WO2009113091A2

WO2009113091A2 - Pharmaceutical compositions comprising valsartan

Info

Publication number: WO2009113091A2
Application number: PCT/IN2009/000040
Authority: WO
Inventors: Ashok Omray; Sandhya Rajendra Shenoy; Monika Srivastav
Original assignee: Usv Limited
Priority date: 2008-01-24
Filing date: 2009-01-13
Publication date: 2009-09-17
Also published as: WO2009113091A3

Abstract

Disclosed herein are pharmaceutical compositions comprising Valsartan and pharmaceutically acceptable additives optionally in combination with Hydrochlorothiazide and process for their preparation.

Description

Pharmaceutical compositions comprising Valsartan

Related application:

This application claims the benefit of Indian Provisional Application No.

171/MUM/2008 filed on 24^th January 2008 and 1625/MUM/2008 filed on 30^th July

2008.

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 novel processes 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) [l,l'-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

QH8CIN3O4S2 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, microcrystalline cellulose, polyethylene glycol, talc and titanium dioxide.

US5399578 discloses process for preparation of Valsartan and its pharmaceutically acceptable salts, pharmaceutical composition containing Valsartan and a method of treating high blood pressure and cardiac insufficiency in a human. EP0750500 discloses use of Valsartan for the treatment of diabetic nephropathy. EP914119 discloses a process for preparation of Valsartan compositions by dry compression method wherein Valsartan is present in an amount of more than 35% by weight of total solid oral dosage form. The process involves grinding the active agent and pharmaceutically acceptable additives and subjecting the mixture to compression using compaction force in the range of 25 to 65 KN to form a comprimate and converting the comprimate to form a granulate and further compressing the granulate to form the compressed solid oral dosage form. However EP '119 discloses compositions prepared in the absence of water.

WO2008006716 discloses a process which involves the steps of: a) providing a mixture comprising: a water-insoluble sartan, a water soluble carrier, a solvent for each of the sartan and the carrier, and b) spray-drying the mixture to remove the solvent or each solvent and obtain a substantially solvent-free nano-dispersion of the sartan in the carrier.

WO2007077581 discloses solid oral dosage forms of hydrophobic active ingredients prepared by treating pharmaceutically effective amounts of the active ingredient with a particle separating agent. This application further discloses solid oral dosage forms of hydrophobic actives without or with a minimum amount of disintegrants.

WO2008056375 discloses pharmaceutical composition of Valsartan prepared by wet granulation wherein the active agent is present in an amount less than 35% by weight based on the total weight of the pharmaceutical composition. 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, the processes for their preparation are tedious and time consuming and therefore there exists a need for developing formulations which are easy, economic and less time consuming.

The present inventors have developed various approaches for formulating Valsartan alone or in combination with Hydrochlorothiazide and pharmaceutically acceptable additives into solid oral dosage forms using novel and simple techniques.

Object of the Invention:

An object of the invention is to provide pharmaceutical compositions comprising Valsartan and additives suitable for preparation of compressed solid oral dosage form optionally in combination with diuretics such as Hydrochlorothiazide wherein said compressed solid oral dosage forms are prepared by a process comprising solvent wetting method.

Another object of the invention is to provide compositions comprising Valsartan, optionally in combination with diuretics such as Hydrochlorothiazide; wherein said compositions are provided as capsule dosage forms and are prepared by a process comprising dry granulation method.

Yet another object of the invention is to provide processes for preparation of pharmaceutical compositions as described herein comprising Valsartan alone or in combination with diuretics such as Hydrochlorothiazide; said processes being efficient, economic, simple, less time consuming and suitable for commercial scale preparation.

Another object of the invention is to provide a method for treating hypertension and heart failure by orally administering to the subject pharmaceutical compositions comprising Valsartan optionally in combination with Hydrochlorothiazide; wherein said compositions are prepared by the processes as described herein.

Summary of the invention:

The present invention provides pharmaceutical compositions comprising Valsartan optionally in combination with diuretics such as Hydrochlorothiazide and pharmaceutically acceptable additives suitable for preparation of compressed solid oral dosage forms.

The present invention further provides a novel process for preparation of pharmaceutical compositions comprising Valsartan alone or in combination with Hydrochlorothiazide; the said process comprising solvent wetting method.

Further, the invention provides pharmaceutical compositions comprising Valsartan, optionally in combination with Hydrochlorothiazide; wherein said compositions are provided as capsule dosage forms and are prepared by a process comprising dry granulation method.

According to one aspect, the present invention provides process for preparation of pharmaceutical compositions of Valsartan comprising solvent wetting method, said process comprising the steps of:

(a) preparing a mixture of Valsartan and one or more diluent or optionally only Valsartan;

(b) wetting the prepared mixture or only Valsartan using suitable solvent;

(c) drying the wet mass and further sizing to form dried material;

(d) lubricating the dried material with suitable pharmaceutical additives to form a blend;

(e) compressing the lubricated blend into tablets;

(f) coating the tablets. According to another aspect, the present invention provides process for preparation of pharmaceutical compositions of Valsartan and Hydrochlorothiazide comprising solvent wetting method, said process comprising the steps of:

(a) preparing a mixture of Valsartan, Hydrochlorothiazide and one or more diluent;

(b) wetting the prepared mixture using suitable solvent;

(c) drying the wet mass and further sizing to form dried material;

(e) compressing the lubricated blend into tablets;

(f) coating the tablets.

According to another aspect, the invention provides process for preparation of pharmaceutical compositions of Valsartan and Hydrochlorothiazide comprising solvent wetting method, said process comprising the steps of:

(a) preparing a mixture of Valsartan and one or more diluent;

(b) wetting the prepared mixture using suitable solvent;

(c) drying the wet mass and further sizing to form dried material;

(d) lubricating the dried material of step (c) with the active ingredient Hydrochlorothiazide and suitable additives; or separately preparing Hydrochlorothiazide granules and lubricating with granules of step (c) to form a blend and

(e) compressing the lubricated blend into tablets;

(f) coating the tablets.

