FIELD OF INVENTION

The invention relates to oral pharmaceutical compositions comprising febuxostat or their pharmaceutically acceptable salts thereof.
Particularly, the invention relates to amorphous dispersion comprising febuxostat, a dispersing agent(s), and optionally other pharmaceutically acceptable excipients.

The invention also relates to process of preparing amorphous dispersion comprising febuxostat, a dispersing agent(s) and optionally other pharmaceutically acceptable excipients.

BACKGROUND OF THE INVENTION

Febuxostat is a xanthine oxidase inhibitor and basically used in the treatment of chronic management of hyperuricemia in patients with gout. Chemically it is known as 2-[3-cyano4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid and is disclosed in U.S. Patent No. 5,614,520.

Febuxostat is a non-hygroscopic, white crystalline powder that is freely soluble in dimethylformamide; soluble in dimethylsulfoxide; sparingly soluble in ethanol; slightly soluble in methanol and acetonitrile; and practically insoluble in water. The melting range is 205°C to 208°C

Febuxostat is commercially available under the trade name ULORIC in the form of a film-coated tablet in the U.S., Europe and other countries as well.Febuxostat is known to exist in different crystalline forms. Different polymorphic forms of the same compound may have completely different properties, especially when compared with an amorphous form of the same active. Amorphous materials have properties that can be of advantage in the preparation of pharmaceutical compositions, such as solubility/dissolution rate, and bioavailability. However, the increased reactivity of an amorphous solid, with a consequent high propensity to spontaneously transform to the crystalline state at a certain conditions such as for example relative humidity, force and temperature among others, may negatively affect the physical and chemical stability of the pharmaceutical composition.

Thus there has always been a need to produce pharmaceutical compositions wherein the drug is retained in the amorphous form, either during formulation processing or during the shelf-life of the formulation. Various approaches used for the formulation of an amorphous material include the use of dry granulation techniques for tableting, complexation, dry mixing, melt-extrusion, co-precipitation, spray drying, and co-milling, to name a few. Compositions comprising amorphous actives suffer from problems of form conversion either during processing or upon stability.

The development of pharmaceutical compositions comprising the amorphous form of febuxostat, which do not show change in XRD pattern of the compositions during manufacturing and upon storage, would be a significant improvement in the delivery of the same.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to oral pharmaceutical compositions comprising febuxostat or their pharmaceutically acceptable salts thereof.
Particularly, the invention relates to amorphous dispersion comprising febuxostat, a dispersing agent(s) and optionally other pharmaceutically acceptable excipients.

The invention also relates to process of preparing an amorphous dispersion comprising febuxostat, a dispersing agent(s) and optionally other pharmaceutically acceptable excipients.
In one embodiment, the invention provides an amorphous dispersion comprising febuxostat or a pharmaceutically acceptable salt thereof, a dispersing agent(s), and optionally other pharmaceutically acceptable excipients; wherein febuxostat or a pharmaceutically acceptable salt thereof within the dispersion is in substantially amorphous form.

Yet in another embodiment, the invention provides a method of preparing an amorphous dispersion comprising febuxostat or a pharmaceutically acceptable salt thereof, a dispersing agent(s), and optionally other pharmaceutically acceptable excipients; which includes forming a mixture comprising febuxostat, a dispersing agent(s), optionally other pharmaceutically acceptable excipients and a solvent; and subjecting it to fluid bed granulation followed by drying, wherein the febuxostat or a pharmaceutically acceptable salt thereof within the dispersion is in substantially amorphous form.

In yet another embodiment, the invention provides a pharmaceutical composition comprising an amorphous febuxostat dispersion comprising febuxostat or a pharmaceutically acceptable salt thereof and a dispersing agent(s), wherein febuxostat or a pharmaceutically acceptable salt thereof within the dispersion is in substantially amorphous form; and at least one pharmaceutically acceptable excipient.

