WO2013114389A1

WO2013114389A1 - Process for preparing solid oral formulations comprising low dose of entecavir

Info

Publication number: WO2013114389A1
Application number: PCT/IN2012/000833
Authority: WO
Inventors: Ajay SUGGALA; Jitendra CHORDIYA; Prakash SHETIYA; Akhilesh DIXIT; Abhijit DESHMUKH
Original assignee: Mylan Laboratories Ltd
Current assignee: Mylan Laboratories Ltd
Priority date: 2011-12-21
Filing date: 2012-12-20
Publication date: 2013-08-08
Anticipated expiration: 2014-06-21

Description

PROCESS FOR PREPARING SOLID ORAL FORMULATIONS COMPRISING LOW DOSE OF ENTECAVIR

FIELD OF INVENTION The invention relates to the pharmaceutical field. More specifically it relates to process for preparing solid oral pharmaceutical formulations comprising low dose of entecavir and one or more pharmaceutically acceptable excipient(s).

BACKGROUND OF THE INVENTION AND RELATED PRIOR ARTS

Entecavir is an oral antiviral drug used in the treatment of hepatitis B infection (HBV). More specifically, entecavir is a guanosine nucleoside analogue with activity against HBV reverse transcriptase, it inhibits HBV replication by competing with the natural substrate, deoxyguanosine at the viral replication process.

Entecavir is described chemically as 2-amino-l, 9-dihydro-9-[(l S, 3R, 4S)- 4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one, monohydrate. Its molecular formula is C₁₂H₁₅N₅0₃ ^»H₂0, which corresponds to a molecular weight of 295.3. Entecavir is a white to off-white powder. It is slightly soluble in water (2.4 mg/ml), and the pH of the saturated solution in water is 7.9 at 25° ± 0.5° C. Entecavir was introduced into the U.S. market under the brand name of

Baraclude^® and is available for oral administration in strengths of 0.5 mg and 1 mg. Baraclude^® 0.5-mg and 1-mg film-coated tablets contain the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, and magnesium stearate. The tablet coating contains titanium dioxide, hypromellose, polyethylene glycol 400, polysorbate 80 (0.5-mg tablet only), and iron oxide red (1-mg tablet only). It appears that the marketed tablet Baraclude^® uses povidone as a binder or adhesive. U.S. Patent No. 6,627,224 discloses a low dose solid oral formulation containing from about 0.001 mg to about 25 mg entecavir and process for preparing the same, wherein the process comprises the steps of: (a) preparing a solution of the entecavir in a solvent along with an adhesive substance at temperatures ranging from about 25° C. to about 80° C, (b) applying the solution as a spray or a stream on the carrier particles, while the carrier substrate particles are in motion, (c) subsequently, the solvent is removed from the carrier surface leaving the entecavir particles adhered to the surface of the carrier substrate, which prevents the separation of entecavir from said carrier substrate and minimizes the loss of entecavir during subsequent processing, (d) dried entecavir coated carrier substrate particles are mixed with one or more pharmaceutically acceptable excipient(s) such as a disintegrant, lubricant and/or glidant and compressed into tablets or filled into capsules. The process conditions are strictly controlled during spray coating of the substrate carrier particles with entecavir solution, to minimize particle agglomeration and drug content variation. The adhesive substance used is preferably, a polymeric material possessing a high degree of tackiness, which acts as a binder, thereby functioning to adhere entecavir to carrier substrate particles and thus prevent the separation of entecavir from the substrate and minimize the loss of entecavir during subsequent processing such as drying and blending, thereby ensuring content uniformity throughout the batch process. According to said patent, suitable adhesive substances include povidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, guar gum, and xanthan gum and mixtures thereof. . Prasanth Sai R.V et al., International Journal of Research in

Pharmaceutical and Biomedical Sciences, Vol. 2 (3), p.1239- 1247, Jul - Sep 2011, discloses entecavir tablet composition comprising entecavir, lactose, microcrystalline cellulose, crospovidone and magnesium stearate, wherein said tablet is prepared by employing direct compression method. Thus, from above, it is clear that it would be difficult to formulate solid oral formulation comprising a low dose of entecavir, having uniform or acceptable content uniformity, by using conventional wet granulation process, due to uneven distribution or segregation of drug particles during mixing or blending (i.e. mixing of drug particles with one or more pharmaceutically excipient(s), and during the granulation process). To ensure uniform distribution or segregation of the drug particles during blending or granulation process, suitable binder or adhesive agent is incorporated in the composition or during the processing steps and preferably spray granulation or spray coating technique is used. Thus, the use of binders or adhesives appears to be mandatory during the processing step to ensure content uniformity, and consistent reproduction of the processing steps.

