FIELD OF INVENTION

The invention is related to oral pharmaceutical compositions comprising deferasirox or its pharmaceutically acceptable salts, polymorphic forms, and mixtures thereof.

More particularly, the invention relates to oral pharmaceutical composition comprising deferasirox or its pharmaceutically acceptable salts, polymorphic forms and mixtures thereof, in the form of a dispersible tablet wherein the active ingredient has a mean particle size less than about 100 μ m and is present in an amount greater than 66% by weight based on total weight of the tablet.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

4-[3,5-Bis (2-hydroxyphenyl)-1H-1, 2, 4-triazol-l-yl]-benzoic acid, having International Non-proprietary Name (INN) as "Deferasirox" and having chemical structure as shown (Fig. I) is an iron chelating agent used for the treatment of chronic iron overload due to blood transfusions.

It is approved in the United States and other countries and is commercially available as dispersible tablet (EXJADE'TM) for oral administration.

Deferasirox is highly water-insoluble. It is highly lipid-soluble, and is observed to possess good permeability. According to the Bio-pharmaceutics Classification System, it is classified as Class II drug, implying that it is a poorly soluble, and highly permeable drug. Though deferasirox is highly water-insoluble, whatever limited solubility it has, that too shows high pH-dependent solubility. Though it is practically insoluble in lower pH; however, even at a pH of 6.8, it still remains practically insoluble, until the buffer strength is altered to get optimal dissolution profile.

Deferasirox being practically insoluble in aqueous media exhibits a generally poor dissolution profile and consequently poor bioavailability. Hence, there exists a need to have a composition comprising deferasirox which would exhibit acceptable dissolution and absorption.

Further, the recommended dosage strength of deferasirox is on the higher side in order to have clinical benefit. Due to its high dosage strength, the overall tablet weight and its volume including its dimension make it inconvenient to administer, in order to provide a pharmacologically active daily dosage amount of deferasirox. Hence there is a need for an oral dosage form having a high drug content which would be convenient for patient administration, as well as from manufacturing point of view. Further, high drug content dosage forms require less amount of inactive ingredients, which makes the dosage form less expensive to manufacture and moreover the dosage form becomes relatively smaller in size which would thereby be easier to swallow, especially for children and geriatric patients.

WO/2004/035026 discloses a dispersible tablet of deferasirox wherein the active ingredient is present in an amount of from 5% to 40% by weight based on total weight of the tablet.

WO/2005/097062 discloses a dispersible tablet of deferasirox wherein the active ingredient is present in an amount of from 42% to 65% by weight based on total weight of the tablet.

WO/2007/045445 discloses a dispersible tablet of deferasirox or a pharmaceutically acceptable salt thereof present in an amount of from 42% to 65% by weight based on total weight of the tablet and at least one pharmaceutically acceptable excipient suitable for the preparation of dispersible tablets and to process for making said dispersible tablet.

WO/2008/065123 discloses crystalline forms of deferasirox and its amorphous form, processes for its preparation thereof, compositions containing same, wherein the active ingredient is preferably in polymorphic form designated as "Form B".

WO/2009/067557 discloses a process of preparing deferasirox formulations having sufficiently high dissolution rate and good bioavailability wherein said process comprises co-milling deferasirox with at least two pharmaceutically acceptable excipients in the absence of any solvent.

It has been now surprisingly found that compositions of deferasirox or its pharmaceutically acceptable salts, polymorphic forms, and mixtures thereof, in the form of a dispersible tablet can be prepared, wherein the active ingredient is present in an amount greater than 66% by weight based on total weight of the tablet and having a mean particle size less than about 100 μ m; thus allowing an oral dosage form with a high drug load, which would be convenient to administer, manufacture and would also be cost-effective and further having a acceptable dissolution and absorption profile.

This and other such needs are addressed by the invention.

SUMMARY AND OBJECTIVE OF THE INVENTION

The invention relates to oral pharmaceutical compositions comprising deferasirox or its pharmaceutically acceptable salts, polymorphic forms, and mixtures thereof, process of preparing such compositions and their uses.