In still another embodiment, the invention provides a use of pharmaceutical compositions comprising amorphous febuxostat dispersion for the treatment of chronic management of hyperuricemia in patients with gout, by administering orally a therapeutically effective amount of pharmaceutical composition comprising an amorphous dispersion comprising febuxostat or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1: Overlaid XRD pattern of crystalline febuxostat active ingredient, placebo and the composition comprising amorphous febuxostat dispersion.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to oral pharmaceutical compositions comprising febuxostat or their pharmaceutically acceptable salts thereof.
Particularly, the invention relates to amorphous dispersion comprising febuxostat, a dispersing agent(s), and optionally other pharmaceutically acceptable excipients.

The invention also relates to process of preparing amorphous dispersion comprising febuxostat, a dispersing agent(s) and optionally other pharmaceutically acceptable excipients.
The invention also relates to pharmaceutical compositions comprising amorphous febuxostat dispersion comprising febuxostat or a pharmaceutically acceptable salt thereof and a dispersing agent(s), wherein febuxostat or a pharmaceutically acceptable salt thereof within the dispersion is in substantially amorphous form; and at least one pharmaceutically acceptable excipient.

In context of the invention, terms like "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for febuxostat or a pharmaceutically acceptable salt thereof and the amorphous dispersion comprising febuxostat or its salt, a dispersing agent (s) and optionally other pharmaceutically acceptable excipients.

The term "dispersion" as used herein refers generally to solid dispersion, unless specified otherwise. It may be used interchangeably and synonymously for "pre-mix" or "admixture" or "composite" or "solid composite" to name a few. It consists of at least two different components, generally a hydrophilic matrix comprising a dispersing agent(s) and a hydrophobic drug. The hydrophilic matrix can be either crystalline or amorphous. The drug can be dispersed molecularly, in amorphous particles or in crystalline particles.

"Substantially amorphous form" according to the invention refers that no recognizable characteristic crystalline febuxostat peaks are present in an X-ray powder diffraction pattern of the solid dispersion and/ or the compositions containing said solid dispersion.

The "dispersing agent(s)" according to the invention can be any pharmaceutical acceptable excipients that once co-processed with febuxostat or a salt thereof, functions to maintain febuxostat in a substantially amorphous form. The dispersing agent(s) to be combined with febuxostat can be crystalline or amorphous.

Non-limiting examples of such dispersing agent(s) include cellulosic polymers such as an alkyl celluloses (e.g., methylcellulose, ethyl cellulose, and the like); modified celluloses such as carboxymethylcellulose, hydroxypropyl methyl cellulose, cross-linked sodium carboxymethylcellulose, hydroxyl alkyl cellulose (e.g., hydroxypropyl cellulose); polyvinylpyrrolidone (Povidone™);
cross-linked homopolymer of N-vinyl-2-pyrrolidone; polyvinylpyrrolidone-vinyl acetate copolymer; polyvinyl alcohol; polysaccharides; a mono or disaccharides (e.g., lactose); sugar alcohol; or a combination comprising at least one of the foregoing dispersing agent.

Febuxostat or its pharmaceutically acceptable salt used in the preparation of the dispersion can be either pure crystalline or pure amorphous form. It further includes febuxostat or its salt in either partially crystalline or partially amorphous form. It also includes febuxostat or its salt comprising a mixture of both crystalline and amorphous form in any ratio.

Various methods of preparing amorphous dispersion known in the art include spray drying; freeze drying (lyophilization); crash cooling from supercritical fluids, solution enhanced dispersion by supercritical fluids; rapid expansion of supercritical solution; vacuum distillation followed by drying and co-precipitation with suitable excipients.

In one embodiment, the dispersion may also be prepared by Fluid-Bed Drying technique, wherein a solution or a suspension comprising febuxostat or its salt, a dispersing agent(s) and optionally other pharmaceutically acceptable excipient in a suitable solvent is dried at atmospheric conditions.

Alternatively, the dispersion is prepared by spray-drying a solution or a suspension comprising febuxostat or its salt, a dispersing agent(s) and optionally other pharmaceutically acceptable excipient in a suitable solvent.
Yet, in another embodiment the amorphous dispersion of febuxostat may also be prepared by a process comprising the steps of:

(a) Preparing a solution by dissolving febuxostat, dispersing agent(s) and one or more pharmaceutically acceptable excipient in a suitable solvent.