Surprisingly, the present inventors have found that the solid oral pharmaceutical formulations of entecavir can be prepared without incorporating or involving the use of any binder in the composition or during the processing step, without compromising or failing in the content uniformity test. Thus, this advancement helps to reduce additional processing time and the number of ingredients in the composition, while still maintaining the requirement of uniform or acceptable content uniformity.

SUMMARY AND OBJECTIVES OF THE INVENTION The invention relates to processes for preparing solid oral pharmaceutical formulation comprising a low dose of entecavir and one or more pharmaceutical excipient(s), preferably in the form of compressed tablets.

An objective of the invention is to prepare solid oral pharmaceutical formulation comprising a low dose of entecavir and one or more pharmaceutically acceptable excipient(s), wherein the process does not involve the use of any binder.

Another objective of the invention is to prepare solid oral tablet formulation comprising a low dose of entecavir and one or more pharmaceutically acceptable excipient(s), wherein the process does not involve the use of any binder.

Another objective of the invention is to prepare solid oral capsule formulation comprising a low dose of entecavir and one or more pharmaceutically acceptable excipient(s), wherein the process does not involve the use of any binder.

Another objective of the invention is to prepare solid oral tablet formulation comprising a low dose of entecavir and one or more pharmaceutically acceptable excipient(s), having uniform, or acceptable content uniformity, wherein the process does not involve the use of any binder.

Another objective of the invention is to prepare solid oral tablet formulation comprising a low dose of entecavir and one or more pharmaceutically acceptable excipient(s) by employing wet granulation process, wherein the process does not involve the use of any binder. Another objective of the invention is to prepare solid oral tablet formulation comprising a low dose of entecavir and one or more pharmaceutically acceptable excipient(s) by employing spray granulation or spray coating process, wherein the process does not involve the use of any binder.

Yet another objective of the invention is to prepare solid oral tablet formulation comprising a low dose of entecavir and one or more pharmaceutically acceptable excipient(s), having comparable in-vitro dissolution profile and in-vivo pharmacokinetic parameters with that of the marketed Baraclude^® tablet, wherein said tablets are prepared employing wet granulation process and said process does not involve the use of any binder. DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

As discussed in the background of the invention, it is difficult to formulate solid oral pharmaceutical formulations comprising a low dose of entecavir, having or possessing uniformity in content, without the use of any binding agent.

The present inventors have developed a wet granulation process of preparing solid oral pharmaceutical formulation comprising low dose of entecavir and one or more pharmaceutically acceptable excipient(s), wherein the process does not involve the use of any binder, and still said solid oral pharmaceutical formulation possess or meets the content uniformity test.

In the context of the invention, the solid oral pharmaceutical formulation of a low dose of entecavir preferably includes granules, pellets, mini-tablets, tablets, bi-layered or multi-layered tablets, capsules, lozenges or troches.

According to the invention, the term "a low dose of entecavir" is used in connection with a solid oral formulation containing from about 0.001 mg to about 25 mg of the entecavir, preferably from about 0.01 mg to about 10 mg of entecavir, most preferably from about 0.01 mg to about 5 mg of entecavir .

In context of the invention, terms like "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for entecavir or its pharmaceutically acceptable salts or esters or derivatives thereof.

According to the invention, entecavir may be present in an amorphous or crystalline form. As used herein, the term "entecavir" is intended to include the active agent itself, as well as its pharmaceutically acceptable salts or derivatives or polymorphs thereof.

According to an embodiment of the invention, the term, "binder" is intended to include any pharmaceutically acceptable ingredient that can be used in either dry or wet state to help bind drug and the excipient particle(s) together in a formulation.

According to the invention, the term, "uniform or acceptable content uniformity" is intended to mean that the percentage relative standard deviation (RSD) of the assay of the composition prepared according to the embodiments of the invention is less than 6.0% and the assay value is within the range of 85% to 115% of the label claim.

