FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
PHARMACEUTICAL COMPOSITIONS OF
TELMISARTAN AND
HYDROCHLOROTHIAZIDE AND PROCESS
FOR PREPARATION THEREOF
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near
Dinesh Hall, Ahmedabad 380 009,
Gujarat, India
The following specification describes the invention:

FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising telmisartan and hydrochlorothiazide; and process for preparation of such composition.
BACKGROUND OF THE INVENTION
Telmisartan, chemically designated as 4'-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1 -ylmethyl]-biphenyl-2-carboxylic acid, is disclosed in EP 502314 B1 as an angiotensin II receptor antagonist useful for the treatment of hypertension and other medical indications. Telmisartan is generally manufactured and supplied in the free acid form, such as Micardis® marketed by Boehringer. Hydrochlorothiazide (hereinafter referred as HCTZ) is a known thiazide diuretic, which is orally administered in the treatment of edema and hypertension.
Combination therapy of telmisartan with HCTZ is expected to show synergistic therapeutic efficacy in the treatment of hypertension (McGill et al., Clin Ther., 23 (6): 833-50). Therefore, it may be desirable to formulate a fixed dose combination composition comprising telmisartan and HCTZ, which may improve patient compliance. However, formulating an oral fixed dose combination composition which may have the features of pharmacologic efficacy, adequate stability and a robust method of manufacture involves overcoming numerous technical problems and difficulties. For example, telmisartan is characterized by its very poor solubility in aqueous systems at the physiological pH range of the gastrointestinal tract of between pH 1 to 7. Moreover, it is known that HCTZ is prone to degradation by certain excipients, particularly basic or alkaline excipients. It is therefore challenging to prepare compositions comprising telmisartan and HCTZ, wherein the composition has the desired dissolution of telmisartan and the stability of HCTZ and telmisartan is also not compromised. It is known in the art that improved dissolution characteristics of telmisartan may be obtained by using basic or alkaline excipient/s in the composition.

WO 2004/28505 application describes that the solubility of telmisartan can be increased several hundred fold in a pharmaceutical composition comprising telmisartan dispersed in a dissolving matrix comprising a basic agent, a surfactant or emulsifier, water soluble diluent in an amount of 25 to 70 wt %, and optionally further excipients.
WO 2007/61415 application discloses a pharmaceutical composition comprising telmisartan in which the solubility of telmisartan is improved, the composition comprising a basic agent, a surfactant, and at least one water-soluble or water-insoluble diluent, wherein water-soluble diluent is present in an amount of less than 25% by total weight of the composition.
To overcome the problem of incompatibility of HCTZ with the basic excipients which are used to increase the solubility of telmisartan, the art teaches compositions wherein telmisartan and HCTZ are present in separate layers and the basic excipient/s are present in the telmisartan layer.
WO 03/59327 application discloses a bilayer pharmaceutical tablet comprising a first layer containing telmisartan in substantially amorphous form in a dissolving tablet matrix and a second layer containing a diuretic such as hydrochlorothiazide in a disintegrating tablet matrix. The dissolving matrix of the telmisartan layer comprises a basic agent, a water-soluble diluent, and, optionally, other excipients. The currently marketed bilayered tablet composition of telmisartan and HCTZ, sold under the brand-name Micardis® HCT by Boehringer, is based on the teachings of WO 03/59327. Similar compositions comprising telmisartan and HCTZ in separate layers, particularly bilayered compositions, are also disclosed in several other references such as WO 2004/28505, WO 2006/63737 and WO2007/60170 applications.
WO 03/59327 also discloses an approach of formulating telmisartan and HCTZ in a compressed tablet wherein HCTZ particles were coated with water soluble polymer in order to reduce the contact surface area of the HCTZ particles with telmisartan formulation during mixing and compressing, but the approach not only

