Field of the Invention

The present invention relates to a stable, solid oral pharmaceutical composition comprising febuxostat, wherein the composition is manufactured by dry processes.

Further, it relates to processes for preparation of said composition.

Background of the Invention

Febuxostat, chemically known as 2-(3-cyano-4-isobutyloxyphenyl)-4-memyl-5- thiazolecarbox lic acid, is a useful therapeutic agent for the treatment of gout and hyperuricemia. Febuxostat was first disclosed in U.S. Patent No. 5,614,520, assigned to ^' l ey in Limited.

Febuxostat is a non-purine selective inhibitor of xanthine oxidase. It works by non-competitively blocking the channel leading to the active site on xanthine oxidase. Xanthine oxidase is needed to successively oxidize both hypoxanthine and xanthine to uric acid. Febuxostat inhibits xanthine oxidase, therefore reducing production of uric acid. For treatment of hyperuricemia in patients with gout, febuxostat is recommended at 40 mg or 80 mg once daily. No dose adjustment is necessary when administering febuxostat in patients with mild to moderate renal and hepatic impairment.

Febuxostat is commercially available as an immediate-release formulation in the form of tablets. According to the Biopharmaceutics Classification System (BCS), febuxostat is classified as a Class 2 compound, exhibiting low solubility and high permeability. It suffers from the disadvantage of being poorly soluble in aqueous media and, as a result, haying an undesirable dissolution profile and, consequently, poor bioavailability within the organism, following oral administration. The therapeutic dose required to be administered must thus be increased in order to compensate for this disadvantage.

U.S. Patent No. 6,225,474 assigned to Teijin Limited discloses six crystal polymorphs of febuxostat including an amorphous form and solvates (methanolate (D) and hydrate (G)), The polymorphs of febuxostat are designated as crystals A, B, C, D, E and G. These polymorphs may interconvert from one to the other. Further, U.S. Patent No. 6,225,474 discloses that if the crystal forms B and D are exposed to moisture, then they may lake water and convert into a hydrous form, i.e., crystal G.

The inventors of the present invention have prepared, using dry processes, stable, solid oral pharmaceutical compositions of febuxostat, which are substantially free from conversion to different polymorphic intercon version issues, are easy to manufacture and have an acceptable dissolution profile.

Further, it is well known that particle size can affect the solubility properties of a pharmaceutical compound. Particle size reduction can increase a compound's dissolution rate and consequently its bioavailability. Particle size can affect how freely the crystals or powdered form of the drug will flow past each other, which has consequences in the production process of pharmaceutical products containing the drug. The present invention utilizes febuxostat of fine particle size, which has good solubility and is well suited for preparing pharmaceutical products.

Summary of the Invention

In one aspect, the present invention relates to a stable, solid oral pharmaceutical composition comprising febuxostat, wherein the compositions are manufactured by dry processes.

Embodiments of the composition may include one or more of the following features. The composition of the present invention may contain about I mg to 500 mg of febuxostat. Preferably, the composition contains about 5 mg to about 200 mg of febuxostat. More preferably, the composition contains about 10 mg to 140 mg of febuxostat.

In one embodiment, febuxostat has an average particle size of from 1 um to 50 um. Particularly, the average particle size of febuxostat ranges from 2 μτη to 25 μτη.

In another embodiment, the composition comprises one or more pharmaceutically acceptable excipients selected from diluent, disintegrant, binder, lubricant, glidant, stabilizer, organoleptic ingredients such as coloring agents, flavoring agents, sweetener and others known to the skilled person in the art.

In still another embodiment, the composition of the present invention can optionally be film-coated. In another aspect, the present invention relates to a process of preparing a stable solid oral pharmaceutical composition of febuxostat by directly compressing the febuxostat.

In yet another aspect, the present invention relates to a process of preparing a stable, solid oral pharmaceutical composition of febuxostat by direct compression comprising the steps of:

(a) blending a mixture of febuxostat, diluents, at least one binder and/or disintegrant to obtain a homogeneous mixture;

(b) optionally adding at least one lubricant to the homogeneous mixture;

(c) dry compressing the homogeneous mixture into tablets.