(b) Subjecting the solution of step (a) to fluid bed drier to get the amorphous dispersion of febuxostat.

Suitable solvents that may be used for preparing the amorphous dispersion include those that do not adversely affect the stability of febuxostat, and are preferably inert. Such solvents may be organic, aqueous, or a mixture thereof. Organic solvents may be aliphatic alcohols such as methanol, ethanol, n-propanol, and isopropanol; aliphatic ketones such as acetone and methyl ethyl ketone; aliphatic carboxylic esters such as ethyl acetate; aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as hexane; aliphatic nitriles such as acetonitrile; chlorinated hydrocarbons such as dichloromethane; aliphatic sulfoxides such as dimethylsulfoxide; and the like, as well as mixtures comprising at least one of the foregoing organic solvents. Specifically aqueous solvents are used, that is, a solvent comprising water and/or a water-miscible organic solvent such as a lower alcohol, acetonitrile, tetrahydrofuran, dimethylacetamide, dimethylformamide, and the like. Combination of various solvents can also be used.
The solvent can be removed by any variety of methods as discussed previously such as evaporation optionally under reduced pressure or under heat or vacuum, precipitation by a non-solvent, freeze drying, spray drying, and the like.

In one embodiment, the invention provides for pharmaceutical compositions comprising the amorphous dispersion of febuxostat. Such compositions are preferably in the form of oral solid dosage forms. The term "solid dosage" defines a system in a solid state in the form of a tablet, mini-tablet, pellet, powder or granule or a micro-granule comprising an amorphous dispersion of febuxostat along with other suitable pharmaceutical excipients such as fillers, binders, disintegrant and lubricants.
Fillers according to the invention are selected from a group comprising lactose, cellulose, mannitol, microcrystalline cellulose, dextrose, calcium phosphate, fructose, maltose and the like or combinations thereof.

Binders according to the invention are selected from a group comprising povidone, copovidone, hyroxypropyl methylcellulose, hyroxypropyl cellulose,polyvinyl alcohol, sodium alginate, sodium carboxymethyl cellulose, polydextrose, methacrylic acid copolymers, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol phthalate, cellulose acetate phthalate and the like or combinations thereof.

Disintegrants according to the invention are selected from a group comprising starch, sodium starch glycolate, calcium carboxymethlycellulose, croscarmellose sodium, polacrillin potassium, alginic acid, crospovidone, low-substituted hydroxypropyl cellulose and the like or combinations thereof.
Lubricants according to the invention are selected from a group comprising magnesium stearate, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and the like or combinations thereof.

Yet in another aspect, the particle size distribution (PSD) of febuxostat is less than or equal to about l00μm i.e. d (0.9) is less than or equal to about 100 urn.

The pharmaceutical compositions comprising amorphous febuxostat dispersion along with other suitable pharmaceutical excipients is prepared by a process involving the steps of:

(a) Preparing granulate comprising febuxostat dispersion along with at least one filler and optionally other excipients, by wet granulation followed by drying;

(b) The granulate of step (a) is further blended with extra-granular excipients followed by lubricating with suitable lubricant;

(c) Compress the lubricated blend of step (b) to get the tablets, and

(d) Finally the tablet of step (c) is coated by film coating material.

Yet in another embodiment, the amorphous dispersion with or without disintegrant(s) and binder may be incorporated in the composition by granulating the mixture with a binder solution, and then followed by compression to get the desirable tablets. The tablets may be optionally coated with a film former or a film coating material.

Determination of phase conversion of febuxostat either in pure form or in the pharmaceutical compositions comprising the dispersions of the said drug can be determined by using analytical techniques like X-ray diffraction analysis, differential scanning calorimetry, optical microscopy etc. The invention uses X-ray diffraction analysis to determine the physical form of the drug in pure form as well as in the composition.