According to an embodiment of the invention, the term "wet granulation" as used herein, relates to a process by which powder particles are made to adhere to each other to form agglomeration of particles called as agglomerates or granules by the addition of a granulation liquid onto a powder blend or powder bed comprising other pharmaceutically acceptable excipients. The addition of the granulating liquid onto the powder blend or powder bed could be done through spraying and/ or by pouring said granulating liquid on to the powder bed/ blend in a controlled manner, until the granulation end point is reached.

According to an embodiment of the invention, the process of preparing solid oral pharmaceutical formulation of a low dose of entecavir involves wet granulation process, wherein the process does not involve the use of any binder.

According to an embodiment of the invention, wet granulation process for preparing solid oral formulation of a low dose of entecavir involves the use of aqueous or non-aqueous or hydro-alcoholic solvent as a granulating liquid.

According to an embodiment of the invention, non-aqueous solvents for use in granulation process steps include, but are not limited to methanol, ethanol, isopropyl alcohol, dichloromethane, acetone, ethyl acetate, dimethylsulfoxide or their combinations thereof.

According to an embodiment of the invention, hydro-alcoholic solvents are mixtures of one or more alcohols and water, in various volume ratios. Preferably, according to an embodiment of the invention, entecavir is dissolved in purified water by heating water at a temperature above 70 °C and below 80°C and the resulting entecavir solution maintained at a temperature of 70±5°C is used as granulating liquid for wet granulation process, to be sprayed over the powder bed/ blend until the granulation end-point is reached.

According to an embodiment of the invention, the wet granulation process of preparing solid oral tablets comprising a low dose of entecavir, without the use of any binder, comprises the step of: a) Dissolving entecavir in water by dispersing it in water and heating the water at a temperature above 70°C and below 80°C to get entecavir solution; b) Sifting one or more pharmaceutically acceptable excipient(s) through size #30 mesh and blending; c) Spray granulating or spray coating the blend obtained in step (b) with the entecavir solution obtained in step (a), which is maintained at temperature 70±5°C, by employing rapid mixer granulator (RMG) or in fluid bed granulator; d) Drying the granules or coated particles of step (c) using fluid bed dryer (FBD) at 50°C to 70°C, and passing or screening the granules through suitable size sieve to get dried granules of desired size; e) Optionally blending the dried granules or coated particles of step (d) with one or more extra-granular pharmaceutically acceptable excipient(s); f) Compressing the blend of step (e) in to tablets; g) Optionally coating the tablets from step (f) with a film-former. According to an another embodiment of the invention, the wet granulation process of preparing solid oral tablets comprising a low dose of entecavir, without the use of any binder, comprises the step of: a) Dispersing entecavir in water; b) Sifting one or more pharmaceutically acceptable excipient(s) through size #30 mesh and blending; c) Spray granulating or spray coating the blend obtained in step (b) with the entecavir dispersion obtained in step (a) by employing rapid mixer granulator (RMG) or in fluid bed granulator; d) Drying the granules or coated particles of step (c) using fluid bed dryer (FBD) at 50°C to 70°C, and passing or screening the granules through suitable size sieve to get dried granules of desired size; e) Optionally blending the dried granules or coated particles of step (d) with one or more extra-granular pharmaceutically acceptable excipient(s); f) Compressing the blend of step (e) in to tablets; g) Optionally coating the tablets from step (f) with a film-former.

According to an embodiment of the invention, the wet granulation process of preparing solid oral capsule comprising a low dose of entecavir, without the use of any binder, comprises the step of: a) Dissolving entecavir in water by dispersing it in water and heating the water at a temperature above 70°C and below 80°C to get entecavir solution; b) Sifting one or more pharmaceutically acceptable excipient(s) through size #30 mesh and blending; c) Spray granulating or spray coating the blend obtained in step (b) with the entecavir solution obtained in step (a), which is maintained at temperature 70±5°C, by employing rapid mixer granulator (RMG) or in fluid bed granulator; d) Drying the granules or coated particles of step (c) using fluid bed dryer (FBD) at 50°C to 70°C, and passing or screening the granules through suitable size sieve to get dried granules of desired size; e) Optionally blending the dried granules or coated particles of step (d) with one or more extra-granular pharmaceutically acceptable excipient(s); f) Filling the blend of step (e) in to suitable size empty capsule shells.

