Field of the invention

The present invention relates to a pharmaceutical composition of febuxostat or a pharmaceutically acceptable salt thereof and a method for producing the same.

Background of the Invention

Febuxostat chemically known as 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid is a new drug molecule having a strong activity for inhibiting xanthine oxidase or a uric acid decreasing action, and it is indicated for use in the treatment of hyperuricemia and chronic gout. The immediate release tablet formulation of febuxostat is approved in various countries with different trade names such as Adenuric (Europe), Febutaz (India) and Uloric (US). The febuxostat molecule is first described in US patent No. 5,614,520 and various crystal polymorphs are disclosed in US patent No. 6,225,474.

Febuxostat is a water insoluble drug and its bioavailability is 49% only. As both solubility and absorption is critical for therapeutic effect of febuxostat, preparation of a pharmaceutical composition having both optimum dissolution and absorption in the gastrointestinal track for better bioavailability is the most challenging work.

US patent 7,361,676 discloses a solid preparation containing a single crystal form of febuxostat. The patent also discloses that, it is not possible to obtain preparations having no variation in the dissolution profiles of febuxostat and solved the problem using a single crystal form of febuxostat.

Chinese patent application No. 101862326 discloses use of surfactant to improve the dissolution of febuxostat in a pharmaceutical composition. Only improving the solubility of febuxostat by using surfactant does not serve the purpose for solving the variation in dissolution profile as variation of dissolution can be due to other factors like disintegration of the composition.

As febuxostat is water insoluble, bioavailability can be increased by increasing the dissolution of the pharmaceutical composition; but dissolution of the active pharmaceutical agent can take place, only after the composition is disintegrated. So if a composition has rapid disintegration then rapid dissolution is possible. If disintegration is slow then rapid dissolution is not possible. Therefore, if one wants an optimum dissolution of a pharmaceutical agent, then one should have at least a disintegrating agent, which aid in disintegration of the composition. But use of too much disintegrant results in poor quality of final composition. Hence there need to be a balance between different excipients for a good quality pharmaceutical composition of febuxostat which will lead to better bioavailability. There is also a need to develop a pharmaceutical composition which will provide both optimum dissolution and absorption in the gastrointestinal track for better bioavailability.

Summary of invention

It is an object of the invention to provide a pharmaceutical composition comprising febuxostat or a pharmaceutically acceptable salt thereof, a super-disintegrant, a binder and a surfactant.

It is another object of the invention is to provide a pharmaceutical composition comprising febuxostat and a super-disintegrant selected from the group selected from croscarmellose sodium, crospovidone, sodium starch glycolate, and other modified starches. The composition may further comprise a binder and a surfactant.

It is another object of the invention is to provide a pharmaceutical composition comprising febuxostat and a surfactant. The composition may further comprise a binder and a super-disintegrant.

It is another object of the invention is to provide a pharmaceutical composition comprising febuxostat and a non-ionic surfactant. The composition may further comprise a binder and a super-disintegrant.

It is another object of the invention is to provide a pharmaceutical composition comprising febuxostat and a non-ionic surfactant selected from the group consisting of alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols with fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides; polyethoxylated fat-soluble vitamins or derivatives; and mixtures thereof. The composition may further comprise a binder and a super-disintegrant.

It is another object of the invention is to provide a pharmaceutical composition comprising febuxostat or a pharmaceutically acceptable salt thereof is present in an amount from about 0.05% to about 50%, the binder in an amount from about 1% to about 25%, the super-disintegrant in an amount from about 0.01% to about 20% and the surfactant in an amount of 0.01% to about 20%, all percentages being based on the total weight of the composition.

It is another object of the invention is to provide a pharmaceutical composition comprising 1 to 50% of febuxostat, 1 to 20% of hydroxyl propyl cellulose, 1 to 20% of Polysorbate 80,1 to 20% croscarmellose sodium, 1 to 10 % of magnesium stearate and 0 to 5 % of colloidal anhydrous silica.

