Field of the invention

The technical field of the present invention relates to oral solid dosage forms of antiviral agent. More particularly, the present invention relates to oral dosage forms of entecavir prepared by wet granulation process.

Background of the invention

Entecavir, as disclosed in US 5,206,244 is a nucleoside analogue of guanosine, used for the treatment of chronic hepatitis B virus infection in adults. US '244 discloses that an effective antiviral dose for oral or parenteral administration will likely be in the range of about 1.0 to 50 mg/kg of body weight and that the desired dose may be administered several times daily at appropriate intervals.

Chemically it is 2-amino-l,9-dihydro-9-[(l-S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-
methylenecyclopentyl]-6H-purin-6-one and is commercially marketed as 0.5mg and lmg film 'coated tablets and 0.05mg/ml solution under the trade name Baraclude® (Bristol Myers Squibb). Baraclude® tablets contain entecavir monohydrate as active ingredient and inactive ingredients include lactose monohydrate, microcrystalline cellulose, povidone, crospovidone, magnesium stearate and coating contains hypromellose, macrogol 400, polysorbates 80 (0.5 mg only), titanium dioxide and iron oxide (1 mg only). As disclosed in EMEA, entecavir is a crystalline, non-hygroscopic, white to off-white powder. The Baraclude® tablets are prepared by wet granulation process which minimizes the impact of the physical characteristics (particle size, shape and surface area) of the active on the content uniformity of the tablets. Entecavir crystalline form has shown not to be affected during manufacture and storage.

US 6,627,224 discloses that compositions containing entecavir in an amount of less than or equal to about 10 mg with good content uniformity cannot be prepared by simply mixing the active substance and the excipients. The traditional methods of granulation are also not suitable for products active at such low doses. Hence, US '224 disclose the preparation method that ensures high potency and good uniformity of the product. The compositions disclosed in US '224 are prepared by depositing the entecavir on the surface of carrier substrate particles, which can be accomplished by forming a solution of the entecavir in a solvent along with an adhesive substance at temperatures ranging from about 25°C to about 80°C and applying the solution as a spray or a stream while the carrier substrate particles are in motion. Subsequently, the solvent is removed from the carrier surface leaving the entecavir particles adhered to the surface of the carrier substrate.

WO 01/30329 discloses compositions comprising combination of lamivudine and entecavir by wet granulation using a solution of povidone followed by addition of extragranular ingredients and compression.

US 2010/0210669 discloses compositions prepared by granulating entecavir, microcrystalline cellulose, lactose using starch paste and then extragranular addition of carboxymethylstarch sodium and magnesium stearate followed by compression.

CN 101371841 discloses compositions by sieving and mixing crystalline entecavir and glidant, together followed by mixing with diluent, binding agent and disintegrant, processing to obtain tablets or capsules.

CN 1931138 discloses entecavir granules prepared by granulating entecavir and excipients using binder solution.

CN 1833643 discloses entecavir/polyvinyl pyrrolidone or entecavir/citric acid solid disperse composites by dissolving entecavir in a solvent and then adding polyvinyl pyrrolidone or citric acid and then removing the solvent by spray drying or concentrating the solution under reduced pressure to make solid.

CN 1732945 discloses process for the preparation of entecavir tablets by melt granulation.

CN 101069687 discloses dispersible tablet prepared by granulating entecavir, mannitol, lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose using a dispersion of hydroxypropylmefhylcellulose, followed by extragranular addition of crosslinked povidone, silica gel, magnesium stearate.

CN 101062418 discloses the entecavir-cyclodextrin inclusion complex.

CN 101244044 discloses dispersible tablet of entecavir, prepared by granulating the excipients blend using a hydroalcoholic solution of binder and entecavir.

CN 101627972 discloses orally disintegrating tablet of entecavir.

CN 101204395 discloses orally disintegrating tablet of entecavir prepared by granulating entecavir and excipents using starch paste.

CN 101057851 discloses effervescent tablet of entecavir prepared by direct compression.