According to another aspect, the present invention provides a process for preparation of pharmaceutical compositions of Valsartan optionally in combination with Hydrochlorothiazide by wet granulation method comprising the steps of:

(a) preparing a mixture of Valsartan and one or more suitable pharmaceutically acceptable additives selected from diluents and disintegrants optionally in combination with Hydrochlorothiazide;

(b) preparing a binder solution by dissolving the binder and/or surfactant in water;

(c) granulating the mixture of step (a) with the binder solution of step (b) to form wet granules;

(d) drying the granules;

(e) further sizing and milling the dried granules;

(f) lubricating the dried granules;

(g) compressing the lubricated granules into tablets; (h) coating the tablets.

(a) preparing a mixture of Valsartan and one or more suitable pharmaceutically acceptable additives selected from diluents and disintegrants;

(c) granulating the mixture of step(a) with the binder solution of step(b) to form wet granules;

(d) drying the granules;

(e) further sizing and milling the dried granules;

(f) lubricating the dried granules with the active ingredient Hydrochlorothiazide and suitable additives; or separately preparing Hydrochlorothiazide granules and lubricating with granules of step (e) and

(g) compressing the lubricated granules into tablets; (h) coating the tablets. According to a further aspect, the present invention provides process for preparation of pharmaceutical compositions of Valsartan by dry granulation method comprising the steps of:

(a) mixing Valsartan with suitable pharmaceutically acceptable additives and optionally Hydrochlorothiazide 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;

(e) filling the lubricated granules into hard gelatin capsules or hard cellulose capsules.

According to another aspect, the present invention provides process for preparation of pharmaceutical compositions of Valsartan and Hydrochlorothiazide by dry granulation method comprising 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 of step (c) with the active ingredient Hydrochlorothiazide and suitable additives; or separately preparing Hydrochlorothiazide granules and lubricating with granules of step (c) and

The invention further provides a method for treating a patient suffering from hypertension and heart failure by orally administering to the patient pharmaceutical compositions as disclosed herein. Description of the invention:

The present invention describes pharmaceutical compositions comprising Valsartan and pharmaceutically acceptable additives suitable for preparation of compressed solid oral dosage form. Further, the invention describes pharmaceutical compositions comprising Valsartan in combination with a diuretic such as Hydrochlorothiazide. A novel process for preparation of said compositions comprising solvent wetting method is also described herein. Particularly, said compositions are provided in the form of tablet dosage forms such as film coated tablet; which are formulated and developed using suitable pharmaceutically acceptable additives.

In practice of the present invention, any commercially available Valsartan can be used or Valsartan as used in the present invention may be prepared by the conventional processes or as specified herein.

Valsartan has low bulk density and hence very fluffy. The fluffy and fine particles of Valsartan are difficult to compress as the required quantity of powder does not fit physically into the die cavity on the tablet press. Further, due to low bulk density of Valsartan the fill volume is more than that which may be accommodated in the die cavity. Prior art teaches Valsartan tablets prepared by dry compaction method to improve the compressiblity of Valsartan.

Hence, the main challenge in the formulation of solid oral dosage forms of Valsartan is the fluffy nature of the active ingredient. The inventors of the present invention have successfully developed pharmaceutical compositions comprising Valsartan involving solvent wetting method, wherein the physical characteristics of Valsartan is improved using suitable solvents by processes as described herein.

In the practice of the present invention, the fluffy particles of Valsartan are converted into free flowing particles by wetting the particles with a suitable solvent by a process comprising the solvent wetting method. The solvent wetting is the process of adding a liquid solution or solvent to the fluffy particles/powders. When the solvents are mixed with the particles/powders they form bonds between the powder particles and the bonds are strong enough to lock them together. The particles adhere to each other because of liquid films of the solvent and bonding starts with particle-particle contact and adhesion due to liquid bridges resulting into particles with increased density. The amount of solvent that may be required for wetting depends on the nature of the particle/powder. Some particles/powders require addition of only small amount of solvent to form a free flowing powder. Wetting with the solvent helps in decreasing the inter particulate distance and increasing the contact area between the particles resulting in improved flow and bulk density of fluffy Valsartan which is essential for compression process.

The present invention describes a process for preparation of pharmaceutical compositions of Valsartan, the process comprising solvent wetting method comprising the steps of mixing Valsartan with pharmaceutically acceptable additives to form a mixture or providing only Valsartan, wetting the mixture or only Valsartan with a suitable solvent, drying and formulating into compressed solid oral dosage form.

According to one embodiment of the present invention, the process for preparation of pharmaceutical compositions of Valsartan comprises solvent wetting method comprising the steps of:

(a) preparing a mixture of Valsartan and one or more pharmaceutically acceptable additives selected from diluent, disintegrant, binder and surfactant or optionally only Valsartan;

(b) wetting the prepared mixture or only Valsartan using suitable solvent;

(c) drying the wet mass and further sizing to form dried material;

(d) lubricating the dried material with suitable pharmaceutical additives to form a blend; (e) compressing the lubricated blend into tablets;

(f) coating the tablets.

According to another embodiment of the present invention, the process for preparation of pharmaceutical compositions of Valsartan comprises solvent wetting method comprising the steps of:

(a) preparing a mixture of Valsartan and one or more pharmaceutically acceptable additives selected from diluent, disintegrant, binder and surfactant;

(b) optionally dissolving the binder or surfactant in a solvent or a mixture of solvent to form a solution;

(c) wetting the mixture of step (a) using suitable solvent or solution of step(b);

(d) drying the wet mass and further sizing to form dried material;

(e) lubricating the dried material with suitable pharmaceutical additives to form a blend;

(f) compressing the lubricated blend into tablets;

(g) coating the tablets.

The invention further describes a process for preparation of pharmaceutical compositions of Valsartan and Hydrochlorothiazide, the process comprising solvent wetting method comprising the steps of mixing Valsartan, Hydrochlorothiazide with pharmaceutically acceptable additives to form a mixture, wetting the mixture with a suitable solvent, drying and formulating into compressed solid oral dosage form.

According to another embodiment of the present invention, the process for preparation of pharmaceutical compositions of Valsartan and Hydrochlorothiazide comprises solvent wetting method comprising the steps of:

(a) preparing a mixture of Valsartan, Hydrochlorothiazide and one or more pharmaceutically acceptable additives selected from diluent, disintegrant, binder and surfactant;

(b) wetting the prepared mixture using suitable solvent;

(c) drying the wet mass and further sizing to form dried material;

(e) compressing the lubricated blend into tablets;

(f) coating the tablets.