It is another object of the invention is to provide a pharmaceutical composition comprising febuxostat or a pharmaceutically acceptable salt thereof, a super-disintegrant, a binder and a surfactant, wherein the weight ratio of febuxostat to super-disintegrant is from 50: 1 to 0.5: 1, the weight ratio of febuxostat to binder is from 60: 1 to 1: 1, the weight ratio of febuxostat to surfactant is from 60: 1 to 1: 1, the weight ratio of super-disintegrant to binder is from 30: 1 to 0.1: 1, the weight ratio of super-disintegrant to
surfactant is from 10: 1 to 0.2: 1 and the weight ratio of binder to surfactant is from 5: 1 to 0.2:1.

It is another object of the invention is to provide a pharmaceutical composition comprising febuxostat or a pharmaceutically acceptable salt thereof which is bioequivalent to the commercial form of febuxostat.

Detailed Description of the Invention

This invention relates to a pharmaceutical composition of febuxostat and the method of preparing the same. Febuxostat is water insoluble and the bioavailability is also low and hence this invention is to prepare a pharmaceutical composition which increases the solubility and bioavailability of febuxostat. The composition of the invention can be administered to the patients who are in need of the drug for the treatment of gout or hyperuricemia.

In one embodiment, a pharmaceutical composition comprises febuxostat or a pharmaceutically acceptable salt thereof, a super-disintegrant, a binder and a surfactant.

The composition may further comprise other additives for the preparation of the composition.

The term "febuxostat" includes various forms of febuxostat such as hydrates, solvates, polymorphs, isomers, stereoisomers, enantiomers, racemates, esters, prodrugs, complexes or mixture thereof and all other forms known in the art. Febuxostat can be present in different physical forms, e.g. in an amorphous form, in one or several crystal form (s) (e.g. anhydrous, solvated or hydrated forms), in the form of mixture of different crystal forms (e.g. anhydrous, solvated or hydrated forms) or as a mixture of an amorphous form and crystal form (s) (e.g. anhydrous, solvated or hydrated forms). Each of these forms is included in the term "febuxostat" as used in the present invention.

The term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian
safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.

The active ingredient, active agent and drug herein can be interchangeably used.

As used herein,"%" refers to the weight percent of a substance as it relates to the overall composition unless otherwise indicated.

The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

In another embodiment, a pharmaceutical composition comprises febuxostat and a super-disintegrant. The composition may further comprise a binder and a surfactant. A disintegrating agent is a substance, or mixture of substances added to the mixture of ingredients which are used to prepare pharmaceutical composition, to facilitate the composition to breakup or disintegration after administration, or disintegration into the primary particles, when placed in water to form a solution which can be drank by the patient. The pharmaceutically active ingredient must be released from the composition matrix as efficiently as possible to allow for its dissolution. There are some disintegrating agents which provide for a more rapid disintegration than others disintegrating agents called super-disintegrants. "Super-disintegrants" are defined to be those disintegrants which can be used in small amount as compared to normal disintegrants, such as corn starch, to obtain the same effect. The non limiting examples of super-disintegrants are crospovidone, modified starches especially sodium starch glycolate and carmellose especially croscarmellose sodium, carboxymethylcellulose calcium. The super-disintegrant can be used in both the wet and dry stages of the granulation process (intra-and extra granularly) as well as in direct compression, so that the wicking and swelling ability of the disintegrant is best utilized.

The super-disintegrant is present in the composition in an amount of from about 1% to about 20 %, preferably from about 1% to about 15%, more preferably from about 1% to about 10%. It is advantageous to use the super-disintegrant in an amount where the weight ratio between febuxostat and super-disintegrant is from 50: 1 to 0.5: 1, preferably around 20: 1 to 0.5: 1. In another embodiment it is from 20: 1 to 0.5: 1, preferably around 10:1 to 0.5:1.

The suitable super-disintegrants for compositions of this invention are carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), croscarmellose sodium available as e.g. Ac-Di-Sol®, Primellose®, Pharmacelt® XL, Explocel®, and Nymcel® ZSX, having a molecular weight of 90 000-700 000; crosslinked polyvinylpyrrolidones (PVP), e. g. crospovidones, e. g. Polyplasdone® XL and Kollidon® CL, in particular having a molecular weight in excess of 1000000, more particularly having a particle size distribution of less than 400 microns or less than 74 microns; modified starches especially sodium starch glycolate e.g. Explosol®, Explotab®, Glycolys®, Primojel®, Tablo®, Vivastar® P, in particular having molecular weight is 500000-11000000. The most preferred disintegrant is Croscarmellose sodium.

