FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
Title
PROCESS FOR PHARMACEUTICAL COMPOSITION COMPRISING VALSARTAN
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 nature of the invention

PROCESS FOR PHARMACEUTICAL COMPOSITION COMPRISING
VALSARTAN
FIELD OF THE INVENTION
The present invention relates to the process of manufacturing pharmaceutical composition comprising active substance valsartan, optionally in combination with another active ingredient, preferably diuretic such as, hydrochlorothiazide (HCTZ), in a solid oral dosage form by wet granulation, which is free from Microcrystalline Cellulose or Crosspovidone or Sodium starch glycolate and has required drug release characteristics.
BACKGROUND OF THE INVENTION
Valsartan, a compound having the chemical name N-(l-oxopentyl)-N-[[2'-(lH-tetrazol-5- yl) [1, l'-biphenyl]-4-yl] methyl]-L-valine, of formula I

belongs to the group of drugs that block receptors of angiotensin II and Hydrochlorothiazide is a loop diuretic of formula II, known as 6-chloro-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfonamide 1, 1 dioxide. Valsartan is used to treat
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hypertension and chronic heart failure. The combination is indicated for treatment of hypertension, in patients failing to achieve the desired effect with monotherapy.
Valsartan, its pharmaceutically acceptable salts and processes for its preparation are described in EP 0443983 Bl. The preparation of valsartan salts is also described in WO 02/06253.
It is known from the prior art that valsartan is not only present as an amorphous solid but can exist as well in several crystalline or partly crystalline forms or as a mixture of various polymorphs with amorphous material (WO 02/06253; WO 03/089417).
Both valsartan and HCTZ are low density solid materials. Thus, preparation of solid dosage forms of acceptable size, suitable for oral administration, is a challenging task.
The tablet dosage form as disclosed in example 92 and 93 of US patent 5399578 is manufactured by wet granulation. The manufacturing details are as below:

Ingredients Wt. (grams) / batch
Active ingredient 500.00
Lactose 500.00
Potato Starch 352.00
Gelatin 8.00
Talc 60.00
Magnesium Stearate 10.00
Silica (highly dispersed) 20.00
Ethanol q.s
The active ingredient is mixed with the lactose and 292 g of potato starch, and the mixture is moistened with an alcoholic solution of the gelatin and granulated by means of a sieve. After drying, the remainder of the potato starch, the talc, the magnesium stearate and the highly disperse silica are admixed and the mixture is
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compressed to give tablets of 145.0 mg weight and 50.0 mg active ingredient content each which, if desired, can be provided with breaking notches for finer adjustment of the dosage.

Ingredients Wt. (grams) / batch
Active ingredient 100.00
Lactose 100.00
Corn Starch 70.00
Talc 8.50
Calcium Stearate 1.50
Hydroxypropylmethylcellulose 2.36
Shellac 0.64
Water q.s
Dichloromethane q.s
The active ingredient, the lactose and 40 g of the corn starch are mixed and moistened and granulated with a paste prepared from 15 g of corn starch and water (with warming). The granules are dried, and the remainder of the corn starch, the talc and the calcium stearate are added and mixed with the granules. The mixture is compressed to give tablets (weight: 280 mg) and these are coated with a solution of the hydroxypropylmethylcellulose and the shellac in dichloromethane (final weight of the coated tablet: 283 mg).
The above processes of compressing valsartan-containing tablets lead to the formation of a high-density product. However, high-density products are problematic in that they do not disintegrate satisfactorily and have very high disintegration time, which leads to improper dissolution and sub-therapeutic concentration levels.
It is imperative that a tablet should provide uniform therapeutic levels of the drug with each dose to the patient for maximum efficacy. The drug should be in solution or fine suspension form in the gastrointestinal fluid for absorption. For most tablets, the
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first important step towards going into the solution form or suspension form is breaking down of the tablet into smaller particles or granules, a process known as disintegration. Thus, the disintegration time of the tablet may give an indication about the extent of the availability of the drug for absorption into the systemic circulation.