The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

A. Febuxostat Dispersion

Febuxostat amorphous dispersions are prepared by dissolving febuxostat, dispersing agent(s) in a hydro-alcoholic / alcoholic solution followed by drying as disclosed in the Example 1 to Example 4.

Example 1

Dispersing Agent Active Ingredient
S. No. Name Weight by Febuxostat
part (Weight by Part)
1 Polyvinylpyrrolidone 0.1-100 1
(Povidone K-30)
2 Polyvinylpyrrolidone 0.1-100 1
(Povidone K-25)
3 Polyvinylpyrrolidone 0.1-100 1
(Povidone K-60)
4 Hydroxypropyl methyl cellulose 0.1-100 1
5 Hydroxypropyl methyl cellulose 0.1-100 1
phthalate
6 Cross-linked homopolymer of N- 0.1-100 1
vinyl-2-pyrrolidone
(Crospovidone)
7 Polyvinylpyrrolidone-vinyl acetate 0.1-100 1
copolymer
I (Copovidone S-630)

Brief Manufacturing Procedure

1. Febuxostat and dispersing agent was dissolved in a mixture of suitable solvents to get a clear solution.

2. The solution of step (1) was evaporated using suitable means to get febuxostat dispersion.

Example 2

S. No. Ingredients Quantity
(mg)
1 Febuxostat 80
2 Povidone 40
3 Ethanol q.sI
4 Water q.s.

Brief Manufacturing Procedure:

1. Febuxostat and povidone was dissolved in a mixture of water and ethanol to get a clear solution.

2. The solution of step (1) was spray dried to get febuxostat dispersion.

Example 3

S. No. Ingredients Quantity
(mg)
1 Febuxostat 80
2 Povidone 100
3 Ethanol q.s
4 Water q.s

Febuxostat amorphous dispersion of example 3 was prepared using the similar procedure as disclosed in Example 2.

Example 4

S. Ingredients Quantity
No. (mg)
1 Febuxostat 80
2 Povidone 40
3 Ethanol q.s
4 Water q.s.

Brief Manufacturing Procedure:

1. Povidone was dissolved in a mixture of water and ethanol to get a clear solution.

2. The solution of step (1) was sprayed on Febuxostat in a fluid bed drier to get febuxostat dispersion.

B. Compositions comprising Febuxostat Dispersion

Example 5

S. Ingredients Mg/tablets
No.
1 Febuxostat 80
2 Povidone 40
3 Ethanol q.s.
4 Water q.s.
5 Lactose 300
6 Microcrystalline cellulose 50
7 Croscarmellose sodium 20
8 Magnesium stearate 10
9 Film coating material 12
[Total weight | 512

Brief Manufacturing Procedure:

1. Febuxostat and povidone was dissolved in a mixture of water and ethanol to get a clear solution.

2. The solution of step (1) was spray dried to get the febuxostat dispersion.

3. Granulate the febuxostat dispersion with lactose in fluid bed drier to get the granules.

4. The granules of step (3) were blended with microcrystalline cellulose followed by lubricating with magnesium stearate.

5. The lubricated mass of step (4) was compressed using suitable tooling to form the tablets.

6. The tablets of step (5) were coated by a film coating material.

Example 6

S. Ingredients Mg/tablets
No.
1 Febuxostat 80
2 Povidone 100
3 Ethanol q.s.
4 Water q.s.
5 Lactose 240
6 Macrocrystalline cellulose 50
7 Croscarmellose sodium 20
8 Magnesium stearate 10
9 Film coating material 12
| Total weight 512

Febuxostat composition of Example 6 was prepared using similar procedure as disclosed in Example 5.