'According to another embodiment of the present invention, the process for preparation of pharmaceutical compositions of Valsartan and Hydrochlorothiazide comprises solvent wetting method comprising the steps of:

(b) wetting the prepared mixture using suitable solvent;

(c) drying the wet mass and further sizing;

(d) blending the dried mass with Hydrochlorothiazide and suitable pharmaceutical additives;

(e) compressing the blend of step (d) into tablet;

(f) coating the tablets.

(b) wetting the prepared mixture using suitable solvent;

(c) drying the wet mass and further sizing to form dried material;

(d) separately preparing the granules of Hydrochlorothiazide by aqueous or non-aqueous granulation;

(e) blending the dried material of step(c) with Hydrochlorothiazide granules of step(d); and

(f) further lubricating with suitable pharmaceutical additives to form a blend;

(g) compressing the blend into tablets; (h) coating the tablets.

(b) wetting the prepared mixture using suitable solvent;

(c) drying the wet mass and further sizing ;

(d) lubricating the dried mass with suitable pharmaceutical additives;

(e) separately preparing the granules of Hydrochlorothiazide;

(f) compressing the lubricated blend of Valsartan and granules of Hydrochlorothiazide to form bilayer tablet.

According to a preferred embodiment, the process for preparation of pharmaceutical . compositions of Valsartan comprising solvent wetting method comprises the steps of:

(a) sifting Valsartan and microcrystalline cellulose through suitable mesh and mixing in a rapid mixer granulator to form a mixture;

(b) wetting the prepared mixture of step (a) using dichloromethane;

(c) air drying the wet mass initially and further drying at 4O⁰C till loss on drying value is less than 5% and further sizing ;

(d) lubricating the dried mass with sifted lactose monohydrate, crospovidone, colloidal silicon dioxide and magnesium stearate; (e) compressing the lubricated blend into tablet and

(f) coating the tablets.

According to another preferred embodiment, the process for preparation of pharmaceutical compositions of Valsartan and Hydrochlorothiazide comprising solvent wetting method comprises the steps of:

(b) wetting the prepared mixture of step (a) using dichloromethane;

(d) blending the dried mass with sifted Hydrochlorothiazide, lactose monohydrate, crospovidone, colloidal silicon dioxide and magnesium stearate;

(e) compressing the blend of step (d) into tablet

(f) coating the tablets.

In the practice of the present invention, wetting of the mixture of Valsartan and other additives may be carried out using 10.0% to 40.0% solvent. Initial drying is performed without application of temperature and further drying is performed for sufficient time at a temperature of 40⁰C till 'Loss on drying' value of less than 5.0% is achieved.

In this approach, the process of mixing and wetting may be carried out either in a rapid mixer granulator or a planetary mixer. Drying of wet mass may be carried out using fluidized bed drier or tray drier. Compression may be carried out using equipments known in the art such as a rotary tablet press or any suitable tabletting machine. Coating may be carried out using equipments known in the art such as spray coating or coating in conventional coating pan or perforated pans. The present invention further describes a process for preparation of compressed solid oral dosage form comprising Valsartan and pharmaceutically acceptable additives, the process comprising the steps of mixing Valsartan and pharmaceutically acceptable additives optionally with Hydrochlorothiazide to form a mixture, granulating the mixture using a binder solution to form granules and further formulating into compressed solid oral dosage form.

According to another embodiment, the present invention provides a process for preparation of pharmaceutical compositions of Valsartan by wet granulation method comprising the steps of:

(d) drying the granules;

(e) further sizing and milling the dried granules;

(f) lubricating the dried granules;

(g) compressing the lubricated granules into tablets; (h) coating the compressed tablets.

According to another embodiment, the present invention provides a process for preparation of pharmaceutical compositions of Valsartan and Hydrochlorothiazide by wet granulation method comprising the steps of:

(a) preparing a mixture of Valsartan, Hydrochlorothiazide and one or more suitable pharmaceutically acceptable additives selected from diluents and disintegrants;

(d) drying the granules;

(e) further sizing and milling the dried granules;

(f) lubricating the dried granules;

(a) preparing a mixture of Valsartan and one or more suitable pharmaceutically acceptable additives selected from diluents and disinte grants;

(d) drying the granules;

(e) further sizing and milling the dried granules;

(f) blending the dried granules with Hydrochlorothiazide and suitable additives;

(g) compressing the blend of step (f) into tablets; (h) coating the compressed tablets.

(d) drying the granules;

(e) further sizing and milling the dried granules;

(f) separately preparing the granules of Hydrochlorothiazide by aqueous or non-aqueous granulation;

(g) blending granules of Valsartan of step(e) with granules of Hydrochlorothiazide of step(f); and

(h) further lubricating with suitable pharmaceutical additives to form a blend; (i) compressing the lubricated blend into tablets; Q) coating the compressed tablets.

According to a preferred embodiment, the present invention provides process for preparation of pharmaceutical compositions of Valsartan by wet granulation method comprising the steps of:

(a) sifting Valsartan, microcrystalline Cellulose and crospovidone through a suitable mesh and mixing in a fluid bed processor;

(b) preparing a binder solution by dissolving polyvinylpyrrolidone and sodium lauryl sulphate in purified water;

(d) drying the granules;

(e) further sizing through a suitable mesh sieve and milling the dried granules;

(f) lubricating the dried granules with crospovidone, colloidal silicon dioxide and magnesium s tear ate;

(g) compressing the lubricated granules into tablets; (h) coating the tablets.

According to another preferred embodiment, the present invention provides process for preparation of pharmaceutical compositions of Valsartan and Hydrochlorothiazide by wet granulation method comprising the steps of:

(b) preparing a binder solution by dissolving polyvinylpyrrolidone in purified water and adding sodium lauryl sulphate;

(d) drying the granules;

(f) sifting Hydrochlorothiazide, crospovidone and colloidal silicon dioxide and magnesium stearate and blending with dried granules of step (e)

In the practice of the present invention, wet granulation may be carried out using equipments known in the art such as rapid mixer granulator or fluid bed processor. In a conventional fluid bed processor both the steps of granulation and drying can be carried out in the same equipment thereby simplifying the process and saving the processing time. Compression may be carried out using equipments known in the art such as a rotary tablet press or any suitable tabletting machine. Coating may be carried out using equipments known in the art such as spray coating or coating in conventional coating pan or perforated pans.