For low dose drugs such as entecavir, attaining content uniformity is difficult with conventional methods of manufacturing. Hence, the above prior art references disclose process for the preparation of entecavir tablets by granulating excipient blend using entecavir and binder solution or by melt granulation. The inventors of the present invention have endeavored to develop alternate solid dosage forms of entecavir by simple granulation process achieving good content uniformity.

Objective of the invention

Accordingly, the main objective of the present invention is to provide oral dosage form comprising entecavir in such a way that the dosage form will comply with the reference product in terms of in vitro parameters like dissolution, disintegration and etc.

Summary of the invention

The present invention provides oral solid dosage form comprising entecavir and one or
more pharmaceutically acceptable excipients, prepared by a process comprising the steps of:

i) blending entecavir and one or more pharmaceutically acceptable excipients,
ii) granulating the blend of step (i) using solvent without binder,
iii) blending the granules of step (ii) with one or more pharmaceutically acceptable excipients, and iv) formulating the blend obtained in step (iii) into solid dosage form.

Brief description of the drawings

Figure 1 shows the comparative dissolution profile of entecavir compositions according to Example-1 and Baraclude® tablets.

Figure 2 shows the comparative dissolution profile of entecavir compositions according to Example-2 and Baraclude® tablets.

Detailed description of the invention

The present invention relates to oral solid dosage form comprising entecavir and one or more pharmaceutically acceptable excipients prepared by wet granulation process.

In another embodiment, the present invention also relates to an oral solid dosage form comprising entecavir and one or more pharmaceutically acceptable excipients, prepared by a process, comprising the steps of:

i) blending entecavir and one or more pharmaceutically acceptable excipients,

ii) granulating the blend of step (i) using solvent without binder,

iii) blending the granules of step (ii) with one or more pharmaceutically acceptable excipients, and

iv) formulating the blend obtained in step (iii) into solid dosage form.

In another embodiment, the present invention also relates to an oral solid dosage form comprising entecavir and one or more pharmaceutically acceptable excipients, prepared by a process, comprising the steps of:

i) blending entecavir and one or more intragranular excipients,
ii) granulating the blend of step (i) using solvent without binder, iii) drying the granules of step (ii) and iv) formulating the dried granules obtained in step (iii) into solid dosage form.

"Entecavir" according to the present invention includes, but not limited to, entecavir free base, its pharmaceutical acceptable salts, esters, ethers, solvates, hydrates, polymorphs, derivatives and the like. The average particle size of entecavir according to present invention is 1 to 200 um.

The amount of entecavir used in the present invention may range from about 0.01 mg to 5mg.

In another embodiment, entecavir is present either in crystalline or amorphous form.
"Pharmaceutically acceptable excipient/s" are the components added to pharmaceutical formulation to facilitate manufacture, enhance stability, control release, enhance product characteristics, enhance bioavailability, enhance patient acceptability, etc. Pharmaceutically acceptable excipients includes, but not limited to, diluents/fillers, binders, disintegrants, sugars, lubricants, glidants, compression aids, colors, sweeteners, preservatives, surfactants, suspending agents, dispersing agents, film formers, flavors, printing inks, etc.

Diluents increase the bulk of the composition. Diluents according to the present invention include, but not limited to, sugars such as lactose, sucrose, dextrose; sugar alcohols such as mannitol, sorbitol, xylitol, lactitol; Starlac® (co-processed mixture of Starch and lactose), Microcelac® (co-processed mixture of microcrystalline cellulose and lactose), starch, corn starch, modified starches, pregelatinized starch, dibasic calcium phosphate, tribasic calcium phosphate, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose and the like or combinations thereof. The diluent may be used in the range of 5-99%, preferably 10-70% by weight of the dosage form.

Binders hold the ingredients in the composition together. Exemplary binders include, but not limited to, cellulose and its derivatives including, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose and hydroxyethyl cellulose, carboxymethyl cellulose; starch and its derivatives; pregelatinized starch, hydrocolloids; sugars; polyvinyl pyrrolidone, copovidone, methacrylic acid copolymers and combinations comprising one or more of the foregoing binders. The binder may be used in the range of 0.1-40%, preferably 1-20% by weight of the dosage form.