The use of Dichloromethane is limited in formulation due to its toxicity, environmental hazards and safety reasons. Also the ethanolic granulation of Valsartan results in formation of hard granules, which causes significant reduction in dissolution. Moreover, Ethanol has GMP related issues, as during granulation special fire proof facilities are required and ethanol needs to be recovered for environmental protection.
Also, excipients like Shellac and gelatin, which are naturally occurring material, are used in prior art formulation. It is hard to ensure the constant property of naturally occurring material from different batches.
The same observation can be drawn from the example 1 given in the international patent application WO 95/24901, which discloses a capsule dosage form, as described in the following composition:

Ingredients Mg / Capsule
1. Active ingredient 80.00
2. Microcrystalline Cellulose 110.00
3. Polyvidone K-30 45.20
4. Sodium Lauryl Sulphate 1.20
5. Crospovidone 26.00
6. Magnesium Stearate 2.60
The first two components are granulated via wet granulation with a solution of the third and fourth components in water. Components 5 and 6 are added to the dry granulate and the mixture is filled into capsules.
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EP 0914119 Bl further discloses that these earlier-published wet granulation methods are not well suitable, especially in their compression into the tablet form. This patent applies a method of dry granulation for production of tablets of valsartan. In this compaction method, coprimate is formed from ground active agent and other additives by compression and then coprimates are converted in to granules and further compressing the granules to tablets. This process is done in absence of water. This patent also discloses that in this dry compaction process, the valsartan is present in more than 35% by total weight of compressed dosage form. The known composition from application WO95/24901 has been slightly modified:

Ingredients Mg / Tablet
1. Valsartan 80.00
2. Hydrochlorothiazide 12.50
3. Colloidal Silica 1.50
4. Microcrystalline Cellulose 31.50
5. Crospovidone 20.00
6. Magnesium Stearate 4.50
Total 150.00
The first to fifth components are mixed and compacted at pressures 25 to 65 kN. The compacted material is further forced through a sieve. Granulate produced in this way is mixed with magnesium stearate and the mixture is compressed into tablets.
The disadvantages of compaction process are as follows:
1. Too much of fine generation during compaction process.
2. Safety hazard for the machine operators.
3. Loss of valuable API during processing.
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4. The compaction process is cumbersome in nature.
5. Flow of granules is not good.
Although microcrystalline cellulose has good compressibility, binding properties, disintegrating properties, However, MCC has several disadvantages as loss of disintegration and drug adsorption on long exposure.
WO 2000/038676 Al discloses solid oral dosage form comprising valsartan and microcrystalline cellulose wherein the weight ratio of valsartan to microcrystalline cellulose is from 2.5:1 to 0.3:1. This patent application also discloses solid oral dosage form comprising 20 - 65% Valsartan, 31 - 65% microcrystalline cellulose and 2 - 13% of crospovidone. The claimed formulation may lead to high disintegration time during stability studies.
WO 2005/041941 Al discloses about valsartan, optionally a combination of valsartan with hydrochlorothiazide, obtainable by direct tabletting, characterized in that it comprises filler having a particle size of 10 to 1000 microns, preferably 50 to 400 microns, in amounts of 20 to 60, preferably 40 to 60% by weight, based on the total weight of the formulation.
The direct compression process of valsartan may lead to various problems like:
1. Erratic powder flow
2. Low blend density
WO 2005/089720 Al discloses tablets comprising valsartan, and at least two disintegrants, wherein the at least two disintegrants are present intragranularly, extra granularly or both. The use of atleast two disintegeants is done to overcome the disintegration and dissolution related issues. In prior art EP 0194119 Bl, Microcrystalline cellulose and Crospovidone are used and both of these excipients
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fall under category of disintegrants. Also, use of high concentration of disintegrant may lead to formulation susceptible to humidity, as the disintegrants may tend to absorb moisture from atmosphere and may detoriate tablet quality.
