FEBUXOSTAT COMPOSITION
Field of the Invention
The present invention relates to an oral pharmaceutical composition of febuxostat which
comprises an intragranular component and an extragranular component. Further, it relates to
processes for preparation of the composition and the method of using the composition.
Background of the Invention
Gout affects number of individuals worldwide and continues to increase in incidence.
Gout includes a group of disorders including painful attacks of acute, monarticular, inflammatory
arthritis due to uric acid crystals, deposition of urate crystals in joints, deposition of urate crystals
in renal parenchyma, urolithiasis (formation of calculus in the urinary tract), and nephrolithiasis
(formation of kidney stones).
The underlying metabolic aberration in gout is hyperuricemia. Hyperuricemia has been
associated with a serum uric acid (sUA) level of 6.8 mg/dL or greater, which is the upper limit of
solubility of uric acid (also called urate) in extracellular fluids. However, hyperuricemia also has
been associated with other levels of serum uric acid depending on factors such as gender and
age, for example. Hyperuricemia leads to gout when urate crystals are formed from
supersaturated body fluids and deposited in joints, tophi, and parenchymal organs. In addition to
gout, other disorders related to elevated serum uric acid levels include gout- associated
inflammation, renal disorders, cardiovascular disease, aberrant metabolic conditions, fatty liver
disease, kidney stones, cognitive impairment and dementia
Known methods for treating gout include the use of uric acid synthesis inhibitors to
inhibit the accumulation of uric acid in the body. For example, xanthine oxidase inhibitors, such
as febuxostat and allopurinol. Febuxostat 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 under the brand name ULORIC @ by Takeda in
two strengths, 40mg and 80mg in the form of film coated tablets.
The chemical name of Febuxostat is 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-
thiazolecarboxylic acid). It has been disclosed in U.S. Patent No. 5,614,520.
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, having an undesirable
dissolution profile and, consequently, poor bioavailability following oral administration.
U.S. Patent No. 6,225,474 discloses various polymorphs of febuxostat including an
amorphous form. The polymorphs of febuxostat are designated as crystal A, B, C, D, E and G.
U.S. Patent No. 7,36 1,676 discloses solid oral dosage forms of febuxostat crystal form A.
PCT Publication No. WO 2007/048332A1 discloses febuxostat composition and its
application in preparation of medicines for treating gout.
Indian Application No. 2 1 16lMUM120 10 discloses compositions comprising febuxostat
and a solubility enhancing agent.
Indian Application No. 3620/CHE/20 10 discloses amorphous dispersion comprising
febuxostat and a dispersing agent.
The present inventors have developed an oral pharmaceutical composition of febuxostat
which is easy to manufacture and has an acceptable dissolution profile.
Summary of the Invention
In one aspect, the present invention relates to an oral pharmaceutical composition of
febuxostat comprising: (A) an intragranular component comprising: (i) an effective amount of
febuxostat, (ii) wetting agent(s), (iii) diluent(s), (iv) binder(s), (v) disintegrant(s) and (vi)
optionally glidant(s); and (B) an extragranular component comprising: (i) diluent(s), (ii)
disintegrant(s), (iii) lubricant(s) and (iv) optionally glidant(s).
Embodiments of the composition may include one or more of the following features. The
composition of the present invention may be in the form of a tablet or a capsule.
In one embodiment, febuxostat is present in an amount ranging from about 2% to about
50%, preferably from about 5% to about 30%, more preferably from about 10% to about 20% by
weight of the composition.
In another embodiment, the median particle size (Dso) of febuxostat ranges from about
0.1 pm to about 6 pm, preferably from about 1 pm to about 4 pm.
In another embodiment, the wetting agent is added to the granulating liquid and is present
in an amount of about 0.01% to about 5%, preferably about 0.1% to about 2% by weight of the
composition.
In another embodiment, a portion of the binder is blended with the drug and the
remaining portion is added to the granulating liquid. The ratio of the binder in the dry mix
portion to that in the granulating liquid portion ranges from about 1: 10 to about1 0: I, preferably
from about 1 :5 to about 5: 1.
In another embodiment, a portion of disintegrant is present in the intragranular
component and the remaining portion is added to the extragranular component. The ratio of the
disintegrant in the intragranular portion to that in the extragranular portion ranges from about 1 :
10 to about 10: 1, preferably from about 1 :5 to about 5: 1.
