FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
Title
PHARMACEUTICAL COMPOSITION COMPRISING VALSARTAN BY MELT GRANULATION
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

PHARMACEUTICAL COMPOSITION COMPRISING VALSARTAN BY
MELT GRANULATION
FIELD OF THE INVENTION
The present invention relates to pharmaceutical composition comprising active substance valsartan, optionally in combination with another active ingredient, preferably diuretic such as, hydrochlorothiazide (HCTZ), in the form of a tablet or capsule manufactured by melt granulation.
The present invention further 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),
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-
1

dihydro-2H-l, 2, 4-benzothiadiazine-7-sulfonamide 1, 1 dioxide. Valsartan is used to treat 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)
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
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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 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 Mg / Tablet
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, which leads to improper dissolution and sub-therapeutic concentration levels.
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 cause significant reduction in dissolution. Moreover, Ethanol has GMP related issues, as during granulation
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special fire proof facilities are required and ethanol needs to be recovered for environmental protection.
Also, excipients like Shellac and gelatine, 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, is described of 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.
However, as per EP 0914119 Bl, these earlier-published wet granulation methods were 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 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:
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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.
4. The compaction process is cumbersome in nature.
5. Flow of granules is not good.
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
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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, extragranularly 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 is used and both of these excipients 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. The EP 0914119 Bl discloses use of valsartan with particle size in the range of 0.1 micron to 200 microns.
Thus, the problem of disintegration and dissolution of valsartan tablets have been tried to resolve by various ways like by changing the process of manufacture such as compaction or direct compression or wet granulation or by changing excipients such as using two disintegrants.
Thus there is a need in the industry to develop pharmaceutical composition of valsartan either alone of in combination with diuretic agent having acceptable dissolution profile, acceptable process. This can be achieved by melt granulation process as disclosed in current invention. The advantages of formulation using melt granulation process over existing prior art are as below:
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1. Neither solvent nor water used in granulation process.
2. Fewer processing steps needed thus time consuming drying steps eliminated.
3. Good compressibility and the entire procedure is simple, continuous and
efficient.
SUMMARY OF THE INVENTION
Accordingly the first aspect of the current invention is a pharmaceutical composition containing active substance valsartan, optionally in combination with another active ingredient, preferably diuretic such as, hydrochlorothiazide (HCTZ), in the form of a tablet or capsule manufactured by melt granulation.
In a preferred embodiment, the pharmaceutical composition containing active ingredient valsartan, optionally in combination with another active ingredient, preferably diuretic such as, hydrochlorothiazide (HCTZ), in the form of a tablet or capsules manufactured by melt granulation, wherein the active ingredient is present in the range of 5% - 90% of the weight of dosage form.
In another preffered embodiment, the melt granulation process include
a) mixing of Valsartan, diluent, melt processible agent, optionally disintegrant thoroughly.
b) transferring the blend to rapid mixer granulator having heating facility.
c) granulating the blend by means of heat in rapid mixer granulator.
d) cooling the granulated blend and sift through appropriate sieve.
e) sifting the lubricants, disintegrants through 60 mesh and mix with blend from step d.
f) Compressing the lubricated blend on suitable punches or filling the lubricated blend to capsules of suitable size.
g) Optionally, filmcoating the tablets.
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DETAILED DESCRIPTION DEFINITIONS AND ABBREVIATIONS
Unless otherwise indicated, this disclosure uses definitions provided below.
"About," "approximately," and the like, when used in connection with a numerical variable, generally refers to the value of the variable and to all values of the variable that are within the experimental error (e.g., within the 95% confidence interval for the mean) or within +- 10% of the indicated value, whichever is greater.
The term "Pharmaceutically acceptable" refers to substances, which are within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
The term "Drug product," "pharmaceutical dosage form," "final dosage form," and the like, refer to the combination of one or more drug substances and one or more excipients (i.e., pharmaceutical composition) that are administered to a patient in need of treatment, and may be in the form of tablets, capsules, and the like.