WO 2006/066961 discloses valsartan formulation having D50 of valsartan below 150 microns. This patent application also discloses wet granulation process using given particle size of valsartan. It have limitations such as requirement of specific particle size of valsartan, use of lubricant in specific concentration, which does not affect the bioavailability of valsartan, and also use of atleast two disintegrants in the formulation and out of these atleast two features are required in order to manufacture valsartan tablets. Also as disclosed in description (page no 17, line 1) and the examples, large amounts of magnesium stearate is used. Due to presence in high concentration of magnesium stearate blending step may be critical. Blending of dried granules with magnesium stearate for higher time interval may cause coating of hydrophobic magnesium stearate over already hydrophobic valsartan and thereby reducing the bioavailability, increasing disintegration time, reducing dissolution, moreover blending for lesser time may result in inefficient distribution of lubricant and causing various mach inability related problems, like punch jamming, sticking etc. Also, microcrystalline cellulose is used in most of the examples, which may cause adsorption of the drug, and may delay the disintegration time during stability.
Thus, various approaches are tried to resolve the problem of disintegration and dissolution observed in the development of valsartan composition including changing the process of manufacture such as compaction or direct compression or by changing excipients such as using two disintegrants.
Inventors have surprisingly found that a simple wet granulation based formulation can be developed without using compaction process or direct compression process and without using microcrystalline cellulose or crospovidone or Sodium starch
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glycolate or using combination of disintegrants and still having good tablet disintegration and dissolution rate with desired bioavailability.
SUMMARY OF THE INVENTION
In a first aspect the present invention relates to process of manufacturing solid oral pharmaceutical composition of valsartan optionally in combination with another active agent, preferably diuretic such as, hydrochlorothiazide by wet granulation.
In another general aspect there is provided a process of manufacturing solid oral pharmaceutical composition of valsartan optionally in combination with another active agent, preferably diuretic such as, hydrochlorothiazide by wet granulation, which is free from Microcrystalline Cellulose or Crospovidone or Sodium starch glycolate.
In another general aspect there is provided a process of manufacturing solid oral pharmaceutical composition of valsartan optionally in combination with another active agent, preferably diuretic such as, hydrochlorothiazide by wet granulation, wherein the said composition comprises less than 1% magnesium stearate by weight, further the said composition is free from Microcrystalline Cellulose or Crospovidone or Sodium starch glycolate.
In another general aspect there is provided a method for preparing a wet-granulated composition comprising:
(a) mixing valsartan optionally in combination with atleast one active ingredient,
preferably Hydrochlorothiazide with lactose, and optionally other excipients;
wherein valsartan and optionally atleast one active ingredient, preferably
Hydrochlorothiazide.
(b) dissolving povidone in sufficient water and adding to the valsartan blend
from step (a) under shear to generate granules;
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(c) optionally milling or sieving said wet granules;
(d) drying said granules;
(e) optionally milling, grinding or sieving said granules;
(f) optionally mixing in other excipients;
(g) forming the composition into unit dosage forms; and
(h) optionally film coating the compressed unit dosage form.
In another general aspect there is provided a multiple unit tableted dosage form comprising valsartan and at least one pharmaceutically additive and wherein the said dosage form exhibits immediate release of active ingredient.
DETAILED DESCRIPTION
The angiotensin II receptor antagonist -Valsartan - is known to be effective in the treatment of congestive heart failure and reducing blood pressure irrespective of age, sex or race and is also well tolerated. Its combination with HCTZ is also known for the treatment of hypertension.
Present invention relates to formulation development of Valsartan alone or optionally in combination with another active ingredient, preferably with diuretic agent by wet granulation method and also having good disintegration rate and dissolution with as simple formulation as possible.
It has now been surprisingly found that a simple wet granulation based formulation can be developed without using compaction process or direct compression process and without using microcrystalline cellulose or crospovidone or sodium starch glycolate or using combination of disintegrants and still having good tablet disintegration and dissolution rate.
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The term "valsartan" as used herein, may include free acid forms of valsartan or its pharmaceutically acceptable salts thereof. Valsartan may be used in an amount which either reduces or halts the progress of the pathological condition being treated or which otherwise cures the condition partly or completely; and the amount may vary from about 10 to about 350 mg.
The valsartan used in the current invention is either crystalline or in an amorphous form, preferably in an amorphous form.
The particles size of valsartan is in the range of 0.1 microns to 200 microns, preferably average particle diameter below 50 microns; more preferably between 5 and 50 microns and D90 below 75 microns.