More particularly, the invention relates to oral pharmaceutical composition comprising deferasirox or its pharmaceutically acceptable salts, polymorphic forms and mixtures thereof, in the form of a dispersible tablet wherein the active ingredient has a mean particle size less than about 100 μ m and is present in an amount greater than 66% by weight based on total weight of the tablet.

An aspect of the invention provides for a dispersible tablet comprising deferasirox or its pharmaceutically acceptable salts, polymorphic forms and mixtures thereof.

An aspect of the invention provides for deferasirox compositions in the form of dispersible tablet wherein the mean particle size of deferasirox is less than about 100 µm.

An aspect of the invention provides for deferasirox compositions in the form of dispersible tablet wherein the active ingredient is present in an amount greater than 66% by weight based on total weight of the tablet.

An aspect of the invention provides for deferasirox compositions wherein the active ingredient is primarily present in polymorphic form designated as "Form A".

An aspect of the invention provides for the process of preparing deferasirox compositions in the form of dispersible tablet wherein the mean particle size of deferasirox is less than about 100 μm.

An aspect of the invention provides for the process of preparing deferasirox compositions in the form of dispersible tablet wherein the active ingredient is present in an amount greater than 66% by weight based on total weight of the tablet.

An aspect of the invention provides for the process of preparing deferasirox compositions in the form of dispersible tablet wherein the active ingredient has a mean particle size less than about l00 μ m and is present in an amount greater than 66% by weight based on total weight of the tablet.

Further aspect of the invention provides for pharmaceutical compositions of deferasirox wherein the in vitro dissolution release profile matches with the commercially available EXJADE™.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to oral pharmaceutical compositions comprising deferasirox or its pharmaceutically acceptable salts, polymorphic forms, and mixtures thereof, process of preparing such compositions and their uses.

An embodiment of the invention provides for a dispersible tablet comprising deferasirox or its pharmaceutically acceptable salts, polymorphic forms and mixtures thereof.

An another embodiment of the invention provides for a dispersible tablet comprising deferasirox or its pharmaceutically acceptable salts, polymorphic forms and mixtures thereof, in the form of a dispersible tablet wherein the active ingredient has a mean particle size less than about 100 μ m and is present in an amount greater than 66% by weight based on total weight of the tablet.

An another embodiment of the invention provides for the process of preparing deferasirox compositions in the form of dispersible tablet wherein the active ingredient has a mean particle size less than about 100|xm and is present in an amount greater than 66% by weight based on total weight of the tablet.

In context of the invention, the terms "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for 4-[3, 5-Bis(2- hydroxyphenyl)-1H-1,2,4-triazol-1 -yl]-benzoic acid or deferasirox or its pharmaceutically acceptable salts, polymorphic forms and mixtures thereof.

The term "dispersible tablet" as used herein refers to a tablet which normally disperses in aqueous phase, e.g. in water, with or without external agitation.

The term "particles" as used herein refers to individual particle of deferasirox or particles of deferasirox or deferasirox compositions.

The term "mean particle size" as used herein refers to the distribution of deferasirox particles wherein about 50 volume percent of all particles measured have a particle size less than the defined mean particle size value and about 50 volume percent of all measurable particles measured have a particle size greater than the defined mean particle size value.

As used herein, the terms D50 and D90 represent the median or the 50'th percentile and the 90th percentile of the particle size distribution, respectively as measured by volume.

The term "D90" as used herein refers to the size in microns below which 90 percent of the particles reside, on a volume basis.

The term "D50" as used herein refers to the size in microns below which 50 percent of the particles reside, on a volume basis.

According to the invention, there is provided pharmaceutical composition comprising deferasirox in the form of dispersible tablet, wherein the mean particle size of deferasirox is less than about 100 μm.

According to the invention, there is provided pharmaceutical composition of deferasirox in the form of dispersible tablet, wherein the mean particle size of deferasirox is about 0.1 μm to about 50μm. More preferably, in some embodiments, there are provided pharmaceutical compositions of deferasirox in the form of dispersible tablet, wherein deferasirox has a mean particle size of about 0.5 μm to about 25 μm and still more preferably some embodiments provide deferasirox compositions having a mean particle size of deferasirox from about 1 μ m to about l0 μm.