According to an embodiment of the invention, the wet granulation process of preparing solid oral capsule comprising a low dose of entecavir without the use of any binder, comprises the step of: a) Dispersing entecavir in water; b) Sifting one or more pharmaceutically acceptable excipient(s) through size #30 mesh and blending; c) Spray granulating or spray coating the blend obtained in step (b) with the entecavir dispersion obtained in step (a) by employing rapid mixer granulator (RMG) or in fluid bed granulator; d) Drying the granules or coated particles of step (c) using fluid bed dryer (FBD) at 50°C to 70°C, and passing or screening the granules through suitable size sieve to get dried granules of desired size; e) Optionally blending the dried granules or coated particles of step (d) with one or more extra-granular pharmaceutically acceptable excipient(s); f) Filling the blend of step (e) in to suitable size empty capsule shells. According to the invention, the wet granulation process for preparing solid oral pharmaceutical formulation comprising low dose of entecavir, does not involve the use of any binder such as povidone, methylcellulose (MC), hydroxymethylcellulose, hydroxypropyl-methylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), gelatin, guar gum, xanthan gum, ethyl cellulose, Eudragit™, starch, pregelatinized starch, alginates and mixtures thereof.

The tablet or capsule dosage form according to the invention may further contain one or more pharmaceutically acceptable excipient(s) selected from a group comprising diluents, disintegrants, glidants, and/ or lubricants.

Suitable diluents according to the invention include, but are not limited to, mannitol, xylitol, sorbitol, lactose, sucrose, cellulose, microcrystalline cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate, calcium phosphate tribasic, starch, calcium trisilicate, magnesium trisilicate, cellulose acetate, dextrose, or combinations thereof.

Suitable disintegrants according to the invention include, but are not limited to, crospovidone, croscarmellose sodium, sodium starch glycolate, low- substituted hydroxypropyl cellulose (L-HPC), pregelatinised starch, starch, microcrystalline cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, polacrilin potassium or combinations thereof.

Suitable glidants and lubricants according to the invention include, but are not limited to, colloidal silicon dioxide, talc, magnesium stearate, sodium stearyl fumarate, calcium stearate or combinations thereof. According to the invention, film coating excipient(s) may be selected from a group comprising of film polymers, plasticizers, opacifiers, and coloring agents, etc. Suitable film polymers according to the invention include, but are not limited to, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl acetate (PVAc), methyl cellulose (MC) and ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methacrylic acid copolymer, cellulose acetate phthalate, cellulose phthalate, hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate, and natural gums and resins such as zein, gelatin, shellac and acacia or combinations thereof.

Suitable plasticizers according to the invention include, but are not limited to, castor oil, polyethylene glycol, propylene glycol, glycerin, triacetin, polysorbates, phthalate esters, dibutyl sebacate, citrate esters, and monoglycerides or combinations thereof.

Suitable opacifiers according to the invention include, but are not limited to, titanium dioxide and talc or combinations thereof. Suitable coloring agents according to the invention include, but are not limited to, FDA approved dyes and lakes such as sunset yellow, tartrazine, erythrosine, iron oxide yellow, and natural colors such as carmine or combinations thereof.

According to the invention ready-to-use film coating systems such as Opadry^® and Instacoat™ may also be used for film coating of tablets.

Content Uniformity Test:

According to an embodiment of the invention, procedure used to determine the content uniformity test is as follows:

Acceptance criteria stage 1:

Assay 10 tablets:

Pass - if both of the following criteria are met 1. Relative Standard Deviation (RSD) of <6.0%, and

2. No tablet assay value outside 85% tol 15% of the label claim. Fail if one or more tablet assay values are outside 75% to 125% of the label claim, if fails to meet above criteria, repeat the test using another 20 tablets.

Acceptance criteria stage 2:

Assay 20 tablets:

Pass - if all 30 tablets met following criteria:

1. Relative Standard Deviation (RSD) of < 7.8%, and

2. Not more than one tablet assay value is out side 85% to 115% of label claim.

According to the invention, assay value for entecavir tablets is determined by using following procedure.

Mobile phase:

Mix 1820 volumes of pH 4.0 buffer with 180 volumes of Solution A and degas.

Diluent -1:

Mix 500 volumes of 0.05% orthophosphoric acid solution and 500 volumes of methanol and degas.

Diluent -2: Degassed mobile phase.

Diluent as blank: Filter a portion of diluent -2 through 0.45 μπι PVDF syringe filter.