In yet another aspect, the present invention relates to a process of preparing a stable, solid oral pharmaceutical composition of febuxostat by dry granulation compris the steps of:

(a) blending a mixture of febuxostat, diluents, at least one binder and/or disintegrant to obtain a homogeneous mixture;

(b) optionally adding at least one lubricant to the homogeneous mixture;

(c) dry compressing the homogeneous mixture into a slug or a compact;

(d) milling the slug or compact into granules;

(e) adding at least one lubricant to the milled granules;

(f) dry compressing the milled granules into a tablet.

In yet another aspect, there is provided a method of heating gout and hyperuricemia by administering to a person in need thereof a stable, solid oral pharmaceutical composition comprising febuxostat and pharmaceutically acceptable excipients manufactured by dry processes.

The pharmaceutical composition of febuxostat may be administered in combination with other therapeutic agents.

The details of one or more embodiments of the inventions are set forth in the description below. Other features and objects of the invention will be apparent from th description and examples. Detailed Description of the Invention

The present invention relates to a stable, solid oral pharmaceutical composition comprising febuxostat, wherein the composition is manufactured by dry processes.

The term "pharmaceutical composition", as used herein, refers to the tablet composition of predetennmed quantity of active substance in association with at least one pharmaceutically acceptable excipieni

The term "stable", as used herein, refers to a dosage form which is physically or polymorphically stable. The dosage form according to the present invention may remain physically stable, that is there are no substantial changes with respect to physical attributes like color, etc. The dosage form according to the prese t invention may remain polymorphically stable, that is the polymorph (crystalline or amorphous) in the dosage form does not convert into another form upon storage.

The term "drug" or "active ingredient" or "febuxostat", as used herein, encompasses anhydrous form, hydrous form, different crystalline forms, amorphous form, solvates or mixtures thereof or any other form of febuxostat. Febuxostat may be present in the present composition in an amount ranging from 1 mg to 500 mg. Preferably, the composition contains about 5 mg to about 200 mg of febuxostat. More preferably, the composition contains about 10 mg to 140 mg of febuxostat.

The drug is present in a microriized form having an average particle size of from I μιη to 50 μιη. The drag particles of the desired particle size ma be obtained by any of the conventional size reduction processes known in the art such as mechanical milling;

supercritical fluid processes; cryogenic spraying or by solvent evaporation process.

Mechanical reduction of particle size may be done by using a hammer mill, air jet mill, ball mill or any other milling equipment known in the art. The particle size distribution of febuxostat particles of the present invention may be determined using an optical microscopic method, sedimentation techniques, for example, pipette analysis using an Andreassen pipette, sedimentation scale, photosedimentometer or sedimentation in a centrifugal force field, pulse methods, for example, using a Coulter counter, or sorting by means of gravitational or centrifugal force, sieve analysis, laser diffraction or ultrasound attenuation spectroscopy. The particle size distribution of febuxostat particles of the present invention is particularly determined by laser diffraction using a Malvern® Mastersizer laser diffraction instrument.

The pharmaceutical compositions, as described herein, may comprise one or more pharmaceutically acceptable excipients selected from diluent, disintegrant, binder, lubricant, glidant, stabilizer, organoleptic ingredients such as coloring agent, flavoring agent, sweetener and others known to the skilled person in the art.

Examples of fillers or diluents include, but are not limited to, corn starch, anhydrous lactose, lactose monohydrate, white sugar, sugar compressible, sugar confectioners, sucrose, glucose, maltose, calcium carbonate, calcium dihydrogen phosphate dihydrates, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, rnanniiol, sorbitol, starch, or a mixture thereof. Particularly, the diluents comprise lactose, microcrystalline cellulose, calcium dihydrogen phosphate dihydrates, or a mixture thereof. The diluent is present in an amount of about 25% to about 85% by weight of the tablet.

Examples of binders include, but are not limited to, carbomer, sodium

carboxymetbylcellulose, microcrystalline celluloses (MCC), microfine celluloses, dextrin, lactose, glucose, guar gum, hypromellose, hydroxypropyl cellulose, pregelatinized starch, starch, povidone, or mixture thereof or other materials known to one of ordinary skill in the art. Particularly, the binder is hydroxypropyl cellulose. The binder is present in an amount of about 0% to about 10% by weight of the tablet.