According to the invention, there are provided pharmaceutical compositions of deferasirox in the form of dispersible tablet, wherein the active ingredient has a D90 of about 50μm or less. More preferably, in some embodiments, there are provided pharmaceutical compositions of deferasirox wherein the active ingredient has a D90 of about 25μm or less and still more preferably, some embodiments provide deferasirox compositions, wherein the active ingredient has a D90 of about 10μm or less.

According to the invention, there are provided pharmaceutical compositions of deferasirox in the form of dispersible tablet, wherein the active ingredient has a D50 of about 25μm or less. More preferably, in some embodiments, there are provided pharmaceutical compositions of deferasirox wherein the active ingredient has a D50 of about 10 μm or less and still more preferably, some embodiments provide deferasirox compositions, wherein the active ingredient has a D50 of about 5 μm or less.

According to the invention, there are provided pharmaceutical compositions of deferasirox in the form of dispersible tablet, wherein the active ingredient has a mean particle size of about 50μm or less. More preferably, in some embodiments, there are provided pharmaceutical compositions of deferasirox wherein the active ingredient has a mean particle size of about 25μm and still more preferably, some embodiments provide deferasirox compositions, wherein the active ingredient has a mean particle size of about 10μm or less.

The desired particle size range material is obtained directly from a synthesis process or alternatively any known particle size reduction processes can be used, such as but not limited to sifting, milling, micronization, fluid energy milling, ball milling and the like.

Particle size can be determined, for example, by laser light scattering using a particle size analyzer, such as the proprietary MastersizerTM apparatus available from Malvern Instruments Ltd.

According to the invention, pharmaceutical compositions comprising deferasirox may be in the form of encapsulated free flowing powders or granules; compressed solid dosage forms such as tablets, including chewable or dispersible or mouth dissolving, as well as the conventional tablets; pellets or beads or spheres or cores filled into sachets or capsules; syrups, suspensions or dispersions; elixirs, lyophilized powders and the like. But pharmaceutical compositions of deferasirox in the form of dispersible tablets are the most preferred.

According to the invention there are provided pharmaceutical compositions of deferasirox in the form of dispersible tablet, wherein the active ingredient is present in an amount greater than about 66% by weight based on total weight of the tablet. Preferably, in some embodiments, there are provided pharmaceutical compositions of deferasirox in the form of dispersible tablet, which comprises active ingredient in an amount ranging from about 66%-86% by weight based on the total weight of the tablet. More preferably, in some embodiments, there are provided pharmaceutical compositions of deferasirox in the form of dispersible tablet, which comprises active ingredient in an amount ranging from about 68%-85% by weight based on total weight of the tablet.

According to the invention, weight of the orally administrable dispersible tablet comprising from about 125-500mg of active ingredient ranges from 150 to 765mg; and preferably between about 155 to 750mg.

The active ingredient according to the invention may be present in free acid form or in pharmaceutically acceptable salts. More preferably, the active ingredient is present in the free acid form. The active ingredient may further be present in various polymorphic forms and mixtures thereof as disclosed in the prior art. More preferably, active ingredient is present in the polymorphic form designated as "Form A", having X-ray diffraction pattern with a peak at an angle of refraction 2 theta (θ) of 10.0°, 10.5°, 14.1°, 16.6°, 23.1°, 25.1°, 25.7°, 26.2° ± 0.2°.

Further, the active ingredient according to invention is primarily present in the polymorphic form designated as "Form A", wherein the percentage of "Form A" is more than 80% by weight of solid deferasirox. The remainder of solid deferasirox i.e., 20% or less of the total weight of active ingredient may be, e.g., other crystalline forms or amorphous form or a mixture of crystalline and amorphous forms. More specifically, the composition contains at least 90% of crystalline "Form A" of deferasirox with respect to total weight of the solid active ingredient in the composition. Further more specifically, the composition may contain at least 95% of crystalline "Form A" with respect to total weight of solid deferasirox in the composition.