failed to achieve the desired prolonged shelf life, but also reduced the dissolution rate of HCTZ due to the gel-forming properties of the polymer.
We have surprisingly found that stable pharmaceutical compositions comprising telmisartan and HCTZ can be prepared without the need of separating the two drugs in different layers as disclosed in the art and still achieve enhanced dissolution of telmisartan.
SUMMARY OF THE INVENTION
In one aspect, the specification discloses a stable pharmaceutical composition comprising;
(i) a first component comprising telmisartan, a basic agent, and at least one
pharmaceutically acceptable excipient;
(ii) a second component comprising hydrochlorothiazide, and at least one pharmaceutically acceptable excipient.
In another aspect, the specification discloses a process for preparation of a stable pharmaceutical composition, wherein the process comprises:
(i) preparing a first component comprising the steps of:
(a) dissolving telmisartan, a basic agent, at least one pharmaceutical^ acceptable excipient in a solvent,
(b) granulating a pharmaceutical^ acceptable excipient with the solution of step (i)(a),
(c) optionally coating the granules of step (i)(b);
(ii) preparing a second component comprising the steps of:
(a) mixing hydrochlorothiazide and at least one pharmaceutical^ acceptable excipient,
(b) granulating the mixture of step (ii)(a) with a solvent;
(c) optionally coating the granules of step (ii)(b);
(iii) mixing the component of step (i), the component of step (ii) and at least
one pharmaceutically acceptable excipient; and
(iv) compressing the mixture of step (iii) into tablets or filling the mixture of
step (iii) into capsules to obtain the pharmaceutical composition.

In yet another aspect, the specification discloses a process for preparation of a stable pharmaceutical composition, wherein the process comprises:
(i) preparing a first component comprising the steps of:
(a) dissolving telmisartan, a basic agent, at least one pharmaceutically acceptable excipient in a solvent,
(b) granulating a pharmaceutically acceptable excipient with the solution of step (i)(a),
(c) optionally coating the granules of step (i)(b);
(ii) coating the first component with the second component comprising hydrochlorothiazide and at least one pharmaceutically acceptable excipient; and
(iii) compressing the product of step (ii) into tablets or filling the product of step (ii) into capsules to obtain the pharmaceutical composition.
DETAILED DESCRIPTION OF THE INVENTION
The term "pharmaceutical composition" as described herein includes compositions like a tablet or a capsule, with the exception that the pharmaceutical composition is not a bilayered or a multi-layered tablet.
The term "telmisartan" as described herein is defined to include telmisartan free acid or pharmaceutically acceptable salts, hydrates, solvates, polymorphs and enantiomers thereof, or mixtures thereof. Telmisartan may be in a crystalline or amorphous form, or mixtures thereof. Telmisartan as described herein may be of varying particle size, for example it may be in micronized or non-micronized form. The particle size of telmisartan as described herein may vary from 1 urn to 200 urn. Telmisartan may be present in an amount ranging from 10 mg to 160 mg in the composition or in amount ranging from 1 % to 80 % by weight of the composition.
The term "hydrochlorothiazide" or "HCTZ" as described herein is defined to include HCTZ free base or pharmaceutically acceptable polymorphs, hydrates and solvates thereof, or mixtures thereof. HCTZ m ay be present as a fine-

crystalline powder, which may optionally be micronized. HCTZ may be present in an amount ranging from 6.25 mg to 50 mg in the composition or in amount ranging from 0.1 % to 30 % by weight of the composition.
The term "stable pharmaceutical composition" as used herein refers to the composition of telmisartan and hydrochlorothiazide wherein the impurities do not exceed the regulatory requirement of country of interest. For example, stable pharmaceutical composition refers to compositions comprising less than 4.0% w/w of total impurity of hydrochlorothiazide and telmisartan combination when stored at 40°C and 75% relative humidity (RH) for a period of at least one week, for example, one month.
The term "component" as described herein means a portion or a part of the pharmaceutical composition. The "component" is in the form of a powder, granule, bead, pellet, spheroid, mini-tablet, micro-tablet or coating. The pharmaceutical compositions as described herein comprise at least one component comprising telmisartan, a basic agent and optionally pharmaceutically acceptable excipients. The pharmaceutical compositions as described herein comprise at least one component comprises HCTZ and optionally pharmaceutically acceptable excipients.
A basic agent as described herein may be selected from metal hydroxides such as sodium hydroxide, potassium hydroxide; metal carbonates such as sodium carbonate, potassium carbonate; metal phosphates such as disodium hydrogen phosphate, dipotassium hydrogen phosphate; metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; basic amino acids such as arginine; meglumine (N-methyl-D-glucamine) or tromethamine; and the like. The basic agent may be present in an amount ranging from 0.1 % to 20 % by weight of the composition.
The pharmaceutical compositions as described herein may comprise at least one pharmaceutically acceptable excipient selected from diluent, disintegrant, binder, glidant, lubricant, surfactant or complexing agent.