Though 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 have successfully overcome that drawback and developed compositions of Valsartan by dry granulation method.

The invention further describes pharmaceutical compositions of Valsartan by dry granulation method provided in the form of capsule dosage forms and a process for preparation of capsule dosage form of Valsartan comprising dry granulation method comprising the steps of mixing Valsartan and pharmaceutically acceptable additives optionally with Hydrochlorothiazide to form a mixture; compacting the mixture at a compaction force below 23 KN, sizing to form granules and further formulating into capsules.

According to one embodiment, the present invention provides process for preparation of pharmaceutical compositions of Valsartan by dry granulation method comprising 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;

In this approach of the present invention, the powder particles of Valsartan are converted into granules by applying the pressure and thereby eliminating the use of any solvent. In the practice of this approach 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, the present invention provides process for preparation of pharmaceutical compositions of Valsartan and Hydrochlorothiazide by dry granulation method comprising the steps of:

(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;

According to another embodiment, the present invention provides process for preparation of pharmaceutical compositions of Valsartan and Hydrochlorothiazide by dry granulation method comprising the steps of:

(b) compacting the mixture of step(a) at a compaction force below 23 KN;

(c) sizing the compacted mixture to form granules;

(d) preparing Hydrochlorothiazide granules using suitable pharmaceutically acceptable additives and optionally using surfactants;

(e) mixing the granules of Valsartan step (c) with granules of Hydrochlorothiazide of step (d);

(f) further lubricating the mixture of step (e) with suitable additives;

(g) filling the lubricated granules into hard gelatin capsules or hard cellulose capsules.

According to a preferred embodiment, the invention provides the process for preparation of pharmaceutical compositions of Valsartan comprising the steps of : (a) mixing co-sifted Valsartan and microcrystalline cellulose and lubricating with crospovidone, colloidal silicon dioxide and magnesium stearate 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 with crospovidone, colloidal silicon dioxide, magnesium stearate and microcrystalline cellulose;

According to a preferred embodiment, the invention provides process for preparation of pharmaceutical compositions of Valsartan and Hydrochlorothiazide comprising the steps of:

(a) mixing co-sifted Valsartan and microcrystalline cellulose and lubricating with crospovidone, colloidal silicon dioxide and magnesium stearate 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 with Hydrochlorothiazide, crospovidone, colloidal silicon dioxide, magnesium stearate and microcrystalline cellulose;

Empty hard gelatin capsule or empty hard cellulose capsule that can be used vary in size from '4' to OO'; preferred being size O', OO', '2' and '4'.

The present invention uses compaction force below 23 KN which gives sufficient flow and bulk density to the powder to be filled in capsules. The process of preparation of capsule dosage form as described herein is simple and faster in comparison to the prior art processes for the preparation of the capsules. Further, in this approach 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 renders a stable product. Further the process does not involve the drying step and hence the process of preparation of capsules is simplified.

According to the present invention Hydrochlorothiazide granules may be prepared by steps comprising of:

(a) mixing Hydrochlorothiazide with suitable pharmaceutically acceptable additives and

(b) granulating with aqueous or non-aqueous solvents optionally containing a binder,

(c) drying the wet mass and sifting through a suitable mesh size.

According to the 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 in an amount from 20 mg to 320 mg; preferably in an amount from 40mg 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.

The weight ratio of Valsartan to Hydrochlorothiazide is in the range of about 30 : 1 to about 3 : 1, preferably 28 : 1 to 5 : 1.

According to one aspect 80mg or 160mg or 320mg of Valsartan is combined with 12.5mg or 25mg of Hydrochlorothiazide.

Suitable pharmaceutically acceptable additives that may be used according to the present invention include, but are not limited to diluents/fillers, binders, disintegrants, lubricants, glidants, surfactants, coating agents, colorants, solvents and the like.

Diluents/fillers include, but are not limited to lactose, microcrystalline cellulose, dibasic calcium phosphate, corn starch, sugar derivatives, dextrates, dextrins, starch and mixtures thereof. Preferred diluent being microcrystalline cellulose. Diluents are used in an amount from about 25.0% to about 60.0% by weight of the total composition.

Solvents for wetting include but are not limited to methylene dichloride, methanol, ethanol, isopropyl alcohol, acetone or mixtures thereof. Preferably used solvent according to the present invention is methylene dichloride. The solvent is used in an amount from about 10.0% to about 40.0% by weight of the total composition.

Binders include, but are not limited to polyvinylpyrrolidone, hydroxypropyl methyl cellulose, hydroxyalkyl celluloses, hydroxpropyl cellulose and the like. Preferable binder according to the present invention is polyvinylpyrrolidone and is used in an amount from about 3% to about 20 % 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 mixtures thereof. Preferred disintegrant being crospovidone. Disintegrants are used in an amount from about 3.0% to about 25.0% by weight of the total composition.

Surfactants include, but are not limited to sodium lauryl sulphate, poloxamer, poloxamer 188, cremophor, docusate sodium and the like. Surfactants are be used in an amount from about 0.2% to about 5.0%by weight of the total composition. Lubricants include magnesium stearate, hydrogenated castor oil, stearic acid, sodium stearyl fumarate and the like. The preferred lubricant being magnesium stearate. Lubricants are used in an amount from about 0.2% to about 10.0% by weight of the total composition.

Glidants include talc, colloidal silicon dioxide and the like. The preferred glidant being colloidal silicon dioxide. Glidants are used in an amount from about 0.2% to about 10.0% by weight of the total composition.

Coating agents include, but are not limited to polysaccharides such as maltodextrin, alkyl celluloses such as methyl or ethyl cellulose; hydroxyalkyl celluloses such as hydroxypropyl cellulose or hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol and the like.