One or more pharmaceutically acceptable excipients used according to the invention includes without any limitations, those that are conventionally used, for e.g. fillers/diluents, disintegrants, binders, surfactants, glidants, lubricants, and optionally outer coating ingredients.

Suitable fillers/diluents according to the invention may include, but are not limited to lactose, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, sugar alcohols, dextrates, dextrin, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, starch, pregelatinized starch, and the like.

Suitable disintegrants according to the invention may include, but are not limited to cross-linked polypyrollidone commercially available as Crospovidone' TM Suitable binders according to the invention may include, but are not limited to starches, hydroxypropyl cellulose, hydroxyethyl cellulose, hypromellose, polyvinylpyrrolidone, gelatin, and the like.

Suitable surfactants according to the invention may include, but are not limited to sodium lauryl sulfate, quaternary ammonium salts, polysorbates.
sorbitan esters, poloxamer, betaines, higher fatty alcohols such as cetyl alcohol and oleyl alcohol and the like.

Suitable glidants and lubricants according to the invention may include, but are not limited to silica, colloidal silica, magnesium trisilicate, talc, stearates, behenates, fumarates, hydrogenated castor oil, and the like.

The tablets according to the invention are prepared by granulation techniques such as dry granulation or wet granulation.

In dry granulation, the ingredients are blended in dry form, made denser by slugging or compaction and reduced to granules by grinding or milling, using suitable equipments. The ground particles or granules are then compressed into tablet form in conventional manner using lubricants, glidants, etc., which can take any of the conventional shapes, e.g., round, elongated, oval, etc. A tablet press fitted with suitably sized punches and dies is used to form the tablet.

More preferably, wet granulation technique can also be used. According to this procedure, the dry active ingredient, other diluents are blended, for example, in a planetary mixer or a rapid mixer granulator. The powders are wetted with a granulating liquid like water, isopropyl alcohol or acetone or dichloromethane and other hydro-alcoholic solvents such as isopropyl alcohol-water mixture. Binders may be included in the granulating liquid. The moist mass is granulated, e.g., by forcing through a screen of suitable mesh size, dried, and, if desired, the particles further reduced in size. Granulates obtained are then compressed in conventional manner, using lubricants, glidants, etc., as required.

In a still another embodiment, the process may involve direct compression, wherein the ingredients are blended or homogeneously mixed in dry form, optionally sized through suitable sieves and directly compressed into tablet form in convention manner, using lubricants, glidants, etc., as required.

In a still another embodiment, the process involves combination of wet granulation and direct compression wherein the ingredients prepared by wet granulation are further blended with extra-granular inactive ingredients, lubricated and compressed to form the tablet.

The dispersible tablet can optionally be coated with an aesthetic outer coat comprising polymers such as cellulose derivatives such as one which is commercially available as O padry™.

Further embodiment of the invention provides for the pharmaceutical composition of deferasirox wherein the in vitro dissolution release profile matches with the commercially available EXJADETM

The compositions according of the invention can be used for the treatment of chronic iron overload due to blood transfusions.

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.

Example 1

A. Composition:

B. Brief Manufacturing Process:

1. Deferasirox, lactose monohydrate, crospovidone and colloidal silicon dioxide were passed through suitable mesh.

2. Sodium lauryl sulphate was dissolved in purified water, followed by addition of povidone with stirring to get the binder solution.

3. Material of step no. 1 was granulated using the solution of step no. 2 to get granules.

4. Granules of step no. 3 were dried in drier.

5. Dried granules of step no. 4 were sized using suitable mesh.

6. Microcrystalline cellulose was passed through suitable mesh and blended with sized granules of step no. 5.

7. Magnesium stearate was sifted through suitable mesh.

8. Material of step no. 6 and step no. 7 was blended together.

9. Blend of step no. 8 was compressed using suitable tooling.

Disintegration time: 60 Seconds

Example 2

B. Brief Manufacturing Process:

1. Sift, Deferasirox, lactose monohydrate and colloidal silicon dioxide, through suitable mesh.

2. Sodium lauryl sulphate is dissolved in purified water, followed by addition of povidone and sodium starch glycolate, to get the binder solution.