Disintegrants according to the present invention include, but not limited to, water swellable substances, for example, cellulose and its derivatives including low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose; cross-linked polyvinylpyrrolidone; cross-linked sodium carboxymethylcellulose, cross-linked calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxy methylcellulose, microcrystalline cellulose; sodium starch glycolate; ion-exchange resins; starch and modified starches including pregelatinized starch; formalin-casein; alginates, gums, and combinations comprising one or more of the foregoing water swellable substances. The disintegrant may be used in the range of 0-30%, preferably 1-20% by weight of the dosage form.

Surfactants are compounds which are capable of improving the wetting of the drug and/or enhancing the dissolution. The surfactants can be selected from hydrophilic surfactants or lipophilic surfactants or mixtures thereof. The surfactants can be anionic, nonionic, cationic, and zwitterionic surfactants. Surfactants according to the present invention include, but not limited to, polyoxyethylene alkylaryl ethers such as polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether; polyethylene glycol fatty acid esters such as PEG monolaurate, PEG dilaurate, Polyethylene glycol 660 12- hydroxyl Stearate Ph.Eur. or Polyoxyl 15 hydroxystearate NF (Solutol HS 15), PEG distearate, PEG dioleate; polyoxyethylene sorbitan fatty acid ester such as polysorbate 40, polysorbate 60, polysorbate 80; sorbitan fatty acid mono esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene castor oil derivates such as polyoxyl castor oil, polyoxyl hydrogenated castor oil, sodium lauryl sulphate, monooleate, monolaurate, monopalmitate, monostearate, sodium dioctyl sulfosuccinate (DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, cremophore RH 40, polyoxyethylene stearates (Macrogol-stearate) and the like or combinations thereof. The surfactant may be used in the range of 0.001-5% by weight of the dosage form.

Lubricants and glidants aids in the processing of powder materials. Exemplary lubricants include, but not limited to, calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, fumaric acid, sodium stearyl fumarate, stearic acid, talc, vegetable oil, zinc stearate, castor wax and combinations comprising one or more of the foregoing lubricants. The
lubricant may be used in the range of 0.01-5%, preferably 0.1-2% by weight of the dosage form. Exemplary glidants include, but not limited to, talc, silicon dioxide, silicic acid, cornstarch, calcium silicate, magnesium carbonate, magnesium oxide, magnesium silicate, colloidal silicon dioxide, starch, castor wax and the like. The glidant may be used in the range of 0.01-5%, preferably 0.1 -2% by weight of the dosage form.

In another embodiment of the present invention, the intragranular excipients include diluent, binder, disintegrant and surfactant.

In another embodiment, the solid dosage form comprises about 0.1% to about 20%w/w of entecavir, 20% to about 98% w/w of diluent, about 0% to about 5% w/w of disintegrant as intragranular excipients.

In another embodiment of the present invention, the granulation is carried out using aqueous or nonaqueous solvent system or mixture of both without using binder.

In another embodiment of the present invention, the aqueous and nonaqueous solvents of the present invention are selected from water, isopropyl alcohol, methanol, ethanol, methylene chloride, acetone and the like or mixture thereof.

In another embodiment, the dried granules are mixed with extra granular excipients such as diluent, disintegrant and lubricant before processing into solid dosage forms.

In another embodiment, the oral solid dosage form comprises 1% to about 20% w/w of diluent, about 1% to about 10% w/w of disintegrant and about 0.01% to about 5% w/w of lubricant as extra granular excipients.

The lubricated granules are then compressed into tablets, filled in capsules or filled into sachets as powder for oral suspension.

The dosage form according to the present invention may be uncoated or optionally coated with film coating/moisture barrier coating composition.

The film coating composition comprises a solution / suspension of film coating polymers and one or more excipients such as lactose, titanium dioxide, solubilizing agent, plasticizer and antisticking agent.

Suitable film coating polymers used according to the present invention are selected from ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose and the like or mixture thereof.

The solubilizing agent of the present invention may be selected from anionic or non-ionic surfactants such as sodium lauryi sulphate, polyethyfene-propyfene glycol copolymer (poloxamer), polyoxyethylene stearates (Macrogol-stearate), polysorbates, propylene glycol, and the like or mixture thereof.