In another embodiment, the pharmaceutical composition of the present invention exhibits
a dissolution of at least 70% in 15 minutes and at least 90% in 30 minutes, when measured using
USP type I1 (paddle) apparatus at 50 rpm, in 900 mL of acetate buffer of pH 5.8 as the
dissolution medium.
In another embodiment, the present invention relates to an oral pharmaceutical
composition of febuxostat comprising: (A) an intragranular component comprising: (i) an
effective amount of febuxostat, (ii) sodium lauryl sulfate as a wetting agent, (iii) mixture of
lactose and microcrystalline cellulose as diluents, (iv) hydroxypropyl cellulose as a binder, (v)
crosscarmellose sodium as a disintegrant and (vi) colloidal silicon dioxide as a glidant; and
(B) an extragranular component comprising: (i) microcrystalline cellulose as a diluent, (ii)
crosscarmellose sodium as a disintegrant, (iii) magnesium stearate as a lubricant and (iv)
remaining portion of colloidal silicon dioxide as a glidant.
In another aspect, the present invention relates to a process of preparing an oral
pharmaceutical composition of febuxostat comprising the steps of:
(a) blending the drug with the first portion of the binder and other intragranular excipients,
(b) preparing a binder solution by dispersing1 dissolving the remaining portion of the binder to
the granulating liquid followed by addition of the wetting agent,
(c) granulating the mixture of step (a) with the binder solution of step (b);
(d) drying the granules obtained in step (c) and adding the extragranular excipients to the dried
granules, and
(e) compressing the granules of step (d) to form a tablet or filling the granules in a capsule.
In yet another aspect there is provided a method of treating gout and hyperuricemia by
administering to a person in need thereof an oral pharmaceutical composition of febuxostat
comprising: (A) an intragranular component comprising: (i) an effective amount of febuxostat,
(ii) wetting agent(s), (iii) diluent(s), (iv) binder(s), (v) disintegrant(s) and (vi) optionally
glidant(s); and (B) an extragranular component comprising: (i) diluent(s), (ii) disintegrant(s), (iii)
lubricant(s) and (iv) optionally glidant(s).
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 the description and
examples.
Detailed description of the invention
In one aspect, the present invention relates to an oral pharmaceutical composition of
febuxostat comprising: (A) an intragranular component and (B) an extragranular component.
Embodiments of the composition may include one or more of the following features. The
intragranular component comprises: (i) an effective amount of febuxostat, (ii) wetting agent(s),
(iii) diluents(s) (iv) binder(s) (v) disintegrant(s) and (vi) optionally glidant(s); and the
extragranular component comprises: (i) diluent(s), (ii) disintegrant(s), (iii) lubricant(s) and (iv)
optionally glidant(s).
The term "pharmaceutical composition", as used herein, refers to the tablet or capsule
composition of a predetermined quantity of active substance in association with at least one
pharmaceutically acceptable excipient.
The term "about", as used herein, when used along values assigned to certain measurements
and parameters means a variation of 10% from such values, or in case of a range of values,
means a 10% variation from both the lower and upper limits of such ranges.
The term "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 is present in the present composition in an amount ranging from about 2% to about
50%, preferably from about 5% to about 30%, more preferably from about 10% to about 20% by
weight of the composition.
The particle size can affect the solubility properties of a pharmaceutical compound. Particle
size reduction can increase the dissolution rate and consequently the bioavailability. In the
present invention, febuxostat is present in a micronized form having a median particle size (D50)
ranging from about 0.1 pm to about 6pm, preferably from about 1 pm to about 4pm.
The drug particles of the desired particle size may be obtained by any of the conventional
processes known in the art such as mechanical milling, supercritical fluid processes, cryogenic
spraying, or solvent evaporation. 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 MalvernB Mastersizer laser diffraction
instrument.
The pharmaceutical compositions of the present invention may comprise one or more
pharmaceutically acceptable excipients selected from diluents, disintegrants, binders, lubricants,
glidants, wetting agents, organoleptic ingredients such as coloring agents, flavoring agents,
sweeteners and others known to the skilled person in the art.