Examples of disintegrants include, but are not limited to, starch, sodium starch glycolate, croscarmellose sodium, crospovidone, alginic acid, low-substituted hydroxy propyl cellulose, carboxymethyl cellulose sodium, microcrystalline cellulose, calcium carbonate, sodium carbonate, alginic acids, agar, guar gum, or mixture thereof. The disintegrant is present in an amount of about 0% to about 20% by weight of the tablet. According to instant invention, the disintegrant may be added in drug granules stage and/or extragranular stage.

Some excipient materials can function as both a diluent and a binder, or a filler and a disintegrant, and some materials may exist that can fulfill all three roles. There is no intention to limit the invention to methods only using three distinct excipient materials, "diluents", "tablet binder", and "tablet disintegrants", but rather the invention is directed to materials fulfilling these functions. For example, the material that is "at least one diluents" also might be the same as the material fulfilling the role of "at least one tablet binder" as long as the material is present in sufficient amount to fulfill both functions.

Examples of lubricants that can be used in the present invention include, but are not limited to, stearic acid, polyethylene glycol, magnesium stearate, calcium stearate, talc, zinc stearate, hydrogenated castor oil, silica, colloidal silica, cornstarch, calcium silicate, magnesium silicate, silicon hydrogel, or mixture thereof. The lubricant is present in an amount of about 0.1 % to about 5% by weight of the tablet.

Examples of glidants that can be used in the present invention include, but are not limited to, colloidal silicon dioxide, colloidal silica, cornstarch, talc, calcium silicate, magnesium silicate, colloidal silicon, silicon hydrogel, or mixture thereof. The glidant is present in an amount of about 0.0% to about 5% by weight of the tablet.

The coloring agents and flavoring agents of the present invention may be selected from any FDA approved colors and flavors for oral use.

The sweetener may be selected from aspartame, saccharin sodium, acesulfame potassium, dried invert sugar, dextrose, glucose, fructose, galactose, ievulose, maltose, neotame, sucralose, or mixture thereof. The preferred sweetener is aspartame.

The present invention teaches methods of making tablets by dry process. The compression step may be carried out using a tablet compression machine commonly used in tabletting.

A general process of preparing a stable, solid oral pharmaceutical composition of febuxostat by direct compression comprises directly compressing the febuxostat.

Another general process of preparing a stable, solid oral pharmaceutical composition of febuxostat by direct compression comprises the steps of:

(a) blending a mixture of febuxostat, diluents, at least one binder and/or

disintegrant to obtain a homogeneous mixture;

(b) optionally adding at least one lubricant to the homogeneous mixture;

(c) dry compressing the homogeneous mixture into tablets. Anoth er process of preparing a stable, solid ora l pharmaceutical composition of febuxostat by dry granulation comprises the steps of:

(a) blending a mixture of febuxostat, diluents, at least one binder and/or

disintegrant to obtain a homogeneous mixture;

(b) optionally adding at least one lubricant to the homogeneous mixture;

(c) dry compressing the homogeneous mixture into a slug or a compact;

(d) milling the slug or compact into granules;

(e) adding at least one lubricant to the milled granules;

(f) dry compressing the milled granules into a tablet.

The blending step is carried out to substantially homogeneous mixture. Factors that may influence the blending step include, but are not limited to, the amount of materials, the physical characteristics of the materials, the equipment, and the speed of mixing. A person skilled in the art can easily determine the equipment and conditions necessary for the blending steps.

The dry compressing step includes compressing the homogeneous mixture into a formulation. The formulation may be shaped as tablets, ribbons or blocks of solid material or slugs. When the formulation is shaped as ribbons or blocks of solid material or slugs, the ribbons or blocks of solid material or slugs are milled. Thereafter, the milled material or granulate is blended with extragranular excipients and compressed into tablets. The compressing step may be carried out using a tablet compression machine commonly used in tableting or other suitable equipment to make slugs, ribbons, or blocks of solid material, for example, a roller compactor.