Chromatographic conditions:

Column : Inertsil ODS-3V, 150 x 4.6 mm, 5 μηι or equivalent

Flow rate : 1.0 mL /minute

Wavelength : 254 nm

Column oven temperature : 30°C ± 2°C

Sample tray temperature : 10°C ± 2°C

Injection Volume : 50 μΐ,

Run time : 6 minutes Standard preparation:

1. Weigh accurately and transfer about 50 mg of entecavir RS/ working standard into a 200 mL volumetric flask, add about 150 mL of diluent- 1, sonicate to dissolve, dilute to volume with diluent- 1 and mix.

2. Pipette 4.0 mL of the solution into a 200 mL volumetric flask, dilute to volume with diluent-2 and mix.

3. Filter the solution through 0.45 μη PVDF syringe filter. Test preparation: (For 1 mg strength)

Transfer one tablet into a 25 mL volumetric flask, add 2 mL of water, shake the flask to disintegrate the tablet completely (which would take about 10 minutes time) using table top shaker at 200 rpm, add about 15 mL of diluent- 1, sonication for about 45 minutes with intermittent shaking, cool to room temperature, dilute to volume with diluent- 1 and mix.

Centrifuge a portion of solution at 5000 rpm, in a centrifuge tube with cap, for about 10 minutes.

Pipette 6.0 mL of the solution into a 50 mL volumetric flask, dilute to volume with diluent -2 and mix.

Filter the solution through 0.45 μηι PVDF membrane filter

Procedure:

Inject diluent as blank, standard preparation (five times) and test preparation into the chromatograph. Record the chromatograms and measure the response for major peak.

Calculation:

Amount of Entecavir A_T W_s 4 25 V, P present as % label claim = x x x x x—— x 100

A_s 200 200 LC V 100

Where,

Αχ = Peak area of Entecavir from test preparation

As = Average peak area of Entecavir from standard preparation Ws = Weight of Entecavir standard taken in mg, for standard preparation.

= 5 for 0.5 mg and 6 for 1 mg

= 20 for 0.5 mg and 50 for 1 mg

LC = Label claim of Entecavir as Entecavir in mg, per unit dose.

P = Potency of Entecavir as Entecavir standard in. %, on as is basis.

The Relative Standard Deviation (RSD) was calculated from content values obtained for each individual tablet samples.

The embodiments of the invention are described in the following examples, but the examples are illustrative and do not limit the scope of this invention.

EXAMPLE 1:

Unit Composition:

Brief manufacturing process: 1. Sifting microcrystalline cellulose, lactose and crospovidone through size

#30 mesh and mixing well. 2. Dispersing entecavir in purified water to get granulating liquid.

3. Granulating the blend obtained in step (1) by spraying the granulating liquid obtained in step (2) by employing rapid mixer granulator (RMG) to get wet mass or granules.

4. Drying the wet mass or granules obtained in step (3) by employing fluid bed dryer (FBD) at 60°C to get LOD of not more than 1.5% at 105°C and sifting or passing dried mass or granules through size #30 mesh to get dried granules.

5. Sifting microcrystalline cellulose through size #40 mesh and blending with dried granules of step (4).

6. Sifting magnesium stearate through size #40 mesh and lubricate the blend of step (5).

7. Compressing the lubricated blend of step (6) in to tablets.

8. Film coating of the tablets obtained in step (7) using Opadry^® dispersion in purified water.

EXAMPLE 2:

Unit Composition:

Brief manufacturing process:

1. Sifting microcrystalline cellulose, lactose and crospovidone through size #30 mesh and mixing well.

2. Dissolving entecavir in water by dispersing entecavir in water and heating the water at a temperature above 70°C and below 80°C to get granulating liquid.

3. Granulating the blend obtained in step (1) by spraying the granulating solution obtained in step (2) maintained at temperature 70±5°C by employing rapid mixer granulator (RMG) to get wet mass or granules.

5. Sifting microcrystalline cellulose through size #40 mesh and blending with the granules of step (4).

6. Sifting magnesium stearate through size #40 mesh and lubricating the blend of step (5).

7. Compress the lubricated blend of step (6) in to tablets.

EXAMPLE 3:

Unit Composition:

Brief manufacturing process:

2. Dissolving entecavir in water by dispersing entecavir in water and heating the water at a temperature above 70°C and below 80 °C to get granulating liquid.

3. Granulating the blend obtained in step (1) by spraying the granulating solution obtained in step (2) maintained at temperature 70±5°C by employing rapid mixer granulator (RMG) to get wet mass or granules. 4. Drying the wet mass or granules obtained in step (3) by employing fluid bed dryer (FBD) at 60°C to get LOD of not more than 1.5% at 105°C and sifting or passing dried mass or granules through size #30 mesh to get dried granules.