Plastisizers include but are not limited to dibutyl phthalate, triethyl citrate, polyethylene glycol, polyethylene derivative and mixtures thereof.

Solvents used in the non-aqueous coating comprises isopropyl alcohol, acetone, methanol and mixtures thereof.

Coloring agents may be selected from any FDA approved colours such as titanium dioxide, iron oxide red , iron oxide yellow and the like.

According to a preferred embodiment, the present invention provides pharmaceutical compositions comprising Valsartan prepared by solvent wetting method, wherein the composition comprises about 35.0% to about 50.0% by weight of Valsartan, about 25.0% to about 60.0% by weight of diluent, about 3.0% to about 25.0% by weight of disintegrant, about 0.2% to about 10.0% by weight of lubricant and 0.2% to about 10.0% by weight of glidant. According to a preferred embodiment, the present invention provides pharmaceutical compositions comprising Valsartan prepared by wet granulation method , wherein the composition comprises about 35.0% to about 50.0% by weight of Valsartan, about 25.0% to about 60.0% by weight of microcrystalline cellulose, about 3.0% to about 20.0% by weight of polyvinylpyrrolidone and about 0.2% to about 5.0% by weight of sodium lauryl sulphate along with acceptable additives.

According to a preferred embodiment, the invention provides pharmaceutical compositions comprising Valsartan prepared by dry granulation method, wherein the composition comprises about 35.0% to about 50.0% by weight of Valsartan about 25.0% to about 60.0% by weight of microcrystalline cellulose, about 3.0% to about 25.0% by weight of crospovidone, about 0.2% to about 10.0% by weight of colloidal silicon dioxide and 0.2% to about 10.0% by weight of magnesium stearate.

The process of preparation of pharmaceutical compositions according to the present invention are efficient, economic, simple, and less time consuming in comparison to the various prior art processes. Further, the process as described herein are suitable for commercial scale preparation of pharmaceutical compositions of Valsartan. The present invention provides stable compositions of Valsartan, wherein the compositions are prepared by processes described herein.

Another embodiment of the invention provides a method for treating hypertension and heart failure by orally administering to the subject a pharmaceutical composition comprising Valsartan or a combination of Valsartan and Hydrochlorothiazide; wherein said compositions are prepared by the processes as described herein.

As used herein, the term "additive" refers to a pharmaceutically acceptable ingredient that is commonly used in the pharmaceutical technology for preparing granules and/or solid oral dosage compositions.

As used herein, the terms "comprise," "comprising," and "include" are intended to be open, non-limiting terms, unless the contrary is expressly indicated.

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

Preparation of N- [(2'-cyanobiphenyl-4-yl)methyl]-N-pentanoyl-(L)- Valine methyl ester :

N- [(2'-cyanobiphenyl-4-yl)methyl] -(L)- Valine methyl ester ( 100 gm ) was reacted with valeroyl chloride ( 57.8 gm ) in presence of methylene dichloride (MDC) ( 600 ml ) and di-isopropyl ethyl amine (116 gm) for 48 hr at 25 to 35°C. After the completion of reaction 2 N hydrochloric acid solution (Cone. HCl 76.8 ml + water 365 ml ) was added to above reaction mass by maintaining at temperature 25 to 35 °C. The reaction mixture was stirred for 30 min. to separate the organic and aqueous layer. The separated organic layer was washed with sodium bicarbonate followed by sodium chloride solution. The organic layer was evaporated under vacuum to get N-[(2'-cyanobiphenyl-4-yl)methyl]-N-pentanoyl- (L)- Valine methyl ester (100 gm).

Preparation of crude Valsartan :

N- [(2'-cyanobiphenyl-4-yl)methyl]-N-pentanoyl-(L)- Valine methyl ester (lOOgm) reacted with tributyl tin azide , prepared from tributyl tin chloride (180 gm) and sodium azide (53.8 gm) in presence of o-xylene (600 ml) at reflux temperature (130 to 140⁰C) for 24 hours. The reaction mass was cooled to 25 to 3O⁰C and aqueous sodium hydroxide solution (100 gm sodium hydroxide dissolved in 800 ml water) was added to it maintaining temperature at 25 to 3O⁰C. The reaction mass was further stirred for 24 hour maintaining the same temperature. The separated aqueous layer was extracted with toluene (350x2). The separated aqueous layer was then cooled to 10 to 20⁰C and pH was adjusted to 7.5 to 8.0 by using cone. HCL acid at temperature 10 to 20⁰C. The reaction mass was extracted with methylene dichloride (MDC) (250 mlx2) and stirred for 30 min. The pH of the aqueous layer was adjusted to 2.0 to 3.0 by using cone. HCl acid . The reaction mass was extracted with MDC (250 mlx2) and stirred for 30 min. at 10 to 20⁰C. 300 ml hexane was added to the the separated organic layer at 20 to 30⁰C to precipitate out the compound followed by cooling to 0 to -5 ⁰C for 1 hour. The material was filtered and the obtained wet cake was washed with chilled MDC + hexane mixture (25 ml x 2) and dried at 25 to 35 ⁰C under vacuum to get 75 gm of Valsartan crude,.

Example 2

50 gm of Valsartan was dissolved in 800 ml of ethyl acetate at 50 to 55°C to get clear solution. 1 gm of charcoal was added to obtained solution and stirred for 10 min. The solution was filtered through hyflo bed and the material was washed with 30 ml of ethyl acetate. 830 ml of hexane was added to the obtained filtrate at 25 to 30⁰C to precipitate out the material maintaining same temperature for 1 hour. The material was filtered and washed with 30ml of hexane. The obtained wet material was slurrifϊed in 1 L n-pentane at 25 to 30⁰C for 30 min and filtered and washed with 0.1 L n-pentane The obtained material was dried under vacuum at 45 to 50⁰C till K_F is less than 2% to get 35 gm of amorphous Valsartan. The amorphous Valsartan thus obtained was passed through 30 mesh to get amorphous Valsartan with Particle size distribution (PSD) dgo < 50 micron, dso < 15 micron and dio < 5 micron. Example 3

100 gm of Valsartan was dissolved in 1.6L of ethyl acetate at 50 to 55⁰C to get clear solution. 2 gm of charcoal was added to obtained solution and stirred for 10 min. The solution was filtered through hyflobed and the material was washed with 60 ml of ethyl acetate. 1.66L of hexane was added to the obtained filtrate at 25 to 30°C to precipitate out the material maintaining same temperature for 1 hour. The material was filtered and washed with 60ml of hexane. The obtained wet material was slurrified in 2 L n-pentane at 25 to 30⁰C for 30 min and filtered. The cake was washed with 0.2 L n-pentane and the obtained material was dried under vacuum at 45 to 50⁰C till K_F is less than 2% to get 40 gm of amorphous Valsartan. The amorphous Valsartan thus obtained was passed through 30 mesh to get amorphous Valsartan with Particle size distribution (PSD) dw < 50 micron, dso < 15 micron and dio < 5 micron.

