Form 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULE 2003
PROVISIONAL SPECIFICATION
[See section 10 and rule 13]
1. TITLE OF THE INVENTION
"Pharmaceutical compositions comprising Valsartan"
2. APPLICANT
(a) NAME: USV LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies ACT 1956
(c) ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Technical field of the invention:
The present invention relates to pharmaceutical compositions comprising Valsartan and optionally Hydrochlorothiazide together with suitable pharmaceutically acceptable additives. Further, the invention relates to a novel process for preparation of said compositions.
Background and Prior art:
Valsartan is an angiotensin II receptor antagonist and is used in the treatment of cardiovascular disorders such as hypertension and heart failure.
Valsartan is chemically described as N-(l-oxopentyl)-N-[[2'-(lH-tetrazol-5-yl) [1,1 '-biphenyl]-4-yl]methyl]-L-valine. Its empirical formula is C24H29N5O3 and its molecular weight is 435.5. Valsartan is a white to practically white fine powder and is soluble in Ethanol and Methanol and slightly soluble in water.
Valsartan is used alone or in combination with other drugs such as diuretics. Several compositions of Valsartan are available commercially. Valsartan is marketed by Novartis as Diovan® and is available in the form of tablets containing 40mg, 80mg, 160mg or 320mg of Valsartan. Diovan® Tablets contain colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, iron oxides, magnesium stearate, microcrystalline cellulose, polyethylene glycol 8000 and titanium dioxide as inactive. Diovan® is also available in the form of capsules containing 40mg, 80mg, 160mg or 320mg of Valsartan. Diovan® capsules contain colloidal silicon dioxide, crospovidone, povidone, sodium lauryl sulphate and microcrystalline cellulose as inactive.
Hydrochlorothiazide is a diuretic and belongs to the thiazide class of diuretics, acting on the kidney to reduce sodium (Na) reabsorption in the distal convoluted tubule which inturn reduces the osmotic pressure in the kidney, causing less water to be reabsorbed by the collecting ducts and thereby leads to an increased urinary


output. Hydrochlorothiazide is used in the treatment of hypertension either alone or with other antihypertensive agents to enhance the effectiveness of other antihypertensive drugs in severe forms of hypertension.
Hydrochlorothiazide is chemically 6-chloro-3,4,dihydro-2H-1,2,4-
benzothiadiazine-7-sulfonamide 1,1-dioxide having molecular formula
C7H8CIN3O4S2 and molecular weight 297.72. Hydrochlorothiazide is a white crystalline powder slightly soluble in water, but freely soluble in sodium hydroxide solution.
Combination of Valsartan and Hydrochlorothiazide has been found to be more effective than either drug given alone. Diovan HCT tablets contain Valsartan and Hydrochlorothiazide, wherein the inactive ingredients are colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, iron oxides, magnesium stearate, macrocrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.
EP0750500 discloses a method of formulating Valsartan Capsules by wet granulation technique. The active ingredient Valsartan and fillers such as microcrystalline cellulose are mixed and granulated with a solution of povidone and sodium lauryl sulphate in water . The mixture is dried and then mixed with crospovidone and magnesium stearate. The resulting mixture is filled in suitable size hard gelatin capsules. However, this method has certain disadvantages such as the process is lengthy and involves use of aqueous fluids for granulation and heat for drying which can adversely affect stability of the product.
US5399578 discloses an antihypertensive pharmaceutical composition containing Valsartan and further discloses a method of treating high blood pressure and cardiac insufficiency in a human.


EP0914119 discloses a process for preparation of a compressed solid oral dosage form of Valsartan wherein Valsartan is present in an amount of more than 35% by weight of total solid oral dosage form.
WO2007052307 discloses compositions containing Valsartan in an amount less than 35% by weight based on the total weight of the solid oral dosage form.
WO03097045 discloses a pharmaceutical composition containing an angiotensin receptor blocker, a calcium channel blocker and a diuretic.
While numerous formulations of Valsartan are known in the art, they are tedious and time consuming and therefore there exists a need for developing formulations which are easy, economic and less time consuming.
Object of the Invention:
The main object of the invention is to provide pharmaceutical compositions used for the treatment of hypertension and heart failure comprising Valsartan alone or in combination with Hydrochlorothiazide; wherein said compositions are provided as capsule dosage form.
Another object of the invention is to provide a process for preparation of compositions of Valsartan and Hydrochlorothiazide by dry granulation method.
Yet another object of the invention is to provide a process which is efficient, economic, simple, less time consuming in comparison to the prior art processes and suitable for commercial scale preparation.
Another object of the invention is to ameliorate one or more drawbacks of the prior art processes.