Example 7

S. No. Ingredients Mg/tablets
1 Febuxostat 80
2 Lactose 300
3 Povidone 40
4 Ethanol q.s.
5 Water q.s.
6 Extra granular
7 Microcrystalline cellulose 50
8 Croscarmellose sodium 20
9 Magnesium stearate 10
10 Film coating material 12
Total weight | 512

Brief Manufacturing Procedure:

1. Povidone was dissolved in a mixture of water and ethanol to get a clear solution.

2. The solution of step (1) was sprayed on febuxostat in a fluid bed drier to get the febuxostat dispersion.

3. Granulate the febuxostat dispersion with lactose in fluid bed drier to get the granules.

4. The granules of step (3) were blended with microcrystalline cellulose followed by lubricating with magnesium stearate.

5. The lubricated mass of step (4) was compressed using suitable tooling to form the tablets and

6. Finally tablets of step (5) were coated by a film coating material.

Example 8

S. No. Ingredients Mg/tablets
1 Febuxostat 80
2 Lactose 320
3 Povidone 16
4 Acetone q.s.
Extra granular
5 Microcrystalline cellulose 62
6 Croscarmellose sodium 15
7 Colloidal silicon dioxide 2
8 Magnesium stearate 5
[Total weight 1 500

Brief Manufacturing Procedure:

1. Dissolve Febuxostat and povidone in acetone to get a solution.

2. Granulate lactose using the solution of step (1) to get granules.

3. The granules of step (2) were blended with microcrystalline cellulose, croscarmellose sodium and colloidal silicon dioxide followed by lubricating with magnesium stearate.

4. The lubricated mass of step (3) was compressed using suitable tooling to form the tablets.

Dissolution Study:

The tablets of febuxostat prepared according to Example-8 was tested for drug release for lhour in dissolution differentiating media comprising 900ml of phosphate buffer having pH of 5.5 using USP Dissolution Apparatus II with paddle speed set at 50 rpm. The samples were periodically withdrawn and spectrophotometrically analyzed for febuxostat content. The dissolution profile obtained was comparable with that of the marketed tablet ULORld® as given in Table-1.

Table-1

Febuxostat Drug Release Profile

Time ULORICf Example - 8
(Min)
10 28 23
20 36 34
30 39 41
45 40 48
60 41 54

WE CLAIM:

1. An amorphous dispersion comprising febuxostat, a dispersing agent(s), and optionally other pharmaceutically acceptable excipients.

2. A process for preparing amorphous dispersion comprising febuxostat, a dispersing agent(s), and optionally other pharmaceutically acceptable excipients, wherein said process involves the following steps:

(a) Dissolving febuxostat, dispersing agent(s) and one or more pharmaceutically acceptable excipients in a solvent to get a solution; and

(b) Drying said solution of step (a) to get the amorphous dispersion of febuxostat.

3. The dispersion according to claim 1 or 2, wherein said dispersing agent(s) is selected from a group consisting of hydroxypropylmethyl cellulose, cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone, cross-linked homopolymer of N-vinyl-2-pyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, or their combinations thereof.

4. The dispersion according to claim 1 or 2,wherein said solvent is selected from a group consisting of, ethanol, n-propanol, isopropanol; acetone, dichloromethane; dimethylsulfoxide; acetonitrile, water or their combinations thereof.

5. The dispersion according to claim 2, wherein said drying is carried out by evaporation under reduced pressure or under heat or vacuum in fluidized bed processor, or by freeze-drying or by spray-drying.

6. The dispersion according to claim 1, wherein said febuxostat has a particle size distribution such that d (0.9) is less than or equal to about l00 µm.

7. A pharmaceutical composition comprising amorphous febuxostat dispersion and at least one pharmaceutically acceptable excipient.

8. A process for preparing a pharmaceutical composition comprising amorphous febuxostat dispersion and at least one pharmaceutically
acceptable excipient, wherein said process involves the following steps:

(a) Preparing granulate comprising febuxostat dispersion along with at least one filler and optionally other excipients, by wet granulation;

(b) Drying said granulate;

(c) Blending said granulate of step (b) with extra-granular excipient;

(d) Compressing said blended granulate of step (c) to get the tablet; and

(e) Optionally coating said tablet with a film coating material.

9. The excipient according to claim 7or 8, is selected from a group consisting of fillers, binders, disintegrants, lubricants or their combinations thereof.