For convenience and ease of patient compliance, most drugs are delivered in the form of unit dosage forms. For solid drug substances, these unit dosage forms are generally in the form of tablets and capsules. In the present invention, the dosage form is in the form of a solid oral dosage form, preferably in the form of a capsule or tablet; most preferably in the form of a tablet.
The preparation of these forms involves a necessary step of filling a die or capsule with powder. In order for the unit dosages to have the same potency within allowable margins (relative standard deviation, RSD, of less than 6% to meet Stage I, and less than 7.8% to meet Stage II of the United States Pharmacopoeia, USP, guidelines), there must not be any significant segregation of formulation components. For this reason, it can be desirable to granulate valsartan, especially when the drug is used at low doses.
Wet granulations bind the drug with excipients and thereby minimize any segregation tendency. In preparation of valsartan compositions by wet granulation, any technique
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known in the art for wet granulation can be used for the purposes of the present invention.
An important element to these processes is that the granulation solution is added to the valsartan composition while the powder blend is under shear. The shear serves to break up incipient clumps and thereby provide a more uniform granulation. Non-limiting examples of shearing processes include high shear wet granulations, fluid-bed granulations, extrusion granulations and low shear wet granulations (such as stirrers, mixers and blenders, including bin blenders). The amount of wet granulation solvent added is determined based on adequate wetting to bind the majority of the fine particles.
The wet granulation solvent addition can be carried out using any technique known in the art. For example, the liquid can be added in single or multiple rapid additions, sprayed onto a stirring powder bed, pumped directly onto the powder or introduced into fluidizing gas. Mixing times with the liquid are generally optimized such that the majority of fine particles are bound in granules, yet the granules themselves are not over-hardened.
Once the granules are formed, it is sometimes advantageous to mill, grind or sieve the material while it is wet (softened), as is known in the art. The wet composition is preferably dried before use in formation of unit dosage forms. Such drying can be accomplished using any method known in the art. Non-limiting examples of these methods include air drying, fluid bed drying, microwave drying, oven drying, and convection oven drying. We have found that the drying temperature is important as increase in drying temperature leads to formation of molten mass. Preferably the drying temperature does not exceed about 60°C; more preferably, the temperature does not exceed about 50°C. Once the granules are dry, it is sometimes desirable to reduce the particle size by milling, grinding or sieving, as is known in the art. After
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this point, a lubricant is typically added followed by a short (about 1-10 minute) mixing period, typically carried out in a low shear blender such as a tumbling blender. Examples of said tumbling blenders include bin-blenders, V-blenders and Turbula" blenders. The preferred lubricant is magnesium stearate. Once the blend is made, unit dosage forms are prepared by procedures known in the art. Preferable the unit dosage forms include tablets or capsules. Tablets are made by filling a die with the valsartan containing composition, then pressing with a matching punch. Capsules are prepared by filling shaped capsule shells then sealing. Such operations are preferably carried out using a rotary tablet press or commercial capsule-filling machine. Non-exclusive examples of commercial rotary tablet presses include those produced by Niro Pharma Systems (Columbia, MD), Kilian and Company (Horsham, PA), Korsch (Berline, Germany) and Elizabet-Hata International (North Huntingdon, PA). Non-exclusive examples of commercial capsule filling equipment include those made by Capsugel (Morris Plains, NJ) and CapPlus Technologies (Phoenix, AZ). Tablets thus prepared can then optionally be coated with a film designed to provide ease of swallowing, a proprietary or identification appearance and/or protection of the dosage form. The final unit dosage form is then packaged using procedures known in the art.
Disintegrants suitable for the current invention also provide for disintegration time of tablets in less than 15 minutes, preferably less than 10 minutes, more preferably less than 5 minutes. Disintegration time is measured using demineralised water at 37.5°C with commercially available disintegration measurement devices.
Disintigrents can be selected from the group comprising of Starch, Croscarmellose Sodium, Crosscarmellose calcium, Alginic acid, Pregelatinized Starch, Carboxymethyl cellulose sodium, Polacrilin potassium, Guar gum, Low - substituted hydroxy propyl cellulose etc. It is preferred that that the excipients include at least
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one disintegrant selected from Starch, Croscarmellose sodium, Croscarmellose calcium.