Summary of the invention:
The present invention discloses pharmaceutical compositions comprising :
(i) an active agent Valsartan and optionally Hydrochlorothiazide;
(ii) suitable pharmaceutically acceptable additives; wherein said compositions are
provided as capsule dosage forms.
Further, the invention discloses novel process for preparation of pharmaceutical compositions of Valsartan by dry granulation method.
According to one embodiment of the invention, the process for preparation of pharmaceutical compositions of Valsartan by dry granulation method comprises the steps of:
(a) mixing Valsartan and optionally Hydrochlorothiazide with suitable pharmaceutically acceptable additives to form a mixture;
(b) compacting the mixture of step(a) at a compaction force below 23 KN;
(c) sizing the compacted mixture to form granules;
(d) further lubricating the granules;
(e) filling the lubricated granules into hard gelatin capsules or hard cellulose capsules.
According to another embodiment of the invention, the process for preparation of pharmaceutical compositions of Valsartan and Hydrochlorothiazide comprises the steps of:
(a) mixing Valsartan with suitable pharmaceutically acceptable additives to form a mixture;
(b) compacting the mixture of step(a) at a compaction force below 23 KN;
(c) sizing the compacted mixture to form granules;
(d) lubricating the granules with Hydrochlorothiazide and suitable additives;
(e) filling the lubricated granules into hard gelatin capsules or hard cellulose capsules.


According to still another embodiment of the invention, the process for preparation of pharmaceutical compositions of Valsartan and Hydrochlorothiazide comprises the steps of:
(a) mixing Valsartan with suitable pharmaceutically acceptable additives to form a mixture;
(b) compacting the mixture of step(a) at a compaction force below 23 KN;
(c) sizing the compacted mixture to form granules;
(d) separately preparing Hydrochlorothiazide granules using suitable pharmaceutically acceptable additives and optionally using surfactants;
(e) mixing the granules of Valsartan with granules of Hydrochlorothiazide;
(f) further lubricating the mixture of step(e) with suitable additives;
(g) filling the lubricated granules into hard gelatin capsules or hard cellulose capsules.
Description of the invention:
The present invention describes pharmaceutical compositions used for the
treatment of hypertension and heart failure comprising :
(i) an active agent Valsartan and optionally Hydrochlorothiazide;
(ii) suitable pharmaceutically acceptable additives.
Particularly, said compositions are provided in the form of capsule dosage forms such as hard gelatin capsules or hard cellulose capsules; which are formulated and developed using suitable pharmaceutically acceptable additives.
The present invention further encompass a novel process for preparation of pharmaceutical compositions of Valsartan by dry granulation method.
Although the prior art states that capsules are not most preferred since large capsules need to be used to accommodate effective amounts of the fluffy drug


Valsartan, the inventors of the present invention has successfully overcome that drawback.
Valsartan has low density and hence very fluffy. One main challenge in the formulation of capsules of Valsartan is the fluffy nature of the active ingredient. However, the inventors of the present invention have successfully developed compositions of valsartan by dry granulation method.
The present invention provides a process of preparation which is efficient, economic, simple, and less time consuming in comparison to the various prior art processes. Further, the process as described herein is suitable for commercial scale preparation of pharmaceutical compositions of Valsartan.
According to one embodiment of the present invention, the process for preparation of pharmaceutical compositions of Valsartan by dry granulation method comprises the steps of:
(a) mixing Valsartan and optionally Hydrochlorothiazide with suitable pharmaceutically acceptable additives to form a mixture;
(b) compacting the mixture of step(a) at a compaction force below 23 KN;
(c) sizing the compacted mixture to form granules;
(d) further lubricating the granules;
(e) filling the lubricated granules into hard gelatin capsules or hard cellulose capsules.
According to the present invention, the powder particles of Valsartan are converted into granules by applying the pressure and there by eliminating the use of any solvent.


In the practice of the present invention, the powders are compacted using either a conventional tabletting machine or a roller compactor. In a roller compactor, the powder mix is squeezed between the two rollers providing a compressed sheet which may further be screened to obtain granules. Milling may be carried out using any conventional milling equipment such as a multimill or a hammer mill.
According to another embodiment of the invention, the process for preparation of pharmaceutical compositions of Valsartan and Hydrochlorothiazide comprises the steps of:
(a) mixing Valsartan with suitable pharmaceutically acceptable additives to form a mixture;
(b) compacting the mixture of step(a) at a compaction force below 23 KN;
(c) sizing the compacted mixture to form granules;
(d) lubricating the granules with Hydrochlorothiazide and suitable additives;
(e) filling the lubricated granules into hard gelatin capsules or hard cellulose capsules.
According to still another embodiment of the invention, the process for preparation of pharmaceutical compositions of Valsartan and Hydrochlorothiazide comprises the steps of:
(a) mixing Valsartan with suitable pharmaceutically acceptable additives to form a mixture;
(b) compacting the mixture of step(a) at a compaction force below 23 KN;
(c) sizing the compacted mixture to form granules;
(d) separately preparing Hydrochlorothiazide granules using suitable pharmaceutically acceptable additives and optionally using surfactants;
(e) mixing the granules of Valsartan with granules of Hydrochlorothiazide;
(f) further lubricating the mixture of step(e) with suitable additives;
(g) filling the lubricated granules into hard gelatin capsules or hard cellulose capsules.