In another embodiment, a pharmaceutical composition comprises febuxostat and a surfactant. The composition may further comprise a binder and a super-disintegrant.

Surfactant otherwise called surface-active agents or solubilizing agents, help to solubilize the active agent either in composition or in-situ at the site of absorption or action.

Surface-active agents include but are not limited to surfactants, cyclodextrin and its derivatives, lipophilic substances or any combination thereof. Non-limiting examples of surfactants include non-ionic, anionic, cationic, amphoteric or zwitterionic or any combination thereof. Non-ionic surfactant is preferable.

Examples of suitable non-ionic surfactants include ethoxylated triglycerides; fatty alcohol ethoxylates; alkylphenol ethoxylates; fatty acid ethoxylates; fatty amide ethoxylates; fatty amine ethoxylates; sorbitan alkanoates; ethylated sorbitan alkanoates; alkyl ethoxylates; alkyl polyglucosides; stearol ethoxylates; and alkyl polyglycosides.

Preferred non-ionic hydrophilic surfactants include alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols with fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides; polyethoxylated fat-soluble vitamins or derivatives; and mixtures thereof.

More preferably, the non-ionic hydrophilic surfactant is selected from the group consisting of polyoxyethylene alkylethers; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglyceryl fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils. The glyceride can be a monoglyceride, diglyceride, triglyceride, or a mixture.

Also preferred are non-ionic hydrophilic surfactants that are reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils or sterols. These reaction mixtures are largely composed of the transesterification products of the reaction, along with often complex mixtures of other reaction products. The polyol is preferably glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

Examples of suitable anionic surfactants include alkylether sulfates; alkylether
carboxylates; alkylbenzene sulfonates; alkylether phosphates; dialkyl sulfosuccinates;
sarcosinates; alkyl sulfonates; soaps; alkyl sulfates; alkyl carboxylates; alkyl phosphates;
paraffin sulfonates; secondary n-alkane sulfonates; alpha-olefin sulfonates; and
isethionate sulfonates.

Examples of suitable cationic surfactants include fatty amine salts; fatty diamine salts; quaternary ammonium compounds; phosphonium surfactants; sulfonium surfactants; and sulfonxonium surfactants.

Examples of suitable zwitterionic surfactants include N-alkyl derivatives of amino acids (such as glycine, betaine, aminopropionic acid); imidazoline surfactants; amine oxides; and amidobetaines.

Mixtures of surface-active agents may be used. In such mixtures there may be individual components which are liquid, provided that the carrier material overall, is a solid. The concentration of surface-active agent in the composition is from range of about 0.01 to about 20.0% (based on the total mass of the pharmaceutical composition), preferably about 0.1 to about 10%, more preferably of about 0.1 to about 5%. The weight ratio of febuxostat to surfactant is from 60: 1 to 1: 1 (preferably 40: 1 to 1: 1), the weight ratio of super-disintegrant to surfactant is from 10: 1 to 0.2: 1 (preferably 5: 1 to 0.5: 1) and the weight ratio of binder to surfactant is from 5: 1 to 0.2: 1 (preferably 5: 1 to 0.5: 1).

