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:
"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 without use of binder and water soluble diluent, and yet has good compressibility, disintegration and dissolution properties. 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%. 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-methyi-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1 -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 and shows no evidence of drug accumulation after repeated administration. A t½ 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 gastrointestinal 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.
US 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.
US 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 containg 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 abence 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%, surfactant ranging from 0.01% to1%, 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, emulsifier and water soluble diluent.
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 objective 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 of Telmisartan without use of surfactant, emulsifier and water soluble diluent and yet has good disintegration and dissolution properties. 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%, surfactant ranging from 0.01% to1%: 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 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) surfactant
E) other pharmaceutically acceptable excipients.
The active ingredient in the formulations of this 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 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% weight of the total composition.
Diluent is a water insoluble diluent. Suitable water insoluble diluent used in the pharmaceutical composition of the present invention is selected from the group consisting of cellulose derivatives such as microcrystalline cellulose, powdered cellulose, starch, calcium carbonate, calcium sulfate, dibasic calcium phosphate, tribasic calcium phosphate, kaolin, magnesium oxide, and magnesium carbonate. Water insoluble diluent used in the formulation is ranging from 30% to 85% 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 ofthe 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% 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
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.
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 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) 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.
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 80.0
2 Meglumine 24.0
3 Sodium hydroxide 6.0
4 Poloxamer 188 3.0
5 Purified water q.s.
Dry mix
6 Microcrystalline cellulose 390.0
7 Crospovidone 36.0
Extragranular
8 Crospovidone 14.0
9 Microcrystalline Cellulose 42.0
10 Magnesium Stearate 5.0
Total 600.0
The dissolution profile in pH 7.5 buffer, 75 rpm, 900 ml. paddle is given below:

Time % drug release
10 64
15 95
20 97
30 97
45 97
60 98

Procedure:
1. Dissolving Telmisartan in solution of Meglumine, poloxamer 188 and sodium hydroxide;
2. Sifting Microcrystalline Cellulose, and Crospovidone through sieve No. 30 (ASTM. 600 microns) and mixing in rapid mixer granulator;
3. Granulating Microcrystalline Cellulose. 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...
Example 2

Sr.
No. Ingredients mg/tablet
Granulating solution
1 Telmisartan 80.0
2 Meglumine 24.0
3 Sodium hydroxide 6.0
4 Poloxamer 188 3.0
5 Purified water q.s.
Dry mix
6 Microcrystalline cellulose 260.0
7 Crospovidone 40.0
Extragranular
8 Crospovidone 40.0
9 Microcrystalline cellulose 23.0
10 Magnesium Stearate 4.0
Total 480.0
The dissolution profile in pH 7.5 buffer, 75 rpm 900 ml. paddle is given below:

Time % drug release
10 68
15 94
20 96

30 98
45 96
60 96
Procedure:
1. Dissolving Telmisartan in solution of Meglumine poloxamer 188 and sodium
hydroxide;
2. Sifting Microcrystalline Cellulose, colloidal silicon dioxide and Crospovidone through sieve No. 30 (ASTM. 600 microns) and mixing in rapid mixer granulator;
3. Granulating Microcrystalline Cellulose. 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.
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) pharmaceutically acceptable excipients.
wherein the said composition is free of binder and water soluble diluent
2. The solid oral pharmaceutical composition as claimed in claim 1, wherein
suitable water insoluble diluent(s) is selected from 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 or magnesium carbonate.
3. The solid oral pharmaceutical composition as claimed in claim 1, wherein the surfactant(s) is selected from poloxamers, polysorbates, polyethoxylated castor oil hydroxylated castor oil or sodium lauryl sulfate
4. 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 or basic amino acids such as arginine.
5. The solid oral pharmaceutical composition as claimed in claim 1. wherein the pharmaceutically acceptable excipients are selected from lubricants, disintegrants or optionally colorants.
6. The pharmaceutically acceptable excipients as claimed in claim 5. wherein the lubricant is selected from magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitosteartae, stearic acid, talc, zinc stearate, hydrogenated vegetable oil, glyceryl behenate or colloidal silicon dioxide.
7. The pharmaceutically acceptable excipients as claimed in 5 wherein the disintegrant is selected from cellulose, croscarmellose sodium, crospovidone, starch or sodium starch glycolate.
8. A solid oral pharmaceutical composition as claimed in claim 1 is prepared by-simple granulation process comprising 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) sifting disintegrant and mixing with dried granules in step (c): and
e) sifting l½ubricant(s) and blending with the blend in step (d) to make it ready for compression.