7. Filling the lubricated blend of step (6) in to empty hard gelatin capsules. Tablet Properties:

Entecavir lmg tablets prepared according to Example 1 and 2 were subjected to in-process quality control tests and the resultant data is compiled in Table 1.

Table - 1

Content Uniformity Test:

Content uniformity of entecavir tablets prepared according to Example 1 and 2 were determined and the resultant data is compiled in Table 2.

Table - 2

Above content uniformity data shows that the tablets prepared according to Example 1 and Example 2 passed the content uniformity test, Example 2 shows excellent content uniformity, when compared to Example 1. Stability Study:

1 mg entecavir tablets prepared according to Example 1 and Example 2 were packed in HDPE bottles, ALU/ ALU blister and PVC/ALU blister packs and were subjected to accelerated stability study at 40°C/75%RH for 12 weeks. The results of the accelerated stability study are tabulated in Table 3 and Table 4 respectively. Table - 3

Table - 4

Above accelerated stability shows that the tablets prepared according to Example 1 and Example 2 are stable at the end of 12 weeks. Bio-equivalence Data:

Entecavir tablets prepared according to Example 2 (test product) and Baraclude^® lmg tablets (reference product) were subjected for the in-vivo bioequivalence study in healthy human volunteers under fasting condition and the resultant data is compiled in Table 5 and Table 6.

Table - 5

Table - 6

Above in-vivo bioequivalence data shows the low dose of entecavir tablets prepared according to the Example 2 showed comparative in-vivo bioequivalence profile with that of marketed Baraclude^® lmg tablets.

Claims

WE CLAIM:

1. A wet granulation process for preparing solid oral formulation comprising entecavir and one or more pharmaceutically acceptable excipients, wherein said process does not involve the use of any binder.

2. A wet granulation process for preparing solid oral formulation comprising entecavir and one or more pharmaceutically acceptable excipients, having uniform content uniformity, wherein said process does not involve the use of any binder.

3. The process according to claim 1 and 2, wherein said solid oral formulation comprises about 0.01 mg to about 10 mg of entecavir.

4. The process according to claim 2, wherein said solid oral formulation has uniform content uniformity with Relative Standard Deviation (RSD) of <6.0% and assay in the range of 85% to 1 15% of the label claim.

5. A wet granulation process for preparing tablet comprising entecavir and one or more pharmaceutically acceptable excipient(s), wherein said process which does not involve the use of any binder, comprises the steps of:

(a) dissolving entecavir in a solvent to get solution;

(b) spray granulating one or more pharmaceutically acceptable excipient(s) with said solution obtained in step (a) to get wet mass;

(c) drying said wet mass obtained in step (b) to get granules;

(d) optionally blending said granules from step (c) with additional pharmaceutically acceptable excipient(s);

(e) lubricating said blend obtained in step (d); and

(f) compressing the lubricated blend into tablet.

6. A wet granulation process for preparing tablet comprising entecavir and one or more pharmaceutically acceptable excipient(s), wherein said process which does not involve the use of any binder, comprises the following steps:

(a) dispersing entecavir in a solvent to get dispersion;

(b) spray granulating one or more pharmaceutically acceptable excipient(s) with said dispersion obtained in step (a) to get wet mass;

(c) drying said wet mass obtained in step (b) to get granules;

(e) lubricating said blend obtained in step (d); and

(f) compressing the lubricated blend into tablet.

7. The process according to claims 5 and 6, wherein the solvent is selected from a group consisting of water, methanol, ethanol, isopropyl alcohol, dichloromethane, acetone, ethyl acetate, dimethylsulfoxide or their combinations thereof.

8. A tablet comprising entecavir having the following unit composition prepared by wet granulation process, wherein said process does not involve the use of any binder:

9. A tablet comprising entecavir devoid of any binder, prepared by wet- granulation process, wherein said tablet exhibit not less than 80% release of entecavir at the end of 10 minutes, when tested according to USP Type II dissolution apparatus at 50 rpm in lOOOmL of Phosphate Buffer pH 6.8 (50mM).

10. A wet granulation process for preparing tablet comprising entecavir and one or more pharmaceutically acceptable excipient(s) as herein described and exemplified.