Suitable anti-sticking agents used according to the present invention are selected from talc, magnesium stearate and the like or a mixture thereof.

In a preferred embodiment, the present invention provides oral solid dosage form comprising entecavir and one or more pharmaceutically acceptable excipients, prepared by a process, comprising the steps of:

i) blending 0.1% to about 20% w/w of entecavir and one or more intragranular excipients
selected from 20% to about 99% w/w of diluent, about 0% to about 5% w/w of disintegrant optionally 1% to about 10% w/w of binder,

ii) granulating the blend of step (i) using solvent without binder, iii) drying the granules of step (ii) and iv) formulating the dried granules obtained in step (iii) into solid dosage form.

In another preferred embodiment, the present invention relates to an oral solid dosage form comprising entecavir and one or more pharmaceutically acceptable excipients, prepared by a process, comprising the steps of:

i) blending 0.1% to about 20% w/w of entecavir and one or more intragranular excipients selected from 20% to about 98% w/w of diluent, about 0% to about 5% w/w of disintegrant, optionally 1% to about 10% w/w of binder and one or more pharmaceutically acceptable excipients,

ii) granulating the blend of step (i) using solvent without binder,
iii) blending the granules of step (ii) with one or more extragranular excipients selected from 1% to about 20% w/w of diluent, about 1% to about 10% w/w of disintegrant and about 0.01% to about 5% w/w of lubricant, and iv) formulating the blend obtained in step (iii) into solid dosage form.

In another preferred embodiment, the present invention provides an oral solid dosage form comprising entecavir and one or more pharmaceutically acceptable excipients, prepared by a process, comprising the steps of:

i) blending 0.1 % to about 20% w/w of entecavir and one or more intragranular excipients selected from 20% to about 98% w/w of diluent selected from lactose, microcrystalline cellulose, dibasic calcium phosphate, mannitol and starch, about 0% to about 5% w/w of disintegrant selected from starch, croscarmellose sodium, crospovidone and pregelatinized starch, optionally 1% to about 10% w/w of binder,

ii) granulating the blend of step (i) using solvent selected from water, methanol and isopropyl alcohol without binder,

iii) blending the granules of step (ii) with one or more extragranular excipients selected from 1% to about 20% w/w of diluent selected from lactose, microcrystalline cellulose, dibasic calcium phosphate, mannitol and starch, about 1% to about 10% w/w of disintegrant selected from starch, croscarmellose sodium, hydroxypropyl cellulose, crospovidone and pregelatinized starch and about 0.01% to about 5% w/w of lubricant selected from magnesium stearate, sodium stearyl fumarate and talc, and iv) formulating the blend of step (iii) into a solid dosage form.

In another embodiment, the "%w/w" according to the present invention is based on total weight of the dosage form.

In another embodiment, the solid dosage form according to the present invention may be presented in any dosage form including,
but not limited to, capsule, tablet, granules, pellets, mini-tablets, beads or the like.

In yet another embodiment, the present invention also provides method of treating chronic hepatitis B virus infection by administering compositions of the present invention.

The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Example 1

The processing steps involved in manufacturing entecavir composition are given below:

i) entecavir, lactose and microcrystalline cellulose were sifted and blended,

ii) the blend of step (i) was granulated using purified water,

iii) the granules of step (ii) were dried and then blended with crospovidone,

iv) the granules of step (iii) were lubricated with magnesium stearate and

v) the lubricated granules were compressed to obtain tablets or filled into capsules.

Example 2
Example 3
Example 4
Example 5
Example 6
Example 7

The compositions described in example 2-7 were prepared using the procedure similar to the one described in example 1.

Figures 1 and 2 shows the comparative dissolution profile of entecavir dosage forms prepared according to the present invention (Examples 1 and 2) and Baraclude® tablets carried out in 1000ml of Phosphate buffer pH 6.8 using Apparatus USP II (Paddle), at 50 rpm speed. It was found that the dissolution profiles of entecavir dosage forms prepared according to Examples 1 and 2 were comparable with that of Baraclude® tablets.