The current invention disclaims the use of Crospovidone and Sodium starch glycolate as disintegrant in the formulation. It was surprisingly found that use of sodium starch glycolate as disintegrant leads to increase in disintegration time in formulation during stability study of valsartan tablets manufactured by wet granulation with water. Also, in all prior art related to valsartan formulation, Crosspovidone was used as disintegrant, the reason being, mostly in all cases dry granulation process was used, and crosspovidone is one of the best super disintegrant.
Compositions of valsartan according to the present invention can be combined with a least one other active ingredient to form unit dosage forms. In the combination of the valsartan composition with at least one other active ingredient to form a unit dosage form, the following non-limiting list describes options for such unit dosage forms: (a) a blend of wet-granulated valsartan with the other active ingredient itself (i. e. , extragranular addition of the other drug to the wet granulated valsartan), as a blend with excipients (i. e. , extragranular addition of the other drug plus excipients to the wet granulated valsartan), or as a granulation (i. e., combination of the other drug granulation with the wet granulated valsartan), formed into tablets or capsules; (b) a single wet granulation of valsartan with the other drug, formed into tablets of capsules; (c) a bilayer tablet comprising wet granulated valsartan in one layer and the other drug and optional excipients in the other layer.
The solid oral dosage form of the present invention is prepared using active ingredient Valsartan optionally with one or more active ingredients and diluents, disintigrents, binders, lubricant, glident and other pharmaceutically acceptable excipients or adjuvants.
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Diluents can be selected from the group comprising of lactose, starch, Dibasic calcium Phosphate anhydrous, Tribasic calcium phosphate, Calcium carbonate, Mannitol, Sorbitol, Maltodextrin, etc.
The current invention disclaims the use of Microcrystalline cellulose as diluent in the formulation. As in all prior art related to valsartan formulation, Microcrystalline cellulose was used as diluent, the reason being, mostly in all cases dry granulation or direct compression process was used, and microcrystalline cellulose plays important role in processability of such formulation. In wet granulation also, microcrystalline cellulose plays an important role. However, in the current invention microcrystalline cellulose is removed from the formulation and has surprisingly achieved the required disintegration and dissolution.
Binder can be selected from the group comprising of polyvinylpyrrolidone or Hydroxypropylmethylcellulose, Pregelatinised starch, Hydroxy propyl cellulose, Hydroxy propyl methyl cellulose, Ethyl cellulose.
Disintigrents can be selected from the group comprising of starch, Croscarmellose sodium, Crosscarmellose calcium, Low-substituted hydroxy propyl cellulose, Alginic acid, Polacrilin potassium, Guar gum etc.
Lubricant can be selected from the group comprising of Stearic acid, Polyethylene glycol, Magnesium stearate, Calcium stearate, Zinc stearate, Talc or Silica, Hydrogenated caster oil, etc. As per the prior art as discussed herein above it is known that the lubricants and its content may play very important role in the bioavailabilty of valsartan. But, in the instant invention by using low content of lubricant it has been surprisingly found that desired formulation characteristics may still be achieved. Hence, in the current invention the lubricant concentration is less than 1% by weight of compressed dosage form.
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Glident can be selected from the group comprising of colloidal silicon dioxide, Talc.
Granulating fluid is water.
Film forming agent can be selected from the group comprising of hydroxypropyl
methyl cellulose (Hypromellose), hydroxyethyl cellulose,
methylhydroxyethylcellulose, sodium carboxymethylcellulose,
hydroxypropylcellulose, polyvinyl pyrrolidone, dimethylaminoethyl
methacrylatemethylacrylate acid ester copolymer, ethylacrylate-methylmacracrylate copolymer, methylcellulose, ethylcellulose, waxes, gums, starch derivatives, sugar derivatives etc.