A diluent may be selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, dibasic calcium phosphate, dibasic sodium phosphate, tribasic sodium phosphate,; sugars such as dextrose, lactose or sucrose; sugar alcohols such as mannitol, sorbitol, xylitol or erythritol; or mixtures thereof. The diluent may be present in an amount ranging from 1 % to 90 % by weight of the composition.
A disintegrant may be selected from starch, pregelatinized starch, croscarmellose sodium, sodium starch glycolate, sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone and mixtures thereof. The disintegrant may be present in an amount ranging from 0.1 % to 20 % by weight of the composition.
A binder may be selected from starches such as maize starch, corn starch, pregelatinised starch; cellulose derivatives such as cellulose powder, microcrystalline cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose ; polyvinyl pyrrolidone, gelatin, zein, polymethacrylates, sodium alginate, gums, synthetic resins and mixtures thereof. The binder may be present in an amount ranging from 0.1% to 20% by weight of the composition.
A lubricant or glidant may be selected from talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, sodium stearyl fumarate, magnesium trisilicate; and mixtures thereof. The lubricant or glidant may be present in an amount ranging from 0.1 % to 10 % by weight of the composition.
A surfactant may be selected from one or more non-ionic or ionic (i. e., cationic, anionic and Zwitterionic) surfactants suitable for use in pharmaceutical compositions. Suitable surfactants include mono fatty acid esters of polyoxyethylene sorbitan such as those sold under the brand name Tween®; sodium lauryl sulfate, polyoxyethylene castor oil derivatives such as those sold under the brand name Cremophor®, polyethoxylated fatty acids and their

derivatives, propylene glycol fatty acid esters, sterol and sterol derivatives; sorbitan fatty acid esters and their derivatives, sugar esters, polyoxyethylene-polyoxypropylene block copolymers such as those sold under the brand name Poloxamer®, soy lecithin, and mixtures thereof. The surfactant may be present in an amount ranging from 0.1 % to 10 % by weight of the composition.
A complexing agent may be selected from cyclodextrin class of molecules, such as cyclodextrins containing from six to twelve glucose units, especially, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, or their derivatives, such as hydroxypropyl beta cyclodextrins, or mixtures thereof.
The pharmaceutical compositions may additionally contain excipients such as colorants selected from known F.D. & C. and D. & C. dyes, and the like.
The pharmaceutical composition as described herein may be obtained in the form of a tablet or a capsule. The composition may comprise a first component of telmisartan, a basic agent and at least one pharmaceutically acceptable excipient and a second component of HCTZ and at least one pharmaceutically acceptable excipient. The pharmaceutical composition or the first or the second component may be prepared using wet granulation, dry granulation or direct compression. For example, the first component may be prepared by dispersing telmisartan, a basic agent and at least one pharmaceutically acceptable excipient in the solvent and spraying the dispersion on the excipient like mannitol. Alternatively, the first component may be prepared by dissolving telmisartan, a basic agent and at least one pharmaceutically acceptable excipient in the solvent and spray drying the solution. Alternatively, telmisartan and a basic agent may be mixed with at least one pharmaceutically acceptable excipient and granulated by a solvent or converted into compacts or slugs to form a first component. Alternatively, the first and the second component may be obtained as granules which may be compressed into a tablet or filled in a capsule of appropriate size. The first or the second component may also be prepared by methods such as melt granulation, extrusion-spheronization, freeze-drying, spray granulation, spray drying, coating, solvent deposition, etc. For example, the first component may be prepared as granules comprising telmisartan, a basic agent and pharmaceutically acceptable