Non limiting examples of surfactants are sodium salts of fatty alcohol sulphates such as sodium lauryl sulphate; or sulphosuccinates such as sodium dioctyl sulphosuccinate; or partial fatty acid esters of polyhydric alcohols such as glycerol monostearate, glyceryl monooleate, glyceryl monobutyrate; or block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropyleneglycol, such as Poloxamer 124, Poloxamer 188, Poloxamer 237, Poloxamer 388, Poloxamer 407 (BASF Wyandotte Corp.); or fatty acid esters of sorbitan such as sorbitan mono laurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan stearate, sorbitan monolaurate etc. such as Span® or Arlacel®, Emsorb®, Capmul®, or Sorbester®, Triton X-200 etc.; or a fatty acid esters of polyhydroxyethylene sorbitan such as polyoxyethylene (20) sorbitan, e.g. polyoxyethylene (20) sorbitan monooleate (Tween® 80), polyoxyethylene (20) sorbitan monostearate (Tween®60), polyoxyethylene (20) sorbitan monopalmitate (Tween®40), polyoxyethylene (20) sorbitan monolaurate (Tween® 20); or polyethylene glycol fatty
acid esters, e.g. PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate; alkylene glycol fatty acid mono esters, e.g. propylene glycol monolaurate (Lauroglycol®); or hydrogenated castor oil and polyoxyethylene castor oil derivates, e.g. polyoxyethyleneglycerol triricinoleate or polyoxyl 35 castor oil (Cremophor® EL; BASF Corp.); or polyoxyethyleneglycerol oxystearate such as polyethylenglycol 40 hydrogenated castor oil (Cremophor RH® 40) or polyethylenglycol 60 hydrogenated castor oil (Cremophor RH® 60); or sucrose fatty acid esters, such as sucrose stearate, sucrose oleate, sucrose palmitate, sucrose laurate, and sucrose acetate butyrate; or vitamin E and its derivatives such as Vitamin E-TPGS® (d-alpha-tocopheryl polyethylene glycol 1000 succinate); or phospholipids, glycerophospholipids (lecithins, kephalins, phosphatidyl serine), glyceroglycolipids (galactopyransoide), sphingophospholipids (sphingomyelin), and sphingoglycolipids (ceramides, gangliosides), DSS (docusate sodium), docusate calcium, docusate potassium, SDS (sodium dodecyl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidic acid, sodium caprylate; or bile acids and salts thereof; or ethoxylated triglycerides; or quaternary ammonium salts such as cetyl-trimethylammonium bromide, cetylpyridinium chloride; or glycerol acetates such as acetin, diacetin and triacetin; or triethanolamine, lecithin, monohydric alcohol esters such as trialkyl citrates, lactones and lower alcohol fatty acid esters, nitrogen-containing solvents, glycerol fatty acid esters such as mono-, di- and triglycerides and a cetylated mono- and di-glycerides; propylene glycol esters, ethylene glycol esters, glycerol, cholic acid or derivatives thereof, lecithins, alcohols and glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-Hexadecyl-N, N-dimethyl-3-ammonio-1-propanesulfonate, anionic (alkyl-arylsulphonates) monovalent surfactants, palmitoyl lysophosphatidyl-L-serine, lysophospholipids (e.g. l-acyl-sn-glycero-3-phosphate esters of ethanolamine, choline, serine or threonine), alkyl, alkoxyl (alkyl ester), alkoxy (alkyl ether)- derivatives of lysophosphatidyl and phosphatidylcholines, e.g. lauroyl and myristoyl derivatives of lysophosphatidylcholine, dipalmitoylphosphatidylcholine, and modifications of the polar head group, that is cholines, ethanolamines, phosphatidic acid, serines, threonines, glycerol, inositol, and the postively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and
lysophosphatidylthreonine, zwitterionic surfactants (e.g. N-alkyl-N, N-dimethylammonio-1 -propanesulfonates, 3-cholamido-l-propyldimethylammonio-l -propanesulfonate, dodecylphosphocholine, myristoyl lysophosphatidylcholine, hen egg lysolecithin), cationic surfactants (quarternary ammonium bases), fusidic acid derivatives-(e.g. sodium tauro-dihydrofusidate etc.), long-chain falty acids and salts thereof C6-Q2 (eg. oleic acid and caprylic acid), acylcarnitines and derivatives, N-a-acylated derivatives of lysine, arginine or histidine, or side-chain acylated derivatives of lysine or arginine, N-a-acylated derivatives of dipeptides comprising any combination of lysine, arginine or histidine and a neutral or acidic amino acid, N-a-acylated derivative of a tripeptide comprising any combination of a neutral amino acid and two charged amino acids, or the surfactant may be selected from the group of imidazoline derivatives, or mixtures thereof. Each one of these specific surface-active agent constitutes an alternative embodiment of the invention.

