Starch Glycolate and Microcrystalline Cellulose through sieve No. 30 ASTM and mix with dried granules. Lubricate the dried granules using Magnesium Stearate which is sifted through sieve No. 30 ASTM and compress it.

Example 7

Ingredients mg/tablet
Binder solution
Telmisartan 80,0
Meglumine 24.0
Sodium hydroxide 6.0
Water q.S.
Dry mix
Mannitol 176.0
Crospovidone 240.0
Extragranular
Sodium Starch Glycolate 266.0
Magnesium Stearate 8.0
Total 800.0
Procedure:
Telmisartan is dissolved in solution of Meglumine and sodium hydroxide. Sift mannitol
and Crospovidone through sieve No. 30 ASTM and granulate the same using the drug
solution. Dry the wet mass, and sift the dried granules through Sieve No. 30 ASTM.
Sift Sodium Starch Glycolate through sieve No. 30 ASTM and mix with dried granules.
Sift Magnesium Stearate through sieve No. 30 ASTM and lubricate the blend ready for
compression.
Example 8

Ingredients mg/tablet
Binder solution
Telmisartan 80.0
Veegum 4.0
Sodium hydroxide 6.0
Water q.s.
Dry mix
Mannitol 226.0
Crospovidone 198.0
Extragranular
Crospovidone 266.0
Colloidal Silicon Dioxide 10.0
Talc 10.0
Total 800.0
Procedure:

Disperse Telmisartan in dispersion of Veegum and sodium hydroxide. Sift Mannitol and Crospovidone through sieve No. 30 ASTM. Granulate Mannitol and Crospovidone using drug dispersion. Dry the wet mass, and sift the dried granules through Sieve No. 25 ASTM. Sift Crospovidone and Colloidal Silicon Dioxide through sieve No. 30 ASTM and mix with dried granules. Sift talc through sieve No. 30 ASTM and lubricate the blend ready for compression.Compress the tablets.

We claim,
1. A solid oral pharmaceutical composition comprising
(a) telmisartan and its pharmaceutical salts in an amount of 5% to 30%;
(b) atleast one water soluble diluent in an amount of 1% to 25%;
(c) one or more basic agents in an amount less than 9 % of the total weight of the composition;
optionally one or more water insoluble diluents alongwith pharmaceutically acceptable excipients wherein the said composition is free of surfactant or emulsifier.
2. The solid oral pharmaceutical composition as claimed in claim 1 wherein the basic agent used in the formulation is selected from alkali metal hydroxides, alkaline hydroxide, alkaline phosphates, alkaline carbonates, meglumine, veegum and basic amino acids such as arginine.
3. The solid oral pharmaceutical composition as claimed in claim 1 wherein suitable water soluble diluent (s) is selected from the group consisting of sugars including lactose, sucrose, glucose, lactulose and dextrose and polyols including mannitol, xylitol, erythritol, dulcitol, ribitol, lactitol and sorbitol..
4. The solid oral pharmaceutical composition as claimed in claim 1 wherein suitable water insoluble diluent(s) is selected from group consisting of cellulose or cellulose derivatives such as microcrystalline cellulose, powdered cellulose, pregelatinized starch, starch, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium oxide and magnesium carbonate.
5. The solid oral pharmaceutical composition as claimed in claim 1 wherein the pharmaceutically acceptable excipients are selected lubricants, disintegrants and optionally colorants.
6. The pharmaceutically acceptable excipients as claimed in claim 1 and 5 wherein the lubricant is selected from a group of magnesium stearate, calcium stearate,

glyceryl monostearate, glyceryl palmitosteartae, stearic acid, talc, zinc stearate, hydrogenated vegetable oil, glyceryl behenate, and colloidal silicon dioxide..
7. The pharmaceutically acceptable excipients as claimed in claim 1 and 5 wherein
the disintegrant is selected from group of cellulose, croscarmellose sodium,
crospovidone, starch, sodium starch glycolate,.
8. A process for preparing solid oral pharmaceutical composition as claimed in
claim 1, wherein said composition is prepared by simple granulation process.