excipients and the second composition comprising HCTZ may be coated on the first component. Alternatively, the first component comprising telmisartan and a pasic agent may be obtained as a bead or a pellet which may be coated with the second component comprising HCTZ. The first or the second component may optionally be coated with a separating coat comprising film-forming polymer such as hydroxypropyl methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, polyvinyl pyrrolidone, and the like. The coating may also comprise of a plasticizer such as glyceryltriacetate, dibutyl sebacate, diethylphthalate, polyethylene glycol, propylene glycol, glycerol, castor oil, copolymers of propylene oxide and ethylene oxide, or mixtures thereof. Such compositions are also available under the brand name of Opadry® or Lustreclear®, sold by Colorcon.
The pharmaceutical compositions as described herein have dissolution profile of telmisartan which is substantially similar to the reference product. The dissolution may be characterized as more than 85 % dissolution at the end of 30 minutes when measured in USP Type II apparatus in 900 ml of phosphate buffer having pH 7.5 with a paddle speed of 75 rpm at 37 ± 0.5°C.
In one embodiment, a pharmaceutical composition may be prepared by
preparing a first component by granulating a mixture of telmisartan, a basic
agent, a diluent, optionally a binder or a disintegrant with a solvent or binder
solution, and drying the granules;
preparing a second component by granulating a mixture of HCTZ, a diluent,
and optionally a disintegrant or a binder, with a solvent or binder solution, and
drying the granules;
mixing both the components with a glidant and a disintegrant; and
compressing the mixture into a tablet or filling the mixture into a capsule.
In another embodiment, a pharmaceutical composition may be prepared by
preparing a first component by dispersing a mixture of telmisartan, a basic agent, a diluent, optionally a binder or a disintegrant in a solvent; spraying the dispersion on a diluent to obtain granules, and drying the granules;

preparing a second component by granulating a mixture of HCTZ, a diluent, and optionally a disintegrant or a binder, with a solvent or binder solution, and drying the granules;
mixing both the components with a glidant and a disintegrant; and compressing the mixture into a tablet or filling the mixture into a capsule.
In another embodiment, a pharmaceutical composition may be prepared by preparing a first component by dissolving a mixture of telmisartan, a basic agent, a binder and optionally a diluent or a disintegrant, in a solvent; spray-drying the solution and drying the granules;
preparing a second component by granulating a mixture of HCTZ, a diluent, and optionally a disintegrant or a binder, with a solvent or binder solution; drying the granules;
mixing both the components with a glidant and a disintegrant; and compressing the mixture into a tablet or filling the mixture into a capsule.
In another embodiment, a pharmaceutical composition may be prepared by preparing granules comprising telmisartan, a basic agent, a diluent, a glidant, and optionally a disintegrant, a binder or a glidant;; coating the granules with a dispersion of HCTZ and a film-forming polymer; mixing granules with at least one pharmaceutically acceptable excipient; and compressing the mixture into a tablet or filling the mixture into a capsule.
The pharmaceutical compositions as described herein may be illustrated by the following examples which are not to be construed as limiting the scope of the invention:
EXAMPLE 1

INGREDIENTS Quantity (mg/tab)
Intragranular
Part A
Telmisartan 80
Sodium hydroxide 6.72
Meglumine 24
Water q.s.

Mannitol 279.28
Part B
Hydrochlorothiazide (HCTZ) 25
Mannitol 164
Hydroxypropyl methylcellulose (HPMC) 6
Extragranular
Mannitol 102.5
Magnesium stearate 12.5
Total 700
Procedure:
First Component: Telmisartan, sodium hydroxide and meglumine were dissolved in water and solution was sprayed on mannitol to obtain granules of telmisartan. Second Component: HCTZ and mannitol were sifted and mixed together and granulated with aqueous solution of hydroxypropyl methylcellulose (HPMC) to obtain granules of HCTZ.
The granules of telmisartan and the granules of HCTZ were mixed with mannitol, lubricated with magnesium stearate and compressed into tablets using appropriate tooling.
EXAMPLE 2