Claims:

1. An oral solid dosage form comprising entecavir and one or more pharmaceutically acceptable excipients, prepared by a process, comprising the steps of:

i) blending entecavir and one or more pharmaceutically acceptable excipients,
ii) granulating the blend of step (i) using solvent without binder,
iii) blending the granules of step (ii) with one or more pharmaceutically acceptable excipients, and
iv) formulating the blend obtained in step (iii) into solid dosage form.

2. The dosage form according to claim 1, wherein one or more pharmaceutically acceptable excipients are selected from diluents, binders, disintegrants, glidants, lubricants, surfactants and combinations thereof.

3. The dosage form according to claim 2, wherein the diluent is selected from the group consisting of lactose, sucrose, dextrose, mannitol, sorbitol, xylitol, lactitol, starch, modified starches, dibasic calcium phosphate, tribasic calcium phosphate, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose and combination thereof.

4. The dosage form according to claim 2, wherein the disintegrant is selected from the group consisting of low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone; cross-linked sodium carboxymethylcellulose, cross-linked calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxy methylcellulose, microcrystalline cellulose; sodium starch glycolate; ion-exchange resins; starch and modified starches including pregelatinized starch; formalin-casein; alginates, gums and combination thereof.

5. The dosage form according to claim 2, wherein the binder is selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose and hydroxyethyl cellulose, carboxymethyl cellulose; starch and its derivatives, hydrocolloids; sugars; polyvinyl pyrrolidone, copovidone, methacrylic acid copolymers and combination thereof.

6. The dosage form according to claim 2, wherein the glidant is selected from the group consisting of talc, silicon dioxide, silicic acid, cornstarch, calcium silicate, magnesium carbonate, magnesium oxide, magnesium silicate, colloidal silicon dioxide, starch, castor wax and combination thereof.

7. The dosage form according to claim 2, wherein the lubricant is selected from the group consisting of calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, fumaric acid, sodium stearyl fumarate, stearic acid, talc, vegetable oil, zinc stearate, castor wax and combination thereof.

8. The dosage form according to claim 1, wherein the solid dosage form is selected from tablet and mini-tablets.

9. An oral solid dosage form comprising entecavir and one or more pharmaceutically acceptable excipients, prepared by a process, comprising the steps of:

i) blending 0.1% to about 20% w/w of entecavir and one or more intragranular excipients selected from 20% to about 98% w/w of diluent, about 0% to about 5% w/w of disintegrant, optionally 1% to about 10% w/w of binder and one or more pharmaceutically acceptable excipients,

ii) granulating the blend of step (i) using solvent without binder,

iii) blending the granules of step (ii) with one or more extragranular excipients selected from 1% to about 20% w/w of diluent, about 1% to about 10% w/w of disintegrant and about 0.01% to about 5% w/w of lubricant, and

iv) formulating the blend obtained in step (iii) into solid dosage form.

10. An oral solid dosage form comprising entecavir and one or more pharmaceutically acceptable excipients, prepared by a process, comprising the steps of:

i)blending 0.1% to about 20% w/w of entecavir and one or more intragranular excipients selected from 20% to about 98% w/w of diluents selected from lctose, microystalline cellulose, disbasic calcium phosphate, mannitol and starch, about 0% to about 5% w/w of disintegrant selected from starch, croscarmellose dosium, cropovidone and pregelatinized starch, optionally 1% w/w of binder,

ii) granulating the blend of step (i) using solvent selected from water, methanol and isopropyl alcohol without binder,

iii) blending the granules of step (ii) with one or more extragranular excipients selected from 1% to about 20% w/w of diluent selected from lactose, microcrystalline cellulose, dibasic calcium phosphate, mannitol and starch, about 1% to about 10% w/w of disintegrant selected from starch, croscarmellose sodium, hydroxypropyl cellulose, crospovidone and pregelatinized starch and about 0.01% to about 5% w/w of lubricant selected from magnesium stearate, sodium stearyl fumarate and talc, and

iv) formulating the blend of step (iii) into a solid dosage form.