Plasticizers can be selected from the group comprising low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multi-block polymers, single block polymers, low molecular weight poly(ethylene glycol), citrate ester-type plasticizers, triacetin, propylene glycol and glycerin. Such plasticizers can also include ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other poly(ethylene glycol) compounds, monopropylene glycol mono isopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol, monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate, acetylributycitrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate. All such plasticizers are commercially available from sources such as Aldrich or Sigma Chemical Co. It is also contemplated and within the scope of the invention, that a combination of plasticizers may be used in the present formulation. The PEG based plasticizers are available commercially or can be made by a variety of methods such as disclosed in Poly (ethylene glycol) Chemistry : Biotechnical and Biomedical Applications (J.M.
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Harris, ed.: Plenum Press, NY) the disclosure of which is hereby incorporated by reference.
Solvent used for film coating is purified water.
Other components may include talc as anti tacking agent, titanium dioxide as opacifier, iron oxides as colouring agents.
The solid dosage form of the present invention containing Valsartan and optionally with one or more active ingredient and adjutants is prepared by following steps:
1. a. Sift Valsartan, Hydrochlorothiazide, diluent, and optionally
disintegrant through 60 # and mix it properly.
b. Dissolve Povidone in water
c. Spray the step lb solution onto dry mix diluents of step la and dry it.
OR
2. a. Sift Valsartan, Hydrochlorothiazide, diluent, and optionally
disintegrant through 60 # and mix it properly.
b. Dissolve Povidone in water.
c) Granulate the powder mix of step la OR 2a with binder solution prepared in step 2b in high speed mixer and dry the granules in Fluid bed dryer. Sift the dried granules through 20#.
3. Lubricate the granules of step lc or 2c with disintegrant, and lubricants like Magnesium Stearate, Talc and mix in cage blender.
4. Then after compress the granules into tablets or fill the granules into capsules.
5. After compression, film coat the tablets using hypromellose as film forming polymer, polyethylene glycol as plasticizer and titanium dioxide & iron oxides as coloring agent in Purified water.
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Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
The term "multi particulate" as used herein includes small beads, particles, granules which are coated with active ingredient.
The term "drug release characteristics" as used herein with respect to valsartan, refers to the weight % of valsartan, based on the total weight of valsartan contained in the tablet, which dissolves within 60 minutes under the following conditions: using a USP Apparatus 2, placing the tablet in 900 mL of pH 6.8 buffer at 37° C, with a paddle speed of 50 rpm, and measuring the amount of valsartan dissolved (If desired, the progress of dissolution may also be monitored at various time points) or the disintegration time of the formulation or both.
The term "weight of dosage form" as used herein refers to weight of dosage form in which the concentration of valsartan or valsartan and optionally another active ingredient ranges from 5 % w/w to 60% w/w based on compressed dosage form.
The present invention has been described by way of example only, and it is to be recognized that modifications thereto which fall within the scope and spirit of the appended claims, and which would be obvious to a skilled person based upon the disclosure herein, are also considered to be included within the invention.
The composition of the present invention comprises the ingredients in the following proportion.
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Examples
Table 1

Ingredients $1 *2 $3 $4 *5 s6 *7
Premixing
Valsartan 160.00 160.00 160.00 80.00 160.00 160.00 160.00
Hydrochlorothiazide 25.00 25.00 25.00 12.50 25.00 - -
Lactose monohydrate 464.00 - 464.00 59.90 - 251.90 285.65
Mannitol 25 - 464.00 - - 464.00 - -
Sodium starch glycolate 14.00 14.00 - 1.80 - - -
Croscarmellose Sodium - - 14.00 - 14.00 - -
Granulation
Povidone 14.00 14.00 14.00 1.80 14.00 28.00 8.00
Purified Water q.s q.s q.s q.s q.s - q.s
Lubrication
Talc - - - - - 2.50 2.50
Sodium Starch Glycolate 21.00 21.00 - 3.00 - - -
Croscarmellose Sodium - - 21.00 - 21.00 52.80 24.00
Magnesium stearate 7.00 7.00 7.00 1.00 7.00 4.80 4.50
Core Tablet weight 705.00 705.00 705.00 160.00 705.00 500.00 485.00
Coating
Hypromellose 10.58 10.58 10.58 2.75 10.58 2.75 2.75
Polyethylene glycol 2.12 2.12 2.12 0.55 2.12 0.55 0.55
Titanium dioxide 2.82 2.82 2.82 0.70 2.82 0.70 0.70
Iron oxides 1.41 1.41 1.41 0.20 1.41 0.20 0.20
Purified water q.s. q.s. q.s. q.s. q.s. q.s. q.s
Total 721.93 721.93 721.93 164.20 721.93 504.20 489.20
# Dissolution (%) 97.10 97.66 98.80 99.32 98.2 95.22 99.39
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# The dissolution of tablets was determined in a paddle apparatus. The rotation speed
was set at 50 ± 2 revolutions per minute, the dissolution medium being pH 6.8
maintained at a fixed temperature of 37 °C. The total volume of the dissolution fluid
was 900 ml. The percentage drug release of valsartan was noted at 60 minutes time
point. The disintegration time of all the tablets in given examples (example 1-7) was
less than 15 minutes.