In the present invention, the wetting agent is present in the intragranular portion. The
wetting agent may be blended with the drug or with the intragranular excipients, and/ or may be
added to the binder solution. Preferably, the wetting agent is added to the binder solution. The
wetting agent is present in an amount ranging from about 0.01% to about 5% by weight of the
composition. The ratio of drug to wetting agent ranges from about 50: 1 to about 1 : 1, preferably
from about 20: 1 to about 5: 1, more preferably about 16: 1. Examples of wetting agents that can
be used in the present invention include, but are not limited to, alkylglucosides; alkylmaltosides;
lauryl macrogolglycerides; caprylocaproyl macrogolglycerides, polyoxyethylene alkyl ethers;
polyoxyethylene alkylphenols; polyethylene glycol fatty acid esters; polyethylene glycol glycerol
fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene
block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene
vegetable oils; polyoxyethylene hydrogenated vegetable oils; sugar esters, sucroglycerides; alkyl
ammonium salts; bile acids and salts, fatty acid derivatives of amino acids, lysophospholipids;
phospholipids; salts of alkyl sulfates; alkyl ether sulfates and docusates or mixtures thereof.
Preferably, the wetting agent is sodium lauryl sulfate.
Suitable examples of diluents or fillers include, but are not limited to, microcrystalline
cellulose, anhydrous lactose, lactose monohydrate, sugar compressible, confectioners sugar,
sucrose, glucose, maltose, calcium carbonate, calcium dihydrogen phosphate dihydrate, calcium
phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, cellulose powdered, dextrin,
dextrose, fructose, kaolin, lactitol, mannitol, sorbitol, starch, corn starch, or mixtures thereof.
Preferably, the diluents comprise lactose, microcrystalline cellulose, or mixtures thereof.
Preferably, the diluent(s) present in the intragranular portion comprises a mixture of lactose and
microcrystalline cellulose and the diluent present in the extragranular portion is microcrystalline
cellulose. The diluent is present in an amount of about 40% to about 90% by weight of the
composition.
In the present invention, the binder is present in the intragranular portion. A portion of
the binder is blended with the active ingredient and the other portion is dispersed or dissolved in
the granulating liquid to form a binder solution. The ratio of binder in the dry mix portion to that
in the granulating liquid ranges from about 1 : 10 to about 10: 1, preferably about 1 :5 to about 5: 1.
The binder is present in an amount of about 0.01% to about 10% by weight of the composition.
Suitable examples of binders include, but are not limited to, hydroxypropyl cellulose,
pregelatinized starch, starch, povidone, carbomer, sodium carboxymethylcellulose,
microcrystalline cellulose (MCC), microfine cellulose, dextrin, lactose, glucose, guar gum,
hypromellose, or mixtures thereof. Preferably, the binder is hydroxypropyl cellulose.
In the present invention, a portion of disintegrant is present in the intragranular
component and the remaining portion is added to the extragranular component. The ratio of the
disintegrant in the intragranular portion to that in the extragranular portion ranges from about
1: 10 to about 10: 1, preferably from about 1 :5 to about 5: 1. The disintegrant is present in an
amount of about 0.01% to about 20%, preferably in an amount of about 1% to about 10% by
weight of the composition. Suitable examples of disintegrants include, but are not limited to,
starch, sodium starch glycolate, croscarmellose sodium, crospovidone, alginic acid, lowsubstituted
hydroxypropyl cellulose, carboxymethyl cellulose sodium, microcrystalline cellulose,
calcium carbonate, sodium carbonate, agar, guar gum, or mixtures thereof. Preferably, the
disintegrant is croscarmellose sodium.
In the present invention, the lubricant is present in an amount of about 0.01 % to about 4%
by weight of the composition. Suitable examples of lubricants 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 mixtures thereof.
In the present invention, a portion of glidant is present in the intragranular component
and the remaining portion is added to the extragranular component. A glidant when added to the
intragranular portion, aids in uniform mixing of the intragranular excipients. The glidant is
present in an amount of about 0.01% to about 2% by weight of the composition. Suitable
examples of glidants include, but are not limited to, colloidal silicon dioxide, colloidal silica,
calcium silicate, magnesium silicate, colloidal silicon, silicon hydrogel, cornstarch, talc, or
mixtures thereof.
The coloring agents and flavoring agents of the present invention may be selected from
any FDA approved colors and flavors for oral use.