The tablets obtained may further be film-coated. Additional excipients such as film-forming polymers, solvents, piasticizcrs, antiadherents, opacifiers and optionally colorants, pigments, antifoam agents, polishing agents can be used in coatings.

Examples of film-forming agents include, but are not limited to, cellulose derivatives such as soluble alkyl- or hydroalkyl-eellulose derivatives such as

methylcelluloses, hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxymethylethyl celluloses, hydroxypropyl methylcelluloses, sodium carboxymethyl celluloses, etc., insoluble cellulose derivatives such as ethylcelluloses and the like, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacry lie- acids, polyvinyl alcohols, poly vinyl acetates, polyvinylpyrrolidones, polymethacrylates and derivatives thereof (Eudragit® products), chitosan and derivatives thereof, shellac and derivatives thereof, waxes and fat substances.

The coating can also be performed using any commercially available ready to coat preparations such as Opadry® AMB, Opadry® White, Opadry® Clear, Opadry® 11, etc. Opadry® formulations generally comprise polymer, plasticizer and, if desired, pigment in a dry concentrate. Opadry® products produce attractive, elegant coatings on a variety of tablet cores and can be used in both aqueous and organic coating procedures.

The pharmaceutical solvents used for coaling process include, but are not limited to, water, ethanol, isopropyl alcohol, acetone and methylene chloride.

Some of the excipients are used as adjuvants to the coating process, including excipients such as plasticizers, opacifiers, antiadhesives and polishing agents.

Examples of plasticizers include, but are not limited to, castor oil , diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycols, propylene glycols, triacetin, triethyl citrate, and mixtures thereof. An opacifier like titanium dioxide may also be present in an amount ranging from about 10% (w/w) to about 20% (w/w) based on the total weight of the coating.

Antiadhesives are frequently used in the film-coating process to avoid sticking effects during film formation and drying. An example of an antiadhesive for this purpose is talc.

Examples of polishing agents include, but are not limited to, polyethy lene glycols of various molecular weights, or mixtures thereof, talc, surfactants (e.g. glycerol monostearate and poloxamers), fatty alcohols (e.g. stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol) and waxes (e.g. carnauba wax, candelilla wax and white wax).

The composition of the invention may be used in treating conditions such as gout and hyperuricemia. The pharmaceutical composition of febuxostat may be administered in combination with other therapeutic agents. The present invention is illustrated below by reference to the following example. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention.

EXAMPLES

# Average particle size <50.00 micron

Procedure:

1. Febuxostat, lactose and microcrystaliine cellulose were sifted through suitable mesh. 2. Hydroxy propyl cellulose, sodium croscarmellose and colloidal silicon dioxide were sifted through suitable mesh.

3. Blends from step 1 and step 2 were mixed in a suitable blender for suitable time.

4. The blend from step 3 was lubricated with magnesium stearate.

5. The blend of step 4 was compressed into tablets with a suitable tooling and the tablets were coated with a suspension of Opadry© Π. ingredients Percent w/w

Febuxostat ^,r 15.38

Lactose 35.66

Microcrystaliine Cellulose 35.57

Hydroxy Propyl Cellulose 3.08

Sodium Croscarmellose 5.00

Colloidal Silicon Dioxide 0.96

Magnesium Stearate 1.44

Core Tablet Weight 97.09

Opadry© 11 2.91

Purified Water q.s.

# Average particle size <50.00 micron

Procedure;

1. Febuxostat, lactose and microcrystaliine cellulose were sifted through suitable mesh.

2. Hydroxy propyl cellulose, sodium croscarmellose and colloidal silicon dioxide were sifted through suitable mesh.

3. Blends from step 1 and step 2 were mixed in a suitable blender for suitable time and compacted using a suitable compactor.

4. The compacts from step 4 were milled using suitable screen.

5. The milled material from step 4 was lubricated with magnesium stearate.

6. The blend of step 5 was compressed into tablets with a suitable tooling and the tablets were coated with a suspension of Opadry® Π,

While several specific embodiments of the invention have been illustrated and described, it will be apparent to a person skilled in the art that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention.