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THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"PHARMACEUTICAL COMPOSITIONS OF TELMISARTAN"
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.

Technical field of the invention:
The present invention is directed to a solid oral pharmaceutical composition comprising the angiotensin II receptor antagonist, Telmisartan. The present invention is further directed to a solid oral pharmaceutical composition comprising telmisartan in an amount ranging from 5% to 30%, water insoluble diluent ranging from 30% to 85%, less than 25% water soluble diluent, surfactant ranging from 0.01% tol%, one or more basic agents in an amount less than 9% of the total weight of the composition and 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 t'/i 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 provided 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 valsartan, 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 a 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 treatment of 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 the range of pH 1 to 7. This Patent Application further describes solubility of Telmisartan can be raised by a 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. A water soluble diluent and surfactant is used to raise the solubility of Telmisartan in the composition.
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 is in an amount 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 containing telmisartan or a derivative thereof comprising a basic agent and water soluble diluent in an amount greater than 70% per weight of the total composition, wherein the formulation neither comprise a surfactant nor a water insoluble diluent. In the absence of surfactant, amount of water soluble diluent is increased to more than 71% in composition to raise the solubility of the Telmisartan.
The above prior arts suffer from one or more drawbacks. The prior art mentions preparation of composition by manufacturing process as either spray drying or fluidized bed processing for granulating wet mass. Both these processes are although sophisticated and advanced, it calls 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.

Most of the prior art teaches that, use of water soluble diluent or surfactants or both are necessary to have good disintegration and dissolution properties of the composition. However, the use of high portion of water soluble diluent has tendency to make composition hygroscopic and use of high quantity of surfactant can cause adverse reaction in sensitive people.
The above constraints have been overcome by the present invention. Accordingly, the present invention further provides a solid oral pharmaceutical composition comprising telmisartan in an amount ranging from 5% to 30%, water insoluble diluent ranging from 30% to 85%, less than 25% water soluble diluent, surfactant ranging from 0.01% tol%, one or more basic agents in an amount less than 9 % of the total weight of the composition and pharmaceutically acceptable excipients.
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 binder..
Another object of the present invention is to provide a solid oral pharmaceutical composition of telmisartan having good compressibility, disintegration, and dissolution properties which further gives rapid and complete drug release.
Yet another object of the invention is to provide a process for preparing solid oral pharmaceutical composition of Telmisartan using simple granulation process thereby the present invention will offer cost effective technology.
Summary of the invention:
In accordance with the above objectives, the present invention is directed to a solid oral pharmaceutical composition comprising telmisartan in an amount ranging from 5% to 30%, water insoluble diluent ranging from 30% to 85%, less than 25% water soluble diluent, surfactant ranging from 0.01% tol%, one or more basic agents in an amount less

than 9% of the total weight of the composition and pharmaceutically acceptable excipients. The present invention also provides a process for manufacturing such composition.
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) basic agent(s),
C) water insoluble diluent (s),
D) water soluble diluent,
E) surfactant, and
F) other pharmaceutically acceptable excipients.
The active ingredient in the formulations of current invention is telmisartan prepared through a synthetic process. The amount of telmisartan is in the range 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 sparingly soluble in a strong acid except hydrochloric acid in which it is insoluble. Telmisartan is soluble in a strong base.
A basic agent is added to the pharmaceutical composition to solublize telmisartan and use this solution for granulating mixture of water insoluble diluent(s) and disintegrant in the manufacturing process as well as to control the pH of the compositon. Basic agent used in the formulation of present invention 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. Amount of total basic agent used in the formulation is less than 9% weight of the total composition.
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 less than 25% 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 30% to 85% by weight of the total composition.
Surfactant used in the present invention is selected from but not limited to poloxamers, polysorbates, polyethoxylated castor oil, hydroxylated castor oil, and sodium lauryl sulfate; ranges from 0.01% to 1% weight of the total composition.
The composition of the present invention further comprises 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; present in the range of about 0.5 to about 2% of total weight of the composition.
Disintegrants is at least one component selected from group consisting of but not limited to croscarmellose sodium, crospovidone, pregelatinized starch, sodium starch glycolate, in the range of about 0.5 to about 65% of total weight of the composition.

In one of the preferred embodiment present invention provides a solid oral pharmaceutical composition comprising telmisartan in an amount of 5% to 30%, water insoluble diluent ranging from 30% to 85%, surfactant ranging from 0.01% tol%, one or more basic agents in an amount less than 9% of the total weight of the composition and other pharmaceutically acceptable excipients.
The pharmaceutical composition of the invention is in solid oral dosage form containing telmisartan in conventional pharmaceutical dosages for example, tablets, pellets, granules and capsules.
According to one embodiment of the present invention an oral solid formulation of telmisartan is prepared by simple granulation method.
In another embodiment, the invention provides a 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 and surfactant;
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) difting disintegrant and mixing with dried granules in step (c); and
e) difting lubricant(s) and blending with the blend in step (d) to make it ready for compression.
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

Sr. No. Ingredients mg/tablet
Granulating solution
1 Telmisartan Form A 80.0
2 Meglumine 22.0
3 Polysorbate 80 1.5
4 Purified Water q.s.
5 Sodium Hydroxide 5.0
Dry Mixing
6 Microcrystalline Cellulose 321.5
7 Mannitol 60.0
8 Sodium starch glycolate 80.0
Extragranular
9 Sodium starch glycolate 25.0
10 Magnesium Stearate 5.0
TOTAL 600.0
Procedure:
1. Dissolving Telmisartan in solution of Meglumine, Polysorbate 80 and Sodium
hydroxide;
2. Sifting Macrocrystalline Cellulose, Mannitol and Sodium starch glycolate through sieve No. 30 (ASTM, 600 microns) and mixing in rapid mixer granulator;
3. Granulating Microcrystalline Cellulose, Mannitol and Sodium starch glycolate using drug solution in step 1;
4. Drying the wet mass, and sifting the dried granules through Sieve No. 25 (ASTM, 710 microns);
5. Sifting Sodium starch glycolate through sieve No. 30 (ASTM, 600 microns) and mixing with dried granules in step 4;
6. Sifting Magnesium Stearate through sieve No. 40 (ASTM, 425 microns) and
lubricating the blend ready for compression; and
7. Compressing the above blend into tablets.
The dissolution profile in pH 7.5 buffer, 75 rpm, 900 ml, paddle is given below:

Time % drug release
10 85
15 91
20 93
30 96
45 99
60 99
Example 2

Sr. No. Ingredients mg/tablet
Granulating solution
1 Telmisartan Form A 40.0
2 Meglumine 11.0
3 Polysorbate 80 0.9
4 Purified Water q.s.
5 Sodium Hydroxide 3.0
Dry Mixing
6 Dibasic calcium phosphate dihydrate 120.1
7 Mannitol 40.0
8 Croscarmellose sodium 40.0
Extragranular
9 Croscarmellose sodium 12.5
10 Dibasic calcium phosphate dihydrate 30
11 Magnesium Stearate 2.5
TOTAL 300.0
Procedure:
1. Dissolving Telmisartan in solution of Meglumine, Polysorbate 80 and Sodium hydroxide;
2. Sifting Dibasic calcium phosphate dihydrate, Mannitol and Croscarmellose sodium through sieve No. 30 (ASTM, 600 microns) and mixing in rapid mixer granulator;
3. Granulating Dibasic calcium phosphate dihydrate, Mannitol and Croscarmellose sodium using drug solution in step 1;
4. Drying the wet mass, and sifting the dried granules through Sieve No. 25 (ASTM, 710 microns);
5. Sifting Croscarmellose sodium and Dibasic calcium phosphate dihydrate through sieve No. 30 (ASTM, 600 microns) and mixing with dried granules in step 4;

6. Sifting Magnesium Stearate through sieve No. 40 (ASTM, 425 microns) and
lubricating the blend ready for compression; and
7. Compressing the above blend into tablets.
The dissolution profile in pH 7.5 buffer, 75 rpm, 900 ml, paddle is given below:

Time % drug release
10 88
15 92
20 95
30 97
45 99
60 100
Example 3

Sr. No. Ingredients mg/tablet
Granulating solution
1 Telmisartan Form A 80.0
2 Meglumine 24.0
3 Poloxamer 188 2.4
4 Purified Water q.s.
5 Sodium Hydroxide 6.0
Dry Mixing
6 Microcrystalline Cellulose 215.6
7 Mannitol 112.0
8 Crospovidone 70.0
Extragranular
9 Crospovidone 50.0
10 Microcrystalline Cellulose 35.0
11 Magnesium Stearate 5.0
TOTAL 600.0
Procedure:
1. Dissolving Telmisartan in solution of Meglumine, poloxamer 188 and sodium hydroxide;
2. Sifting Microcrystalline Cellulose, Mannitol and Crospovidone through sieve No. 30 (ASTM, 600 microns) and mixing in rapid mixer granulator;

3. Granulating Microcrystalline Cellulose, Mannitol and Crospovidone using drug
solution in step 1;
4. Drying the wet mass, and sifting the dried granules through Sieve No. 25 (ASTM, 710 microns);
5. Sifting Crospovidone and Microcrystalline Cellulose through sieve No. 30 (ASTM, 600 microns) and mixing with dried granules in step 4;
6. Sifting Magnesium Stearate through sieve No. 40 (ASTM, 425 microns) and
lubricating the blend ready for compression; and
7. Compressing the above blend into tablets.
The dissolution profile in pH 7.5 buffer, 75 rpm, 900 ml, paddle is given below:

Time % drug release
10 93
15 96
20 96
30 97
45 98
60 100

We claim,
1. A solid oral pharmaceutical composition comprising
(a) telmisartan and its pharmaceutical salts in an amount of 5% to 30% of the total weight of the composition;
(b) atleast one water insoluble diluent in an amount of 30% to 85% of the total weight of the composition;
(c) atleast one surfactant 0.01% to 1% of the total weight of the composition;
(d) atleast one or more basic agents in an amount less than 9 % of the total weight of the composition;
(e) less than 25% water soluble diluent and
(f) pharmaceutically acceptable excipients.
wherein the said composition is free of binder.
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 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.
4. The solid oral pharmaceutical composition as claimed in claim 1, wherein the surfactant(s) is selected from group consisting of poloxamers, polysorbates, polyethoxylated castor oil, hydroxylated castor oil, and sodium lauryl sulfate.
5. 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.

6. The solid oral pharmaceutical composition as claimed in claim 1, wherein the said composition further comprises pharmaceutically acceptable excipients selected from lubricants, disintegrants and optionally colorants.
7. The pharmaceutically acceptable excipients as claimed in claim 1 and 6, 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.
8. The pharmaceutically acceptable excipients as claimed in claim 1 and 6 wherein the disintegrant is selected from group of cellulose, croscarmellose sodium, crospovidone, starch and sodium starch glycolate.
9. A process for preparing solid oral pharmaceutical composition as claimed in claim 1, wherein said composition is prepared by simple granulation process comprising following steps:

a) dissolving telmisartan in solution of surfactant and 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 mixing with dried granules in step (c); and
e) sifting lubricant(s) and blending with the blend in step (d) to make it ready for compression.