$- Granulation performed in rapid mixer granulator.
*- Granulation performed in top spray fluid bed granulator.
Manufacturing Process:
1) a. Sift Valsartan, Hydrochlorothiazide (except in example 6 & 7),
diluent, and optionally disintegrant through 60 # and mix it properly.
b. Dissolve Povidone in water
c. Spray the step lb solution onto dry mix diluents of step la and dry it.
OR
2) a. Sift Valsartan, Hydrochlorothiazide, diluent, and optionally
disintegrant through 60 # and mix it properly.
b. Dissolve Povidone in water.
c. Granulate the powder mix of step la OR 2a with binder solution
prepared in step 2b in high speed mixer and dry the granules in Fluid
bed dryer. Sift the dried granules through 20#.
3) Lubricate the granules of step lc or 2c with disintegrant, and lubricants like Magnesium Stearate, Talc and mix in cage blender.
4) Then after compress the granules into tablets or fill the granules into capsules.
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5) After compression, film coat the tablets using hypromellose as film
forming polymer, polyethylene glycol as plasticizer and titanium dioxide & iron oxides as coloring agent in Purified water.
Example - 7
Step A - Formula for Drug coating on to the granular Lactose:
Table 2

Ingredients Quantity in mg / Tablet
Dry mix blend composition
Lactose monohydrate (DCL 11) 350.00
Drug coating composition
Valsartan 40.00
Hydroxy propyl methyl cellulose E-15 10.00
Purified water q.s
Tablet composition
Croscarmellose sodium 16
Magnesium stearate 2.40
Talc 1.20
Hydroxy propyl methyl cellulose 2.75
Polyethylene glycol 0.55
Titanium dioxide 0.70
Iron oxides 0.20
Purified water q.s.
Total 423.80
Procedure
1. Lactose monohydrate was passed through 40 # and added into fluidized bed processor.
2. Hydroxy propyl methyl cellulose (E-15) was dissolved in Purified water and Valsartan was added and homogenized for 15 minutes.
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3. The drug suspension prepared into step 2 was spray using wurster apparatus onto fluidized powder/ granular bed.
Step B- Preparation of tablets:
1. Drug coated pellets; Croscarmellose sodium, Magnesium stearate and Talc were
mixed and compressed into tablets The disintegration time of tablets manufactured as above was less than 5 minutes.
The reference, i.e., Co-Diovan® is the Valsartan and Hydrochlorothiazide tablet from the innovator, Novartis. The dissolution rate of the tablets prepared in the instant invention was found to be more than 85% in 60 minutes. Thus, the dissolution of the tablets prepared according to the instant invention is acceptable.
Dated this on 08th August, 2006
Praveen Chand Gandhi,
Torrent Pharmaceuticals Limited
Torrent Research center
P.O.Bhat – 382428, Gandhinagar
Gujraat, India

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ABSTRACT
The present invention relates to process of manufacturing pharmaceutical composition comprising active substance valsartan, optionally in combination with another active ingredient, preferably diuretic such as, hydrochlorothiazide (HCTZ), in the form of a solid oral dosage form by wet granulation, wherein the said composition comprises less than 1% magnesium stearate by weight, further the said composition is free from Microcrystalline Cellulose or Crospovidone or Sodium starch glycolate.