In one of the aspects the present invention relates to an oral pharmaceutical composition
of febuxostat comprising: (A) an intragranular component comprising: (i) an effective amount of
febuxostat, (ii) sodium lauryl sulfate as a wetting agent, (iii) mixture of lactose and
microcrystalline cellulose as diluents, (iv) hydroxypropyl cellulose as a binder, (v)
crosscarmellose sodium as a disintegrant and (vi) colloidal silicon dioxide as a glidant; and (B)
an extragranular component comprising: (i) microcrystalline cellulose as a diluent, (ii)
crosscarmellose sodium as a disintegrant, (iii) magnesium stearate as a lubricant and (iv)
remaining portion of colloidal silicon dioxide as a glidant.
In another aspect, the present invention relates to an oral pharmaceutical composition of
febuxostat comprising: (i) about 40% - 90% by weight of febuxostat, (ii) about 0.01% - 5% by
weight of sodium lauryl sulfate, (iii) about 40% - 90% by weight of lactose and microcrystalline
cellulose, (iv) about 0.01% - 10% by weight of hydroxypropyl cellulose (v) about 0.01% - 20%
by weight of crosscarmellose sodium and (vi) about 0.01% - 2% by weight of colloidal silicon
dioxide; and (vii) about 0.01% - 4% by weight of magnesium stearate.
Another general aspect relates to a process of preparing the febuxostat composition of the
present invention. Preferably, the present invention is prepared by a wet granulation method and
comprises the following steps:
(a) blending the drug with the first portion of the binder and other intragranular excipients,
(b) preparing a binder solution by dispersing dissolving the remaining portion of the binder to
the granulating liquid,
(c) granulating the mixture of step (a) with the binder solution of step (b);
(d) drying the granules obtained in step (c) and adding the extragranular excipients to the dried
granules, and
(e) compressing the granules of step (d) to form a tablet or filling the granules in a capsule.
Another general process of preparing the febuxostat composition of the present invention
comprises the following steps:
(a) blending the drug with the first portion of the binder and other intragranular excipients,
(b) preparing a binder solution by dispersing dissolving the remaining portion of the binder to
the granulating liquid followed by addition of the wetting agent,
(c) granulating the mixture of step (a) with the binder solution of step (b);
(d) drying the granules obtained in step (c) and adding the extragranular excipients to the dried
granules, and
(e) compressing the granules of step (d) to form a tablet or filling the granules in a capsule.
Examples of granulating liquid used for wet granulation include, but are not limited to,
water, ethanol, isopropyl alcohol, acetone, dichloromethane or hydroalcoholic solvents such as
isopropyl alcohol-water mixture. The granulating liquid may include at least one
pharmaceutically acceptable excipient. Particularly, the binder is a part of the granulating liquid.
Optionally, the wetting agent is also a part of the granulating liquid.
The composition of the present invention may be in the form of a tablet or a capsule. The
tablets or capsules obtained may further be film-coated. Additional excipients such as filmforming
polymers, solvents, plasticizers, antiadherents, opacifiers and optionally colorants,
pigments, antifoam agents, and polishing agents can be used in coatings.
Examples of film-forming agents include, but are not limited to, cellulose derivatives
such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxymethylethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl
cellulose, ethyl cellulose; dextrins, starches and starch derivatives; polymers based on
carbohydrates and derivatives thereof, natural gums such as gum arabic; xanthans; alginates;
polyacrylic acids; polyvinyl alcohols; polyvinyl acetates; polyvinylpyrrolidones;
polymethacrylates and derivatives thereof; chitosan and derivatives thereof; shellac and
derivatives thereof; waxes and fat substances.
The coating can be performed using any commercially available ready-to-coat
preparations such as OpadryB AMB, OpadryB White, OpadryB Clear, OpadryB 11, etc.
Suitable excipients are used as adjuvants in the coating process, include plasticizers,
opacifiers, antiadhesives and polishing agents.
In one embodiment, the composition of the present invention exhibits no significant
difference in rate and/or extent of absorption of febuxostat as compared to the marketed
formulation of febuxostat available under the brand name ULORIC~.