The term "melt granulation process" or "melt granulation" as used herein is a process by which pharmaceutical powders are efficiently agglomerated by the use of a melt-processible agent which can be a molten mass, a solid or a solid that melts during the process.
The term "Amorphous" refers to solid-state particles that lack a regular crystalline structure and as a consequence give a diffuse, i.e., non-distinctive, powder x-ray diffraction (PXRD) pattern. "Crystalline" refers to solid-state particles having a regular ordered structure, which, in contrast to amorphous material, give a distinctive PXRD pattern with defined peaks.
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The term "immediate release "as used herein in relation to composition according to the invention or used in any other context means release which is not modified release and releases more than 60% of the active ingredient within 60 minutes.
DETAILED DESCRIPTION
Melt granulation is a process by which pharmaceutical powders are efficiently agglomerated by the use of a melt-processible agent which can be a molten liquid, a solid or a solid that melts during the process. Melt-processible agent is in solid state at room temperature but melts in the temperature range of 50 - 180°C. This melted melt processible agent then acts like a binding liquid. There is no need of drying phase since dried granules are obtained by cooling it to room temperature.
In last few years, melt granulation technique in a high shear mixture has been successfully applied to develop sustained release formulations using lipophilic melting binders (Thies R. et al, "Melt pelletisation of a hygroscopic drug in a high shear mixer. Part 1. Influence of process variables. Int. J. Pharm. 188, 131 - 143).
The current invention relates to a pharmaceutical composition containing active substance valsartan, optionally in combination with another active ingredient, preferably diuretic such as, hydrochlorothiazide (HCTZ) in the form of a tablet or capsule manufactured by melt granulation, which results in immediate release of active substance.
The Valsartan particles are used either directly from the process of forming valsartan or after a milling operation. The particles of valsartan are in the range from 0.1 microns to 200 microns. The preferred average particle diameter is below 50 microns; more preferably between 5 and 50 microns and D90 below 75 microns.
In the current invention the formulation and process to manufacture the immediate release tablets of Valsartan, optionally in combination with another active
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ingredient, preferably diuretic such as, hydrochlorothiazide (HCTZ) by melt granulation is disclosed.
The melt processible agent include, without limitation, ionizable and nonionizable cellulosic polymers, including those having ether or ester or ether and ester substituents and copolymers thereof, including so-called "enteric" and "non-enteric" polymers; vinyl polymers and copolymers having hydroxy, alkylacyloxy, and cyclicamido substituents, including methacrylic acid copolymers and aminoalkyl methacrylate copolymers; various synthetic and naturally occurring polymeric ethers and esters of polyhydric alcohols; and mixtures thereof. In one embodiment, the melt-processible agent is an ionic or ionizable cellulosic polymer as described herein. In one embodiment, the melt-processible agent is a nonionizable cellulosic polymer as described herein. In one embodiment, the melt-processible agent is a vinyl polymer as described herein. In one embodiment, the melt- processible agent is a vinyl co-polymer as described herein. In one embodiment, the melt-processible agent is a methacrylic acid co-polymer as described herein. In one embodiment, the melt-processible agent is an aminoalkyl methacrylate copolymer as described herein. In one embodiment, the melt-processible agent is polymeric ether of a polyhydric alcohol as described herein. In one embodiment, the melt-processible agent is a polymeric ester of a polyhydric alcohol as described herein.