Empty hard gelatin capsule or empty hard cellulose capsule can be used in the size from '4' to '00'; preferred being size '0', '00’, '2' and '4'.
The process of preparation as described herein is simple and faster in comparison to the prior art processes. Further the present invention uses compaction force below 23 KN which gives sufficient flow and bulk density to the powder to be filled in capsules. In the practice of the present invention, the process does not employ the use of any aqueous or non- aqueous fluids as binder and the absence of these aqueous or non- aqueous fluids render more stable product. Further the process does not involve the drying step and hence the exposure of drug to elevated temperature is avoided.
Suitable pharmaceutically acceptable additives that can be used according to the present invention include, but are not limited to diluents, disintegrants, lubricants, glidants, surfactants and the like.
Diluents/fillers include, but are not limited to microcrystalline cellulose, lactose, dibasic calcium phosphate, corn starch, sugar derivatives, dextrates, dextrins, starch and mixtures thereof and is used in an amount from 30.0% to 60.0% by weight of the total composition.
Disintegrants include, but are not limited to one or more of crospovidone, carboxy methylcellulose calcium, sodium starch glycollate, starch, croscarmellose sodium and combinations thereof. Preferably, the disintegrant is used in an amount from 3.0% to 15.0% by weight of the total composition.
Surfactants include, but are not limited to sodium lauryl sulphate, poloxamer 188 and is used in an amount from 0.5% to 15.0% by weight of the total composition.


Lubricants and glidants include talc, colloidal silicon dioxide, magnesium stearate, hydrogenated castor oil, stearic acid, sodium stearyl fumarate and the like and is used in an amount from 0.5% to 15.0% by weight of the total composition.
According to the present invention, Valsartan is present in an amount from 35.0% to about 50.0% by weight of total composition.
According to one aspect, Valsartan is present in the composition preferably in an amount from 20 mg to 320 mg; preferably in an amount from 40 mg to 320mg.
According to a preferred aspect of the present invention, the pharmaceutical compositions may contain Valsartan in various doses such as 40mg, 80mg, 160mg and 320 mg.
According to one aspect, 80mg or 160mg or 320mg of Valsartan is combined with 12.5mg of Hydrochlorothiazide. According to another aspect, 80mg, 160mg or 320mg of Valsartan is combined with 12.5mg or 25mg of Hydrochlorothiazide.
Weight ratio of Valsartan to Hydrochlorothiazide is in the range of about 30 : 1 to about 3:1, preferably 28 : 1 to 5 : 1.
The pharmaceutical compositions prepared by the process as described herein shows in-vitro dissolution profile similar to that of the Valsartan tablets (Diovan®) by innovator.
The pharmaceutical compositions of the present invention may be used for the treatment of hypertension and heart failure.


Another aspect of the invention is to provide a method for treating hypertension and heart failure by administering a pharmaceutical composition comprising Valsartan or a combination of Valsartan and Hydrochlorothiazide prepared according to the present invention to patients in need thereof.
The present invention is further illustrated by reference to the following examples which do not limit the scope of the invention in any way. It will be apparent to those skilled in the art that many modifications, both to the materials and methods, can be practiced without departing from the purpose and scope of the disclosure.
Examples :
Example 1
Co-sifted Valsartan (160g) and microcrystalline cellulose (136.5g) were mixed in a suitable mixer and was further sifted using a suitable mesh. This blend was lubricated with crospovidone (12.5g), colloidal silicon dioxide (3.25g) and magnesium stearate (1.5g) and was compacted to form slugs. The slugs were milled and sifted through suitable mesh to get sized granules. The sized granules were lubricated with crospovidone (12.5g), colloidal silicon dioxide (3.25g), magnesium stearate (0.5g) and microcrystalline cellulose (30g). The lubricated granules were filled into capsules of suitable size.
Example 2
Co-sifted Valsartan (160g), lactose anhydrous (67.5g) and microcrystalline cellulose (67.5g) were mixed in a suitable mixer and was further sifted using a suitable mesh. This blend was lubricated with crospovidone (12.5g), colloidal silicon dioxide (3.25g) and sodium stearyl fumarate (2g) and was compacted to form slugs. The slugs were milled and sifted through suitable mesh to get sized granules. The sized granules were lubricated with crospovidone (12.5g), colloidal