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
Example 1 :
Procedure:
1. Febuxostat and lactose were sifted together through a suitable mesh.
2. Microcrystalline cellulose, croscarmellose sodium (intra-granular), colloidal silicon dioxide
(intra-granular) and hydroxypropyl cellulose (dry mix portion) were sifted together through a
suitable mesh.
3. Extragranular microcrystalline cellulose, croscarmellose sodium and colloidal silicon dioxide
were sifted together through a suitable mesh.
4. A binder solution was prepared by dispersing the second portion of hydroxypropyl cellulose
in water under mechanical stirring.
5. Sodium lauryl sulfate was dissolved into solution of step 4 under mechanical stirring.
6. The sifted material of step 1 and step 2 were loaded into the bowl of Rapid mixer granulator
and dry mixing was carried out.
7. The material of step 6 was granulated using binder solution of step 5.
8. The granules obtained in step 7 were dried in a suitable dryer and milled.
9. The extragranular material of step 3 was added to the granules of step 8 and blended.
10. The blend from step 9 was lubricated with magnesium stearate.
1 1. The blend of step 10 was compressed into tablets with suitable tooling, and the tablets were
coated with a suspension of OpadryB 11.
Example 2:
Magnesium Stearate 0.49
I Film Coating I
I
Purified Water q S 1
Procedure:
The tablets of example 2 are prepared by following the same procedure as example 1.
Example 3: Dissolution study
Table 1 provides dissolution data of Febuxostat tablets prepared as per example 2 wherein the
median particle size D5() of febuxostat is 1.8pm. For determination of drug release rate, USP type
I1 (paddle) apparatus (75 rpm) was used wherein 900 mL of Phosphate buffer of pH 6.8 was used
as the dissolution medium.
Table 1
Example 4:
Time (minutes)
10
15
3 0
Percent Drug Release
100
100
100
Procedure
The tablets of example 4 are prepared by following the same procedure as example 1.
Microcrystalline Cellulose
Croscarmellose Sodium
Colloidal Silicon Dioxide
Magnesium Stearate
Example 5: Dissolution study
Table 2 provides dissolution data of Febuxostat tablets prepared as per example 4 wherein the
median particle size DS0 of febuxostat is 2.46pm. For determination of drug release rate, USP
type I1 (paddle) apparatus (75 rpm) was used wherein 900 mL of Phosphate buffer of pH 6.8 was
used as the dissolution medium.
Table 2
8.74
1.94
0.24
0.49
Film Coating
Time (minutes)
10
15
3 0
OpadryB I1
Purified Water
Percent Drug Release
100
100
100
Example 6:
2.9 1
q S
Ingredients Percent w/w
Zntra-granular
Febuxostat
Lactose monohydrate
Microcrystalline Cellulose
Hydroxypropyl Cellulose
Croscarmellose Sodium
16
15.3
49.75
2
3
Procedure:
The tablets of example 6 are prepared by following the same procedure as example 1.
Sodium Lauryl Sulfate
Colloidal Silicon Dioxide
Purified Water
Reference Example 1 :
1
0.25
q S
Procedure:
1. Febuxostat and lactose were sifted together through a suitable mesh.
2. Microcrystalline cellulose, croscarmellose sodium (intra-granular) and hydroxypropyl
cellulose (dry mix portion) were sifted together through a suitable mesh.
Extra-granular
Croscarmellose Sodium
Microcrystalline Cellulose
Colloidal Silicon Dioxide
Magnesium Stearate
2
10
0.2
0.5
3. Extragranular croscarmellose sodium and colloidal silicon dioxide were sifted together
through a suitable mesh.
4. A binder solution was prepared by dispersing the second portion of hydroxypropyl cellulose
in water under mechanical stirring.
5. The sifted material of step 1 and step 2 were loaded into the bowl of Rapid mixer granulator
and dry mixing was carried out.
6. The material of step 5 was granulated using binder solution of step 4.
7. The granules obtained in step 6 were dried in a suitable dryer and milled.
8. The extragranular material of step 3 was added to the granules of step 7 and blended.
9. The blend from step 8 was lubricated with magnesium stearate and was compressed into
tablets with suitable tooling.
Example 7: Dissolution study in 900 mL of Phosphate buffer of pH 6.8 as the dissolution
medium
Table 3 provides dissolution data of Febuxostat tablets prepared as per Example 6 and
Reference example 1 and reference formulation (ULORICB tablet). For determination of drug
release rate, USP type I1 (paddle) apparatus (75 rpm) was used wherein 900 mL of Phosphate
buffer of pH 6.8 was used as the dissolution medium.