In another embodiment, a pharmaceutical composition comprising febuxostat and a non-ionic surfactant selected from the group consisting of alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols with fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides; polyethoxylated fat-soluble vitamins or derivatives; and mixtures thereof. The composition further comprises a binder and a super-disintegrant.

In another embodiment, a pharmaceutical composition comprises febuxostat and a binder.

The composition may further comprise a super-disintegrant and a surfactant. The composition according to the invention can comprise binders, such as polyvinyl pyrollidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, polymers

of acrylic acid and its salts, starch, celluloses and celluloses derivatives like methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, ethylhydroxyethylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose etc., maltrin, sucrose solution, dextrose solution, acacia, tragacanth, locust bean gum, gelatine, guar gum, starch, pregelatinised starch, partially hydrolysed starch, alginates, xanthan or polymethacrylate, or mixtures thereof. It is preferable to use a binder with good water solubility. In a preferred embodiment of the invention the excipients include at least one binder selected from hydroxypropyl cellulose and povidone.

The binding agent is present in the composition in an amount of from about 1% to about 25%, preferably from about 1%, to about 15%, more preferably from about 1% to about 10%. The weight ratio of febuxostat to binder is from 60: 1 to 1: 1 (preferably 40: 1 to 1: 1), the weight ratio of super-disintegrant to binder is from 30: 1 to 0.1: 1 (preferably 5: 1 to 0.5: 1) and the weight ratio of binder to surfactant is from 5: 1 to 0.2: 1 (preferably 5: 1 to 0.5: 1).

In one embodiment, a pharmaceutical composition comprising febuxostat or a pharmaceutically acceptable salt thereof is present in an amount from about 0.05% to about 50%, the binder in an amount from about 1% to about 25%, the super-disintegrant in an amount from about 0.01% to about 20% and the surfactant in an amount of 0.01% to about 20%, all percentages being based on the total weight of the composition.

In another embodiment, a pharmaceutical composition comprising 1-50% of febuxostat, 0.5-20% of a super-disintegrant, 1-20% of a binder and 0.1-20% of a surfactant, preferably 1-40% of febuxostat, 1-15% of a super-disintegrant, 1-15% of a binder and 1-15% of a surfactant and most preferably 5-30% of febuxostat, 1-10% of a super-disintegrant, 1-10% of a binder and 1-10% of a surfactant. The composition further may comprise 10-70% of a diluent, 1-10% of a lubricant and additives other than the ones mentioned above.

In another embodiment, a pharmaceutical composition comprising the above- indicated components wherein the weight ratio of febuxostat to super-disintegrant is from 50: 1 to 0.5: 1 (preferably 20: 1 to 0.5: 1), the weight ratio of febuxostat to binder is from 60: 1 to 1: 1 (preferably 40: 1 to 1: 1), the weight ratio of febuxostat to surfactant is from 60: 1 to 1: 1 (preferably 40: 1 to 1: 1), the weight ratio of super-disintegrant to binder is from 30: 1 to 0.1: 1 (preferably 5: 1 to 0.5: 1), the weight ratio of super-disintegrant to surfactant is from 10: 1 to 0.2: 1 (preferably 5: 1 to 0.5: 1) and the weight ratio of binder to surfactant is from 5: 1 to 0.2: 1 (preferably 5: 1 to 0.5: 1).

In another embodiment, a pharmaceutical composition, e. g. in form of a tablet, of febuxostat or a pharmaceutical acceptable salt thereof and a super-disintegrant in a weight ratio of e. g. between 50: 1 to 0.5: 1, e. g. 50: 1 to 0.5:1, 40: 1 to 0.5:1, 30: 1 to 0.5:1, 20: 1 to 0.5:1, 15: 1 to 0.5:1,10: 1 to 0.5:1, 8:1 to 0.5: 1, 7.5:1 to 0.5: 1, 5:1 to 0.5: 1, 3:1 to 0.5:1,2.5:1 to 0.5:1,2:1 to 0.5:1,1.5:1 to 0.5:1.

In another embodiment, a pharmaceutical composition comprising febuxostat as the active agent and diluent wherein the weight ratio of febuxostat to diluent is from 5: 1 to 0.1:1, e. g., 3:1 to 0.1:1,2: 1 to 0.1: 1,1:1 to 0.2:1.