Example 4

Valsartan (16Og) was sifted through a suitable mesh sieve and transferred to a mixer and was then wetted with dichloromethane. The wet mass was dried and sifted through suitable mesh. The sized material was blended with microcrystalline cellulose (104.02g ), lactose monohydrate (35.98g), crospovidone (50g) and lubricated with colloidal silicon dioxide (5g) and magnesium stearate (5g). The lubricated blend was compressed using a suitable compression machine fitted with suitable punches and the tablets were coated using opadry (10 g).

Example 5

Valsartan (16Og) and microcrystalline cellulose (104.02g) were co-sifted and mixed in a suitable mixer. The mass was made wet with dichloromethane. The mass was then dried and sifted through suitable mesh sieve. Sized material was then blended with lactose monohydrate (35.98g), crospovidone (50g) and lubricated with colloidal silicon dioxide (5g) and magnesium stearate (5g). The lubricated blend was compressed into tablets using a suitable compression machine fitted with suitable punches and the tablets were coated using opadry (1Og).

Comparative in vitro dissolution study:

A dissolution study was conducted using the tablets prepared according to

Example 5 in comparison with Diovan® tablets of Novartis.

The dissolution test was carried out by USP II method (50 rpm, 1000 ml, 0.067 M

Phosphate buffer pH 6.8). Table 1 shows the in-vitro release profile.

Table 1

Example 6

Valsartan (160g), microcrystalline cellulose (104.8g) and crospovidone (2Og) was co-sifted through suitable mesh sieve and the sifted materials were mixed in a fluid bed processor to form a blend. Binder solution was prepared by dissolving polyvinylpyrrolidone (16g) in purified water to obtain a clear solution. Sodium lauryl sulphate (2g) was added to the polyvinylpyrrolidone solution and further stirred to get clear solution. The above blend was granulated using the binder solution and the granules were dried and sized through a suitable mesh sieve. The dried granules were lubricated with pre-sifted crospovidone (50g) and colloidal silicon dioxide (3.6g) and was further lubricated with magnesium stearate (3.6g). The lubricated granules were compressed to yield the tablets using suitable punches and the tablets were coated using opadry (10 g). Example 7

In vivo Study: A single-dose crossover in vivo study was conducted on healthy, adult, human subjects under fasted conditions. In vivo bioequivalence study for Valsartan tablets prepared according to the present invention with respect to the Diovan 160mg tablets (Innovator) was conducted on 9 healthy subjects under fasting condition. The parameters C_max, AUCo-t , AUCo-inf were estimated during the study and recorded in table 2 and 3.

AUCo-t = Area under the plasma concentration versus time curve, from time zero to the last measurable concentration.

AUCo-inf ⁼ Area under the plasma concentration versus time curve, from time zero to infinity.

Crn_ax = maximum plasma concentration.

The ratios of log transformed mean values for C_max and AUC for test and reference (T/R ratio) is a measure of the bioequivalence between the test and reference product.

The summary statistics of pharmacokinetic parameters of Valsartan 160mg film coated tablets prepared according to example 5 as test and Diovan® tablets by Novartis as reference is shown below in Table 2:

Table 2:

The summary statistics of pharmacokinetic parameters of Valsartan 160mg film coated tablets prepared according to example 6 as test and Diovan tablets by Novartis as reference shown below in Table 3 :

Statistical analysis was done on the log transformed values; the antilog of the mean is reported.

Example 8

Valsartan (8Og), microcrystalline cellulose (52.4g) and crospovidone (1Og) was co-sifted through suitable mesh sieve and the sifted materials were mixed in a fluid bed processor to form a blend. Binder solution was prepared by dissolving polyvinylpyrrolidone (8g) in purified water to obtain a clear solution. Sodium lauryl sulphate (Ig) was added to the polyvinylpyrrolidone solution and further stirred to get clear solution. The above blend was granulated using the binder solution and the granules were dried and sized through a suitable mesh sieve. The dried granules were lubricated with pre-sifted crospovidone (25 g) and colloidal silicon dioxide (1.8g) and was further lubricated with magnesium stearate (1.8g). The lubricated granules were compressed to yield the tablets using suitable punches and the tablets were coated using opadry (6g).

Example 9

Valsartan (4Og), microcrystalline cellulose (26.2Og) and crospovidone (5g) was co-sifted through suitable mesh sieve and the sifted materials were mixed in a fluid bed processor to form a blend. Binder solution was prepared by dissolving polyvinylpyrrolidone (4g) in purified water to obtain a clear solution. Sodium lauryl sulphate (0.5g) was added to the polyvinylpyrrolidone solution and further stirred to get clear solution. The above blend was granulated using the binder solution and the granules were dried and sized through a suitable mesh sieve. The dried granules were lubricated with pre-sifted crospovidone (12.5g) and colloidal silicon dioxide (0.9g) and was further lubricated with magnesium stearate (0.9g). The lubricated granules were compressed to yield the tablets using suitable punches and the tablets were coated using opadry (3 g).