Table 3
The results show that the two different compositions of Example 3 (with wetting agent) and
reference example 1 (without the wetting agent) show similar dissolution even at 15 minutes
interval, when the dissolution is carried out in 900mL of Phosphate buffer of pH 6.8.
Time
(minutes)
15
3 0
Example 8: Dissolution study in 900 mL of acetate buffer of pH 5.8 as the dissolution medium
Table 4 provides dissolution data of Febuxostat tablets prepared as per example 6 and
Reference example 1 and reference formulation (ULORICB tablet). For determination of drug
Percent Drug Release
Example 3
98
98
Reference Example 1
101
103
Reference
102
103
release rate, USP type I1 (paddle) apparatus (50 rpm) was used wherein 900 mL of acetate buffer
of pH 5.8 was used as the dissolution medium.
Table 4
The results show that the two different compositions of Example 3 (with wetting agent)
and reference example 1 (without the wetting agent) show distinct dissolution profiles when test
is carried out in 900 mL of acetate buffer of pH 5.8 as the dissolution medium, clearly
highlighting the difference between the two formulations.
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.
Time
(minutes)
10
15
3 0
Percent Drug Release
Reference
8 0
88
94
Example 3
70
74
92
Reference Example 1
67
72
76

WE CLAIM:
1. An oral pharmaceutical composition of febuxostat comprising: (A) an intragranular
component comprising: (i) an effective amount of febuxostat, (ii) wetting agent(s), (iii)
diluent(s), (iv) binder(s), (v) disintegrant(s) and (vi) optionally glidant(s); and (B) an
extragranular component comprising: (i) diluent(s), (ii) disintegrant(s), (iii) lubricant(s)
and (iv) optionally glidant(s).
2. The pharmaceutical composition according to claim 1, wherein febuxostat is present in an
amount of about 2% to about 50% by weight of the composition.
3. The pharmaceutical composition according to claim 1, wherein the median particle size
of febuxostat ranges from about 0.1 ym to about 6 ym.
4. The pharmaceutical composition according to claim 1, wherein a portion of the binder is
blended with the drug and the remaining portion is added to the granulating liquid.
5. The pharmaceutical composition according to claim 4, wherein the ratio of binder in the
dry mix portion to that in the granulating liquid portion ranges from about 1:10 to about
1O:l.
6. The pharmaceutical composition according to claim 1, wherein the disintegrant is present
an amount of about 0.01% to about 20% by weight of the composition.
7. The pharmaceutical composition according to claim 1, having a dissolution of at least
70% in 15 minutes and at least 90% in 30 minutes, when measured using USP type I1
(paddle) apparatus at 50 rpm, in 900mL of acetate buffer of pH 5.8 as the dissolution
medium.
8. A process of preparing an oral pharmaceutical composition of febuxostat comprising the
steps of:
(a) blending the drug with the first portion of the binder and other intragranular
excipients,
(b) preparing a binder solution by dispersing1 dissolving the remaining portion of the
binder to the granulating liquid followed by addition of the wetting agent,
(c) granulating the mixture of step (a) with the binder solution of step (b);
(d) drying the granules obtained in step (c) and adding the extragranular excipients to the
dried granules, and
(e) compressing the granules of step (d) to form a tablet or filling the granules in a
capsule.
9. A method of treating gout and hyperuricemia by orally administering to a person in need
thereof an oral pharmaceutical composition of febuxostat comprising: (A) an
intragranular component comprising: (i) an effective amount of febuxostat, (ii) wetting
agent(s), (iii) diluent(s), (iv) binder(s), (v) disintegrant(s) and (vi) optionally glidant(s);
and (B) an extragranular component comprising: (i) diluent(s), (ii) disintegrant(s), (iii)
lubricant(s) and (iv) optionally glidant(s).
10. An oral pharmaceutical composition of febuxostat as described and illustrated in the
examples herein.
Dated this the 1 2da~y o~f Fe bruary, 2013.
For Ranbaxy Laboratories Limited
(Dr. Santanu De)
Associate Director - Intellectual Property
Head - IP India