A typical composition may comprise: 1 to 50% of febuxostat, 1 to 20% of hydroxyl propyl cellulose, 1 to 20% of Polysorbate 80,1 to 20% croscarmellose sodium, 1 to 10 % of magnesium stearate and 0 to 5 % of colloidal anhydrous silica.

In one embodiment, the pharmaceutical composition of febuxostat comprises febuxostat and pharmaceutical excipients particularly a super-disintegrant, a surfactant and a binder.
In one preferred embodiment, the pharmaceutical composition of febuxostat comprises febuxostat and pharmaceutical excipients particularly a super-disintegrants, a non-ionic surfactant and a binder. Other and further excipients can also be contained.

Other excipients such as diluents, lubricants and glidants commonly used in pharmaceutical composition may be used and reference is made to the extensive literature on suitable substances [see in particular "Handbook of Pharmaceutical Excipients" edited by Raymond C Rowe, Paul J Sheskey & Sian C Owen (2006)] the content of which is incorporated herein by reference.

Other excipients are also used in the preparation of the pharmaceutical composition like diluents such as microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugar, fructose, dextranes, other sugars such as mannitol, sorbitol, lactitol, saccharose or a mixture thereof, siliconised microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate or mixtures thereof. A preferred further diluent that also causes reduced sticking properties of tablets to the equipment used for tabletting is silica, preferably colloidal or fumed silica. Preferably, the excipients include at least one diluent selected from microcrystalline cellulose and lactose monohydrate.

The composition according to the invention can also comprise lubricants, such as stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogols, or mixtures thereof. It is preferred that the excipients include at least one lubricant, selected from stearic acid, magnesium stearate, calcium stearate and sodium lauryl sulphate, more preferably from stearic acid, magnesium stearate and calcium stearate. The composition can also comprises glidants such as colloidal silica (e. g. Aerosil®), magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

One or more of these additives may be selected and used by the skilled artisan having regard to the particular desired properties of the pharmaceutical composition by routine experimentation and without any undue burden. The absolute amounts of each additive and the amounts relative to other additives is similarly dependent on the desired properties of the pharmaceutical composition and may also be chosen by the skilled artisan by routine experimentation without undue burden.

Optionally, cores/tablets can be coated with conventional materials used for film coating, i. e. as described in "Pharmaceutical Coating Technology", 1995, edited by Graham Cole. Film coating formulations usually contain the following components: polymer (s), plasticizer (s), colourant (s) /opacifier (s), vehicle (s). In film coating suspension the minor quantities of flavours, surfactants and waxes can be used. The majority of the polymers used in film coating are either cellulose derivatives, such as the cellulose ethers, or acrylic polymers and copolymers. Occasionally encountered are high molecular weight polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol and waxy materials.

Typical cellulose ethers are hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose. Acrylic polymers comprise a group of synthetic polymers with diverse functionalities. Some of them can be further modified to enhance swelling and permeability by the incorporation of materials such as water soluble cellulose ethers and starches in order to ensure complete disintegration/dissolution of the film.

The commonly used plasticizers can be categorized into three groups: polyols (glycerol, propylene glycol and macrogols), organic esters (phthalate esters, dibutyl sebacetate, citrate esters, triacetin), oils/glycerides (castor oil, acetylated monoglycerides, fractionated coconut oil).

Colourants/opacifiers are classified into several groups: organic dyes and their lakes, inorganic colours, natural colours. Combination of different materials form each group can be combined in defined ratios. Film coating suspensions can be used as ready-to-make preparations which are available on the market.

Film coating dispersion can be prepared by using different solvents (water, alcohols, ketones, esters, chlorinated hydrocarbons), preferably water.

A composition of coating suspension (calculated on dry material) is particularly preferred which comprises: 1-99% by weight of polymer, preferably 1- 95% of polymer; 1-50% by
weight of plasticizer, preferably 1-40% of plasticizer; 0.1-20% of colourant/opacifier, preferably 0.1- 10% of colourant/opacifier, all the percentage are based on the total weight of coating material.