Exemplary ionic cellulosic polymers include, without limitation,
carboxymethylcellulose (CMC) and its sodium or calcium salts;
carboxyethylcellulose (CEC); carboxymethylethylcellulose (CMEC);
hydroxyethylmethylcellulose acetate phthalate; hydroxyethyl methylcellulose
acetate succinate; hydroxypropylmethylcellulose phthalate (HPMCP);
hydroxypropylmethylcellulose succinate; hydroxypropylcellulose acetate
phthalate (HPCAP); hydroxypropylcellulose acetate succinate (HPCAS);
hydroxypropylmethylcellulose acetate phthalate (HPMCAP);
hydroxypropylmethylcellulose acetate succinate (HPMCAS);
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hydroxypropylmethylcellulose acetate trimellitate (HPMCAT);
hydroxypropylcellulose butyrate phthalate; carboxymethylethylcellulose and its sodium salt; cellulose acetate phthalate (CAP); methylcellulose acetate phthalate; cellulose acetate trimellitate (CAT); cellulose acetate terephthalate; cellulose acetate isophthalate; cellulose propionate phthalate; cellulose propionate trimellitate; cellulose butyrate trimellitate; and mixtures thereof. Exemplary nonionic cellulosic polymers include, without limitation, methylcellulose (MC); ethyl cellulose (EC); hydroxyethyl cellulose (HEC); hydroxypropylcellulose (HPC); hydroxypropylmethylcellulose (HPMC); hydroxypropylmethylcellulose acetate; hydroxyethylmethylcellulose; hydroxyethylcellulose acetate; hydroxyethylethylcellulose; and mixtures thereof.
Exemplary vinyl polymers and copolymers include, without limitation, methacrylic acid copolymers and aminoalkyl methacrylate copolymers, which are available, for example, from Rohm Pharma under the trade names EUDRAGIT(R) L, S, NE, RL1 RS, and E. Other exemplary polymers include carboxylic acid functionalized polymethacrylates and amine-functionalized polymethacrylates; polyvinyl acetal) diethylaminoacetate; polyvinyl alcohol (PVA); and polyvinyl alcohol/polyvinyl acetate (PVA/PVAc) copolymers; and mixtures thereof.
Additional vinyl polymers and copolymers include, without limitation homopolymers of N-polyvinyl pyrrolidone (NVP), including, for example, water-soluble polyvinylpyrrolidones (PVPs or povidones), such as KOLLIDON(R) 12 PF, 17 PF, 25, 30, and 90 F; water-soluble copolymers of PVP and vinylacetate (VA), such as KOLLIDON(R) VA64; and water-insoluble cross-linked polyvinylpyrrolidones (crospovidone), such as KOLLIDON(R) CL, CL-M, and SR, which are available from BASF; and mixtures thereof.
Exemplary polymeric ethers and esters of polyhydric alcohols include, without limitation, polyethylene glycol (PEG) like PEG 1500, PEG 4000, PEG 6000.; polypropylene glycol (PPG) homopolymers and copolymers (PEG/PPG);
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polyethylene/polyvinyl alcohol (PE/PVA) copolymers; dextrin; pullulan; acacia; tragacanth; sodium alginate; propylene glycol alginate; agar powder; gelatin; starch; processed starch; glucomannan; chitosan; and mixtures thereof. Other exemplary polymeric ethers include polyethylene oxides, polypropylene oxides, and polyoxyethylene-polyoxypropylene block copolymers (poloxamers) such as those available from BASF under the trade names LUTROL(R) F 68, F 127, and F 127-M; and mixtures thereof.
The melt granulation process includes addition of molten melt processible agent to dry powder blend or melting of melt processible agent and dry powder blend in rapid mixer granulator by applying heat by suitable means or by hot melt extrusion of melt processible agent and dry powder blend to obtain granules.
The melt granulation process can be performed as discussed below:
1. Mixing Valsartan, diluent, melt processible agent, optionally disintegrant thoroughly.
2. Transferring the blend to rapid mixer granulator having heating facility.
3. Granulating the blend by means of heat in rapid mixer granulator.
4. Cooling the granulated blend and sift through appropriate sieve.
5. Sifting the lubricants, disintegrants through 60 mesh and mix with blend from step 4.
6. Compressing the lubricated blend using punch of appropriate size or filling the lubricated blend in capsules of appropriate size.
7. Optionally, film coating the tablets.
For tablet dosage forms, depending on dose, the drug may comprise about 5 % to about 90% of the dosage form, but more typically comprises about 5% to about 60% of the dosage form, based on weight of compressed dosage form.