INGREDIENTS Quantity (mg/tab)
Intragranular
Part A
Telmisartan 80
Sodium hydroxide 6.72
Meglumine 24
Water q.s.
Mannitol 329.28
Magnesium Stearate 10
Part B
Stage A
Hydrochlorothiazide (HCTZ) 24.8
Hydroxypropyl methylcellulose (HPMC) 6
Water qs.
Mannitol 150
Stage B
Hydrochlorothiazide (HCTZ) 0.2
Hydroxypropyl methylcellulose (HPMC) 9

Extragranular
Mannitol 53
Magnesium stearate 7
Total 700
Procedure:
First Component: Telmisartan, sodium hydroxide and meglumine were dissolved
in water and solution was sprayed on mannitol to obtain granules of telmisartan.
The granules were lubricated with magnesium stearate.
Second Component: HCTZ (about 99% by weight of total HCTZ) and HPMC were
dispersed in water and the dispersion was sprayed on mannitol to form granules.
The granules were coated with a dispersion of HCTZ (remaining about 1% by
weight of total HCTZ) and HPMC.
The granules of telmisartan and the granules of HCTZ were mixed with mannitol,
lubricated with magnesium stearate and compressed into tablets using
appropriate tooling.
EXAMPLE 3

INGREDIENTS Quantity (mg/tab)
Intragranular
Mannitol 503
Telmisartan coating
Telmisartan 80
Sodium hydroxide 6.72
Water q.s.
Barrier coating
Hydroxypropyl methylcellulose (HPMC) 6
Water q.s.
HCTZ coating
Hydrochlorothiazide (HCTZ) 25
Hydroxypropyl methylcellulose (HPMC) 9
Water q.s.
Extragranular
Mannitol 59.78
Magnesium stearate 10.5
Total 700

Procedure:
First Component: Telmisartan and sodium hydroxide were dissolved in water and
solution was sprayed on mannitol to obtain granules of telmisartan. The granules
were coated with the solution of HPMC in water to obtain barrier-layered
granules.
Second Component: HCTZ and HPMC were dispersed in water and the
dispersion of was sprayed on barrier-layered granules of first component to
obtain a coat of the second component.
The coated granules were mixed with mannitol, lubricated with magnesium
stearate and compressed into tablets using appropriate tooling.
EXAMPLE 4

INGREDIENTS Quantity (mg/tab)
Intragranular
Part A
Telmisartan 80
Polyvinyl pyrrolidone (PVP) 24
Sodium hydroxide 6.72
Meglumine 24
Water q.s.
Mannitol 255.28
Part B
Hydrochlorothiazide (HCTZ) 25
Mannitol 164
Hydroxypropyl methylcellulose (HPMC) 6
Extragranular
Mannitol 102.5
Magnesium stearate 12.5
Total 700
Procedure:
First Component: Telmisartan, PVP, sodium hydroxide and meglumine were dissolved in water and solution was spray-dried to obtain granules of telmisartan.

Second Component: HCTZ and mannitol were sifted and mixed together and granulated with aqueous solution of hydroxypropyl methylcellulose (HPMC) to obtain granules of HCTZ.
The granules of telmisartan and the granules of HCTZ were mixed with mannitol, lubricated with magnesium stearate and compressed into tablets using appropriate tooling.
Table 1: Comparative dissolution profile of Examples 1-3 and Reference product using USP Type II apparatus in 900 ml of phosphate buffer containing pH 7.5, 75 rpm paddle speed, 37 ± 0.5°C.

Time (min) % telmisartan dissolved
EXAMPLE 1 EXAMPLE 2 EXAMPLE 3 #Reference Product
10 75.1 54.4 70.3 63.3
20 99.9 87.6 98.3 96.6
30 100.1 97.6 99.3 100.1
45 100.5 97.9 99.3 99.5
60 100.6 98.1 99.3 98.5

# Bilayered tablet composition of telmisartan and HCTZ, sold under the brand-name Micardis®Plus by Boehringer in Europe, which is available in different strengths.
As is evident from Table-1, compositions of EXAMPLES 1-3 show dissolution profile of telmisartan which is substantially similar to that of the Reference Product.

ABSTRACT
The present invention relates to a pharmaceutical composition comprising telmisartan and hydrochlorothiazide; and process for preparation of such composition.