Although febuxostat is water insoluble, but particle size of API does not have any impact on the dissolution and bioavailability of the composition of the invention. Hence, there are no particular restrictions to the average particle size of the drug substance contained in the pharmaceutical composition of the invention. But use of drug particles having uniform diameter is advantageous for handling and preparing the composition. In another embodiment, the present invention relates to a pharmaceutical composition containing febuxostat particles characterized in that the D50 of said febuxostat particles is less than 250 urn, preferably less than 200 um and more preferably 175 urn.

In one embodiment, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, soft and hard gelatine capsules, suppositories etc. The dosage form is preferably suitable for oral application. The compositions are preferably formulated in a unit dosage form, each dosage containing about 1 to about 200 mg, more usually about 20 to about 160 mg of febuxostat, most preferably about 40 to about 80mg of febuxostat. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of febuxostat calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The pharmaceutical composition of the present invention is preferably a tablet which may or may not be coated.

A pharmaceutical composition according to the present invention may be in the form of dragees in which case the composition is provided with a coating typically a sugar, shellac or other film coating entirely conventional in the art. Attention is drawn to the numerous known methods of coating employed in the art, e. g. spray coating in a fluidized bed, e. g. by the known methods using apparatus available from Aeromatic,
submerged sword coating method. The additives commonly used in confectioning are employed in such methods are well known in the art.

The present pharmaceutical compositions are prepared by known technological procedures, e.g. direct compression, dry granulation or wet aqueous granulation, using well known and readily available excipients. In the preparation of the compositions of febuxostat, the active ingredient will usually be mixed with an excipient or mixture of excipients, or diluted by an excipient or mixture of excipients, or enclosed within an excipient or mixture of excipients which may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle or medium for the febuxostat.

The composition preparations of the invention can be produced by compressing a mixture of the drug substance of the invention with excipients. For example, one method for the production includes mixing the febuxostat with the materials for the preparation by a suitable mixer, and directly compressing the mixture to tablets. Other methods include a dry granulating step to produce granules for tablets using dry granulating machines or roller compacters, and a wet granulating step to produce granules for tablets using water, ethanol and solutions containing binders.

In another embodiment, at least 75 % of drug are dissolved from the pharmaceutical composition in a phosphate buffer of pH=6.2 in 30 minutes, when dissolution is performed using a paddle apparatus according to Ph. Eur. or an apparatus 2 according to USP, at a temperature of the dissolution medium of 37±0.5DC, speed of rotation of the paddle 75 rpm and volume of the dissolution medium 900 ml. Preferably the drug release rate of the composition of the invention is more than 70% in 15 minutes, above 80%, e. g. 90%, over 30 minutes, and above 95% over 45 minutes.

The composition of the invention containing febuxostat is preferably administered 1 to 3 times a day in an amount of 0.8 to 200 mg/day. The exact dose of active agent and the particular formulation to be administered depend on a number of factors, e. g. the
condition to be treated, the desired duration of the treatment and the rate of release of the active agent. For example, the amount of the active agent required and the release rate thereof may be determined on the basis of known in vitro or in vivo techniques, determining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect.

In one embodiment, the pharmaceutical composition comprises from about 1 to about 200 mg of febuxostat. In one preferred embodiment, the pharmaceutical composition comprises 20,40, 80, or 160mg of febuxostat.

The pharmaceutical compositions of the present invention are useful in the known indications of the particular active agent incorporated therein including treatment of hyperuricemia and chronic gout or both. In one embodiment, a method for treating the gout or hyperuricemia by administering to patient in need thereof, the pharmaceutical composition of the invention containing febuxostat, and a method for producing the therapeutic agent for treating the gout or hyperuricemia.

In yet another embodiment, the pharmaceutical composition comprises, besides febuxostat, a further active ingredient. Preferably, this further active ingredient is another inhibitor of xanthine oxidase, uric acid reducing agent, gout therapeutic agent or hyperuricemia therapeutic agent. Most preferred is allopurinol. If used, the weight ratio of febuxostat and the further ingredient (preferably allopurinol) is between 10: 1 and 15: 1.

In one embodiment, a pharmaceutical composition comprising febuxostat or a pharmaceutically acceptable salt thereof of the invention has a comparable bioavailability to the commercial form of febuxostat. In one preferred embodiment, a pharmaceutical composition comprising febuxostat is bioequivalent to commercial form of febuxostat.