Example 10

Valsartan (16Og), microcrystalline cellulose (105g) and crospovidone (2Og) was co-sifted through suitable mesh sieve and the sifted materials were mixed in a fluid bed processor to form a blend. Binder solution was prepared by dissolving polyvinylpyrrolidone (15.68g) in purified water to obtain a clear solution. Sodium lauryl sulphate (2g) was added to the polyvinylpyrrolidone solution and further stirred to get clear solution. The above blend was granulated using the binder solution and the granules were dried and sized through a suitable mesh sieve. The dried granules were lubricated with pre-sifted Hydrochlorothiazide (25g), crospovidone (50g) and colloidal silicon dioxide (1.5g) and was further lubricated with magnesium stearate (1.8g). The lubricated granules were compressed to yield the tablets using suitable punches and the tablets were coated using opadry (10 g).

Example 11

Valsartan (16Og), microcrystalline cellulose (105g) and crospovidone (2Og) was co-sifted through suitable mesh sieve and the sifted materials were mixed in a fluid bed processor to form a blend. Binder solution was prepared by dissolving polyvinylpyrrolidone (15.68g) in purified water to obtain a clear solution. Sodium lauryl sulphate (2g) was added to the polyvinylpyrrolidone solution and further stirred to get clear solution. The above blend was granulated using the binder solution and the granules were dried and sized through a suitable mesh sieve. The dried granules were lubricated with pre-sifted Hydrochlorothiazide (12.5g), crospovidone (5Og) and colloidal silicon dioxide (1.5g) and was further lubricated with magnesium stearate (1.8g). The lubricated granules were compressed to yield the tablets using suitable punches and the tablets were coated using opadry (10 g).

Example 12

Valsartan (16Og) was sifted through a suitable mesh sieve and transferred to a mixer and was then wetted with dichloromethane. The wet mass was dried and sifted through suitable mesh. The sized material was lubricated with Hydrochlorothiazide (25g), microcrystalline cellulose (10Og), lactose monohydrate (35.98g), crospovidone (50g), colloidal silicon dioxide (5g) and magnesium stearate (5g). The lubricated blend was compressed using a suitable compression machine fitted with suitable punches and the tablets were coated using opadry (10 g).

Example 13

Valsartan (16Og) was sifted through a suitable mesh sieve and transferred to a mixer and was then wetted with dichloromethane. The wet mass was dried and sifted through suitable mesh. The sized material was lubricated with Hydrochlorothiazide (12.5g), microcrystalline cellulose (10Og), lactose monohydrate (35.98g), crospovidone (5Og), colloidal silicon dioxide (5g) and magnesium stearate (5g). The lubricated blend was compressed using a suitable compression machine fitted with suitable punches and the tablets were coated using opadry (10 g).

Example 14

Valsartan (16Og) and microcrystalline cellulose (10Og) were co-sifted and mixed in a suitable mixer. The mass was made wet with dichloromethane. The mass was then dried and sifted through suitable mesh sieve. The sized material was then lubricated with Hydrochlorothiazide (12.5g), lactose monohydrate (35.98g), crospovidone (5Og), colloidal silicon dioxide (5g) and magnesium stearate (5g). The lubricated blend was compressed into tablets using a suitable compression machine fitted with suitable punches and tablets were coated using opadry (1Og).

Example 15

Valsartan (16Og) and microcrystalline cellulose (10Og) were co-sifted and mixed in a suitable mixer. The mass was made wet with dichloromethane. The mass was then dried and sifted through suitable mesh sieve. The sized material was then lubricated with Hydrochlorothiazide (25g), lactose monohydrate (35.98g), crospovidone (50g), colloidal silicon dioxide (5g) and magnesium stearate (5g). The lubricated blend was compressed into tablets using a suitable compression machine fitted with suitable punches and tablets were coated using opadry (1Og).

Example 16

Co-sifted Valsartan (16Og) 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 (3Og). The lubricated granules were filled into capsules of suitable size.

Example 17

Co-sifted Valsartan (16Og), lactose anhydrous (67.5g) and microcrystalline cellulose (67.5 g) 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 18

Co-sifted Valsartan (16Og) 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 19

Co-sifted Valsartan (16Og) 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 (3Og). The lubricated granules were filled into capsules of suitable size.

Example 20

Co-sifted Valsartan (16Og), 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 (3Og). The lubricated granules were filled into capsules of suitable size.

Example 21

Co-sifted Valsartan (16Og) 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 22

Co-sifted Valsartan (16Og) 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 (1Og). The lubricated granules were filled into capsules of suitable size.

Example 23

Comparative in vitro dissolution study:

A dissolution study was conducted using Valsartan capsules prepared according to example 16 and example 19 in comparison with Diovan® tablets of Novartis.

The 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 shown in Table 4:

Table 4:

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.

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.

Claims

We claim,

1. A pharmaceutical composition comprising Valsartan and pharmaceutically acceptable additives wherein said composition is prepared by a process comprising solvent wetting method.

2. The composition as claimed in claim 1, wherein Valsartan is present in an amount from about 35.0% to about 50.0% by weight of total composition.

3. The composition as claimed in claim 1, wherein Valsartan is present in an amount from about 20 mg to about 320 mg.

4. The composition as claimed in claim 3, wherein Valsartan is present in unit dose of 40mg, 80mg, 160mg and 320 mg.

5. The composition as claimed in claim 1 additionally comprises a diuretic such as Hydrochlorothiazide.

6. The composition as claimed in claim 5, wherein the weight ratio of Valsartan and Hydrochlorothiazide is from about 30 : 1 to about 3 : 1.

7. The composition as claimed in claim 5, wherein Valsartan is present in an unit dose of 80mg, 160mg or 320 mg and Hydrochlorothiazide is present in an unit dose of 12.5mg or 25mg.

8. The composition as claimed in claim 1, wherein the pharmaceutically acceptable additives comprises one or more of diluents, binders, disintegrants, surfactants, lubricants, glidants and coating agents.

9. The composition as claimed in claim 8, wherein the diluent is selected from a group consisting of lactose, microcrystalline cellulose, dibasic calcium phosphate, corn starch, sugar derivatives, dextrates, dextrins, starch and mixtures thereof and is present in an amount from about 25.0% to about 60.0% by weight of the total composition.

10. The composition as claimed in claim 8, wherein the binder is selected from a group consisting of polyvinylpyrrolidone, hydroxypropyl methyl cellulose, hydroxyalkyl cellulose, hydroxpropyl cellulose and mixtures thereof and is present in an amount from about 3.0% to about 20 % by weight of the total composition.

