FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
"A SOLID ORAL PHARMACEUTICAL COMPOSITION OF
TELMISARTAN"
2. APPLICANT (S):

(a) NAME: FDC Limited

(h)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 11 receptor antagonist. 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, one or more
basic agents in an amount less than 9% of the total weight of the composition and
pharmaceuticall
y acceptable excipients.

Background and prior art:

Telmisartan is a non-peptide angiotensin II receptor antagonist. Its chemical name is 4'-
[2-n-propel-4-methyl-6-(1-methvlbenzimidazol-2-vl)-benzimidazol-I-vlmethvl]-
biphenvl-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. Telrnisartan with a
long duration of action and shows no evidence of drug accumulation after repeated
administration. A t% of approximately 24 hours for telmisartan, considerably longer than
that observed with other agents in this class (all 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: I 1 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.

W02009004064 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 does 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 provides a solid oral pharmaceutical composition comprising telmisartan in an amount ranging from 5% to 30%, water insoluble diluent, one or more basic agent in an amount less than 9% of the total weight of the composition and 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. emulsifier or water soluble diluent and yet have good disintegration and dissolution properties which give immediate and complete drug release. It has also been found that such compositions are not hygroscopic in nature.

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, emulsifier and water soluble diluent.

Another object of the present invention is to provide a solid oral pharmaceutical composition of telmisartan having good 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.

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, 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%, 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) 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.
The solid oral pharmaceutical composition of telmisartan of the present invention is having good disintegration and dissolution properties to give rapid and complete drug release. Approximate 95 % of the drug is released in 60 mins.
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 used in the present invention 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.
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 gl.vcolate, 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 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 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. Ingredients mg/tablet
No.
Granulatin solution
I Telmisartan 80.0
2 Me lumine 24.0
3 Sodium hydroxide 6.0
4 Purified water .s.
Dry mix
5 Micro crystalline cellulose 241.0
6 Colloidal silicon dioxide 5.0
7 Crospovidone 40.0
Extra ranular
8 Crospovidone 40.0
9 Magnesium Stearate 4.0
Total 440.0

The dissolution profile in pH 7.5 buffer, 75 rpm, 900 ml, paddle is given below:

Time % drug 7jejease
10 89
15 95
20 96
30 95
45 96
60 95

Procedure:
1. Dissolving Telniisartan in solution of Meglumine 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 l;
4. drying the wet mass. and sifting the dried granules through Sieve No. 25 (ASTM, 710 microns);
5. sifting Crsopovidone 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. Ingredients mg/tablet
No.
Granulating solution
I Telmisartan 40.0
2 Me lumine 9.0
3 Sodium hydroxide 1.5
4 Purified water . s.
D mix
5 Microc stalline cellulose 172.0
6 Sodium starch glycolate 35.0
Extra ranular
7 Sodium starch glycolate 25.0
8 Microcrvstalline cellulose 15.0
9 Magnesium Stearate 2.5
Total 300.0

The dissolution profile in pH 7.5 buffer. 75 rpm, 900 ml, paddle is given below:

Time %drug release
10 72
15 93
20 96
30 95
45 95
60 95

Procedure:
1. Dissolving Telmisartan in solution of Meglumine and sodium hydroxide;
2. sifting Microcrystalline Cellulose, and Sodium starch glycolate through sieve No. 30 (ASTM, 600 microns) and mixing in rapid mixer granulator;
3. granulating Microcrystalline Cellulose, and Sodium starch glycolate using drug
solution in step i;
4. drying the wet mass; and sifting the dried granules through Sieve No. 25 (ASTM. 710 microns);
5. sifting Microcrystalline Cellulose, and 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.

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) at least one water insoluble diluent in an amount of 1% to 70% of the total
weight of the composition;
(c) at least one basic agent in an amount less than 9 % of the total weight of the
composition; and
(d) pharmaceutically acceptable excipients,
wherein the said composition is free of surfactant, emulsifier and water soluble
diluent.
2. The solid oral pharmaceutical composition as claimed in claim 1, wherein the
basic agent is selected from alkali metal hydroxides, alkaline hydroxide, alkaline
phosphates, alkaline carbonates, meglumine, veegum and basic amino acids such
as arginine.

The solid oral pharmaceutical composition as claimed in claim 1, wherein the water insoluble diluent 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.
4. The solid oral pharmaceutical composition as claimed in claim 1, wherein the
pharmaceutically acceptable excipients are selected from lubricant, disintegrant
and colorant.
5. The pharmaceutically acceptable excipients as claimed in claims 1 and 4. wherein
the lubricant is 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.

6,

The pharmaceutically acceptable excipients as claimed in claims 1 and 4, wherein
the disintegrant is selected from a group consisting of cellulose, croscarmellose sodium, crospovidone and sodium starch glycolate.

A process for preparing a 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 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.