The commercial form of febuxostat may be Uloric, Adenuric, Febutaz or any other forms available in the market worldwide.

The following experimental details are set forth to aid in an understanding of the invention, and are not intended, and should not be construed, to limit in any way the invention set forth in the claims that follow thereafter. A person skilled in the art will readily recognize the various modifications and variations that may be performed without altering the scope of the present invention. Such modifications and variations are encompassed within the scope of the invention and the examples do not in any way limit the scope of the invention.

Examples
Method of Preparation: Febuxostat, lactose, a part of microcrystalline cellulose, a part of croscarmellose sodium were weighed, sieved and mix for sufficient time in granulator; granulated the drug mixture with a binder solution prepared by dissolving hydroxypropyl cellulose and polysorbate 80/ poloxamer 407 in suitable quantity of water; dried the
granules and sized; added remaining microcrystalline cellulose, remaining croscarmellose sodium and colloidal silicon dioxide to the granules; lubricated with magnesium stearate and compressed into suitable tablets. Finally, the tablets were coated with coating composition.

The compositions in which sodium lauryl sulphate is use as a surfactant, the formulation is prepared as above except sodium lauryl sulphate is added in place of polysorbate 80/ poloxamer 407 as dry mix with drug excipient blend instead of mixing it with the binder solution.

The disintegration tests are performed as per USP using distilled water as medium at 37± 2°C. The results are as follows:

The In vitro dissolution test was performed at rotation speed of the paddle 75 rpm with USP apparatus II (Paddle), using pH 6.2 phosphate buffer as a dissolution media. The dissolution medium used was 900 ml; maintained at 37 ± 0.5°C.

The dissolution profiles of various formulations and the CV values (coefficient of variation) are provided as follows:

We Claim:

1. A pharmaceutical composition comprising febuxostat or a pharmaceutical ly acceptable salt thereof, a super-disintegrant, a binder and a surfactant.

2. The pharmaceutical composition of claim 1, wherein the super-disintegrant is selected from the group selected from croscarmellose sodium, crospovidone, sodium starch glycolate, and other modified starches.

3. The pharmaceutical composition of claim 2, wherein the super-disintegrant is croscarmellose sodium.

4. The pharmaceutical composition of claim 2, wherein the super-disintegrant is crospovidone.

5. The pharmaceutical composition of claim 1, wherein the surfactant is a non-ionic surfactant.

6. The pharmaceutical composition of claim 5, wherein the non-ionic surfactant is selected from the group consisting of alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols with fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides; polyethoxylated fat-soluble vitamins or derivatives; and mixtures thereof.

7. The pharmaceutical composition of claim 1, wherein febuxostat or a pharmaceutically acceptable salt thereof is present in an amount from about 0.05% to about 50%, the binder in an amount from about 1% to about 25%, the super-disintegrant in an amount from about 0.01% to about 20%, and the surfactant in an amount of 0.01% to about 20%, all percentages being based on the total weight of the composition.

8. A pharmaceutical composition comprising 1 to 50% of febuxostat, 1 to 20% of hydroxyl propyl cellulose, 1 to 20% of Polysorbate 80, 1 to 20% croscarmellose sodium, 1 to 10% of magnesium stearate and 0 to 5% of colloidal anhydrous silica.

9. A pharmaceutical composition comprising febuxostat or a pharmaceutically acceptable salt thereof, a super-disintegrant, a binder and a surfactant, wherein the weight ratio of febuxostat to super-disintegrant is from 50: 1 to 0.5: 1, the weight ratio of febuxostat to binder is from 60: 1 to 1: 1, the weight ratio of febuxostat to surfactant is from 60: 1 to 1: 1, the weight ratio of super-disintegrant to binder is from 30: 1 to 0.1: 1, the weight ratio of super-disintegrant to surfactant is from 10: 1 to 0.2: 1 and the weight ratio of binder to surfactant is from 5: 1 to 0.2: 1.

10. The pharmaceutical composition of claim 1, wherein the composition is bioequivalent to commercial form of febuxostat.