11. The composition as claimed in claim 8, wherein the disintegrant is selected from a group consisting of crospovidone, carboxy methylcellulose calcium, sodium starch glycollate, starch, croscarmellose sodium and mixtures thereof and is present in an amount from about 3.0% to about 25.0% by weight of the total composition.

12. The composition as claimed in claim 8, wherein the surfactant is selected from a group consisting of sodium lauryl sulphate, poloxamer, cremophor, docusate sodium and mixtures thereof and is present in an amount from about 0.2% to about 5.0% by weight of the total composition.

13. The composition as claimed in claim 8, wherein the lubricant is selected from a group consisting of magnesium stearate, hydrogenated castor oil, stearic acid, sodium stearyl fumarate and mixtures thereof and is present in an amount from about 0.2% to about 10.0% by weight of the total composition.

14. The composition as claimed in claim 8, wherein the glidant is selected from a group consisting of talc, colloidal silicon dioxide and mixtures and is present in an amount from about 0.2% to about 10.0% by weight of the total composition.

15. The composition as claimed in claim 1, wherein the composition comprises about 35.0% to about 50.0% by weight of Valsartan, about 25.0% to about 60.0% by weight of diluent, about 3.0% to about 25.0% by weight of disintegrant, about 0.2% to about 10.0% by weight of lubricant and 0.2% to about 10.0% by weight of glidant.

16. The composition as claimed in claim 1, wherein the composition is a tablet.

17. The composition as claimed in claim 16, wherein the tablet is coated.

18. The composition as claimed in claim 5, wherein the composition is optionally a bilayered tablet.

19. A process for preparing a pharmaceutical composition comprising Valsartan and pharmaceutically acceptable additives, the process comprising solvent wetting method comprising the steps of mixing Valsartan with pharmaceutically acceptable additives to form a mixture, wetting the mixture with a suitable solvent, drying and formulating into compressed solid oral dosage form.

20. A process for preparing a pharmaceutical composition comprising Valsartan, Hydrochlorothiazide and pharmaceutically acceptable additives, the process comprising solvent wetting method comprising the steps of mixing Valsartan, Hydrochlorothiazide with pharmaceutically acceptable additives to form a mixture, wetting the mixture with a suitable solvent, drying and formulating into compressed solid oral dosage form.

21. A process for preparing a pharmaceutical composition comprising Valsartan, Hydrochlorothiazide and pharmaceutically acceptable additives, the process comprising solvent wetting method comprising the steps of mixing Valsartan with pharmaceutically acceptable additives to form a mixture, wetting the mixture with a suitable solvent, drying and further mixing with Hydrochlorothiazide or separately prepared granules of Hydrochlorothiazide and formulating into compressed solid oral dosage form or bilayered solid oral dosage form.

22. The process as claimed in claim 21, wherein the granules of Hydrochlorothiazide are prepared by aqueous or non-aqueous granulation.

23. The process as claimed in claim 19, 20 or 21, wherein the solvent used in the solvent wetting method is selected from a group consisting of dichloromethane, methanol, ethanol, isopropyl alcohol, acetone or mixtures thereof.

24. The process as claimed in claim 23, wherein solvent wetting may optionally be carried out using a solution prepared by dissolving binder and/or surfactant in a solvent.

25. A process for preparing a compressed solid oral dosage form comprising Valsartan and pharmaceutically acceptable additives, the process comprising the steps of mixing Valsartan and pharmaceutically acceptable additives optionally with Hydrochlorothiazide to form a blend, granulating the blend using a binder solution to form granules and further formulating into compressed solid oral dosage form.

26. The process as claimed in claim 25, wherein the process optionally comprises mixing the said granules with the active ingredient Hydrochlorothiazide or separately prepared granules of Hydrochlorothiazide and formulating into compressed solid oral dosage form or bilayered dosage form, wherein the granules of Hydrochlorothiazide are prepared by aqueous or non-aqueous granulation.

27. The process as claimed in claim 25 or 26, wherein the binder solution- is prepared by dissolving binder and /or surfactant in water.

28. A pharmaceutical composition prepared by the process as claimed in claim 25, comprising Valsartan and pharmaceutically acceptable additives optionally with Hydrochlorothiazide.

29. The composition as claimed in claim 28, wherein the composition comprises about 35.0% to about 50.0% by weight of Valsartan, about 25.0% to about 60.0% by weight of microcrystalline cellulose, about 3.0% to about 20.0% by weight of polyvinylpyrrolidone and about 0.2% to about 5.0% by weight of sodium lauryl sulphate.

30. A process for preparation of capsule dosage form of Valsartan comprising dry granulation method comprising the steps of mixing Valsartan and pharmaceutically acceptable additives optionally with Hydrochlorothiazide to form a mixture; compacting the mixture at a compaction force below 23 KN, sizing to form granules and further formulating into capsules.

31. The process as claimed in claim 30, wherein the process optionally comprises mixing the said granules with the active ingredient Hydrochlorothiazide or separately prepared granules of Hydrochlorothiazide and formulating into capsules, wherein the granules of Hydrochlorothiazide are prepared by aqueous or non-aqueous granulation.

32. A capsule dosage form prepared by the process as claimed in claim 30, comprising Valsartan and pharmaceutically acceptable additives optionally with Hydrochlorothiazide.

33. The capsule dosage form as claimed in claim 32, wherein the composition comprises about 35.0% to about 50.0% by weight of Valsartan, about 25.0% to about 60.0% by weight of microcrystalline cellulose, about 3.0% to about 25.0% by weight of crospovidone, about 0.2% to about 10.0% by weight of colloidal silicon dioxide and 0.2% to about 10.0% by weight of magnesium stearate.

34. The process as claimed in any of the preceding claims, wherein the pharmaceutically acceptable additives comprise one or more of diluents, solvents, binders, disintegrants, surfactants, lubricants, glidants and coating agents.

35. A method of treating a patient suffering from hypertension and heart failure comprising the step of administering to the patient a composition as claimed in any of the preceding claims.

36. Pharmaceutical compositions of Valsartan alone or in combination with Hydrochlorothiazide and process for their preparation substantially as herein described and illustrated by examples 1 to 23.