silicon dioxide (3.25g), sodium stearyl fumarate (1.5g) and lactose anhydrous (15g) and microcrystalline cellulose (15g) . The lubricated granules were filled into capsules of suitable size.
Example 3
Co-sifted Valsartan (160g) and dibasic calcium phosphate(131.5g) were mixed in a suitable mixer and was further sifted using a suitable mesh. This blend was lubricated with crospovidone (12.5g), colloidal silicon dioxide (3.25g), sodium lauryl sulphate (2.5g) and magnesium stearate (1.5g) and was compacted to form slugs. The slugs were milled and sifted through suitable mesh to get sized granules. The sized granules were lubricated with crospovidone (12.5g), colloidal silicon dioxide (3.25g), sodium lauryl sulphate(2.5 mg), magnesium stearate (0.5g) and microcrystalline cellulose (30g). The lubricated granules were filled into capsules of suitable size.
Example 4
Co-sifted Valsartan (160g) and microcrystalline cellulose (131.5g) were mixed in a suitable mixer and was further sifted using a suitable mesh. This blend was lubricated with crospovidone (12.5g), colloidal silicon dioxide (3.25g) and combination of magnesium stearate (1.5g) and sodium lauryl sulphate (2.5g) and was compacted to form slugs. The slugs were milled and sifted through suitable mesh to get sized granules. The sized granules were lubricated with crospovidone (12.5g), colloidal silicon dioxide (3.25g), magnesium stearate (0.5g), sodium lauryl sulphate (2.5g) and microcrystalline cellulose (30g). The lubricated granules were filled into capsules of suitable size.


Example 5
Co-sifted Valsartan (160g), Hydrochlorothiazide (12.5g) and microcrystalline cellulose (119g) were mixed in a suitable mixer and was further sifted using a suitable mesh. This blend was lubricated with crospovidone (12.5g), sodium lauryl sulphate (2.5g), colloidal silicon dioxide (3.25g) and magnesium stearate (1.5g) and was compacted to form slugs. The slugs were milled and sifted through suitable mesh to get sized granules. The sized granules were lubricated with crospovidone (12.5g), colloidal silicon dioxide (3.25g), magnesium stearate (0.5g), sodium lauryl sulphate (2.5g) and microcrystalline cellulose (30g). The lubricated granules were filled into capsules of suitable size.
Example 6
Co-sifted Valsartan (160g) and microcrystalline cellulose (119g) were mixed in a suitable mixer and was further sifted using a suitable mesh. This blend was lubricated with crospovidone (12.5g), sodium lauryl sulphate (2.5g), colloidal silicon dioxide (3.25g) and magnesium stearate (1.5g) and was compacted to form slugs. The slugs were milled and sifted through suitable mesh to get sized granules. The sized granules were lubricated with crospovidone (12.5g), Hydrochlorothiazide (12.5g), colloidal silicon dioxide (3.25g), magnesium stearate (0.5g), sodium lauryl sulphate (2.5g) and microcrystalline cellulose (30g). The lubricated granules were filled into capsules of suitable size.


Example 7
Co-sifted Valsartan (160g) and microcrystalline cellulose (99g) were mixed in a suitable mixer and was further sifted using a suitable mesh. This blend was lubricated with crospovidone (12.5g), sodium lauryl sulphate (2.5g), colloidal silicon dioxide (3.25g) and magnesium stearate (1.5g) and was compacted to form slugs. The slugs were milled and sifted through suitable mesh to get sized granules. Hydrochlorothiazide (12.5g) and microcrystalline cellulose ( 40 g) were mixed in a suitable mixer and was further sifted using a suitable mesh. This blend was granulated with a binder solution of hydroxypropyl methylcellulose in Purified Water. The granules obtained were dried in drier. The granules were further sized using suitable mesh sieve. The sized granules of valsartan and Hydrochlorothiazide were lubricated with crospovidone (12.5g), colloidal silicon dioxide (3.25g), magnesium stearate (0.5g), sodium lauryl sulphate (2.5g) and microcrystalline cellulose (10g). The lubricated granules were filled into capsules of suitable size.
A dissolution test was carried out by USP II method ( 50 rpm, 1000 ml, 0.067 M Phosphate buffer pH 6.8) and the in-vitro release profile is as follows:

Time in minutes Innovator -Diovan TabletsDrug Release (%) Example 1 Drug Release (%) Example 4 Drug Release (%)
15 93.73 91.10 92.90
30 94.05 92.20 95.20
45 94.13 93.00 96.10


While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its spirit and scope, as defined by the appended claims.