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The tablets may include one or more disintegrants, surfactants, glidants, lubricants, binding agents, and diluents, either alone or in combination.
Examples of disintegrants include, without limitation, sodium starch glycolate; CMC, including its sodium and calcium salts; croscarmellose; crospovidone, microcrystalline cellulose; Low- substituted HPC; starch; pregelatinized starch; sodium alginate; and mixtures thereof.
Tablets may optionally include surfactants, such as sodium lauryl sulfate and polysorbate 80; glidants, such as silicon dioxide and talc; and lubricants, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and sodium lauryl sulfate, and mixtures thereof.
As noted above, tablet formulations may include binders and diluents. Binders are generally used to impart cohesive qualities to the tablet formulation. Examples of binders include, without limitation, starch, microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, PVP, pregelatinized starch, HPC, and HPMC.
One or more diluents may make up the balance of the tablet formulation. Examples of diluents include, without limitation, lactose monohydrate, spray-dried lactose monohydrate, anhydrous lactose, and the like; mannitol; xylitol; dextrose; sucrose; sorbitol; microcrystalline cellulose; starch; dibasic calcium phosphate dihydrate; and mixtures thereof.
The 'plasticizer' includes all the compounds capable of plasticizing of softening of polymer used in invention. The plasticizer should be able to lower the melting temperature of the polymer. Plasticizers, such as PEG 6000, Glyceryl monopalmetostearate / Glyceryl monostearate, Dibutyl phthalate, Triethyl citrate, Macrogol are included.
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The polymer coating can be selected from hydroxypropyl methylcellulose, hydrogenated castor oil, hydroxypropyl cellulose, beeswax, Eudragit El00 and their mixture thereof.
Other components may include talc as antitacking agent, titanium dioxide as opacifier, iron oxides as colouring agents.
Another active ingredient with valsartan can be selected from the following: Antihypertensive agents like diuretics, ACE inhibitors, Beta-blockers, the most preffered being diuretic such as, Hydrochlorothiazide.
Other angiotensin receptor antagonist like, irbesartan, candesartan can also be prepared by melt granulation process.
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.
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Examples
The ingredients used in the preparation of tablets containing Valsartan and its pharmaceutically acceptable salt there of in the instant invention by melt granulation process are given below along with the method of preparation of said
tablets.

Table 1
Ingredients Mg / Tablet
1 2
Valsartan 80.00 160.00
Lactose monohydrate 58.80 283.65
Polyethylene Glycol 4000 2.80 10.00
Croscarmellose Sodium 16.00 24.00
Magnesium Stearate 1.60 4.85
Talc 0.80 2.50
Hydroxy propyl Methyl cellulose 2.75 2.75
Polyethylene Glycol 0.55 0.55
Titanium Dioxide 0.70 0.70
Iron Oxides 0.20 0.20
Purified Water q.s q.s
Total 165.20 491.20
"Dissolution (%) 91.23 95.32
# 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 was less than 10 minutes.
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Procedure:
Valsartan, Lactose monohydrate, Polyethylene glycol 4000 and optionally Croscarmellose sodium were passed through mesh # 40. The sifted materials were blended together and added to rapid mixer granulator and heated to a temperature of 58-60°C. The molten mass was cooled to room temperature and passed through mesh # 20 and blended with a compression mixture comprising of Crosscarmellose sodium, Magnesium Stearate and Talc previously sieved through mesh # 60. The final blend thus obtained was compressed tablets on a tablet compression machine. Compressed tablets were film coated.
Dated this on 05th August, 2006


ABSTRACT
The present invention relates to pharmaceutical composition comprising active substance valsartan, optionally in combination with another active ingredient, preferably diuretic such as, hydrochlorothiazide (HCTZ), in the form of a tablet or capsule manufactured by melt granulation. Further, present invention also relates to a process for preparing said dosage form.