3. Granulate the material of step no. 1 using the binder solution of step no. 2.

4. Dry the material of step no. 3 in drier.

5. Material of step no. 4 is passed through suitable mesh.

6. Microcrystalline cellulose is sifted through suitable mesh and mixed with material of step no. 5.

7. Magnesium stearate is sifted through suitable mesh.

8. Blend the material of step no. 6 and step no. 7.

9. Compress the blend of step no. 8 using suitable tooling.

Disintegration time: 60 Seconds

Example 3

B. Brief Manufacturing Process:

1. Deferasirox and crospovidone passed through suitable mesh.

2. Sodium lauryl sulphate was dissolved in purified water, followed by addition of povidone with stirring to get the binder solution.

3. Material of step no. 1 was granulated using the solution of step no. 2.

4. Granules of step no. 3 were dried in drier.

5. Dried granules of step no. 4 were sized using suitable mesh.

6. Microcrystalline cellulose was passed through suitable mesh and blended with sized granules of step no. 5.

7. Magnesium stearate was sifted through suitable mesh.

8. Material of step no. 6 and step no. 7 was blended together.

9. Blend of step no. 8 was compressed using suitable tooling,

Disintegration time: 100 seconds

Example 4

B. Brief Manufacturing Process:

1. Sift, Deferasirox, lactose monohydrate, crospovidone and colloidal silicon dioxide, through suitable mesh.

2. Sodium lauryl sulphate is dissolved in purified water, followed by addition of povidone with stirring to get a binder solution.

3. Granulate the material of step no. 1 using the solution of step no 2.

4. Dry the material of step no. 3 in drier.

5. Material of step no. 4 is passed through suitable mesh.

6. Microcrystalline cellulose is sifted through suitable mesh and mixed with material of step no, 5.

7. Magnesium stearate is sifted through suitable mesh.

8. Blend the material of step no. 6 and step no. 7.

9. Compress the blend of step no. 8 using suitable tooling.

Disintegration time: 100 seconds

Example 5

B. Brief Manufacturing Process:

1. Deferasirox, crospovidone (part 1), colloidal silicon dioxide (part 1), and sodium lauryl sulphate are mixed and passed through suitable mesh.

2. Material of step no. 1 was dry granulated to yield the granules.

3. Crospovidone (part 2), and colloidal silicon dioxide (part 2) was sifted through suitable mesh.

4. Blend the material of step no. 2 and step no. 3.

5. Magnesium stearate was sifted through suitable mesh.

6. Material of step no. 4 and step no. 5 was blended together.

7. Compress the blend of step no. 6 using suitable tooling.

Disintegration time: 30 seconds

Example 6

B. Brief Manufacturing Process:

1. Sift, Deferasirox, lactose monohydrate, crospovidone and colloidal silicon dioxide, through suitable mesh.

2. Sodium lauryl sulphate is dissolved in purified water, followed by addition of povidone with stirring to get a binder solution.

3. Granulate the material of step no. 1 using the solution of step no 2.

4. Dry the material of step no. 3 in drier.

5. Material of step no. 4 is passed through suitable mesh.

6. Microcrystalline cellulose, crospovidone and colloidal silicon dioxide is sifted through suitable mesh and mixed with material of step no. 5.

7. Magnesium stearate/sodium lauryl sulfate (Stear-o-wet™) is sifted through suitable mesh.

8. Blend the material of step no. 6 and step no. 7.

9. Compress the blend of step no. 8 using suitable tooling.

Dissolution Study

The above exemplified compositions comprising deferasirox were tested in vitro for drug release and was compared with the commercially available EXJADE™.

Medium: pH 6.8 phosphate buffer with 0.5% w/v Tween™ 20.

Apparatus: USP type II (Paddle).

Volume: 900 mL.

Rotation Speed: 50rpm.

WE CLAIM

1. An oral pharmaceutical composition comprising deferasirox or pharmaceutically acceptable salts thereof, wherein deferasirox is present in an amount at least 66% by weight based on total weight of said composition.

2. An oral pharmaceutical composition comprising deferasirox or pharmaceutically acceptable salts thereof, wherein the mean particle size of deferasirox is less than about 100µm.

3. The oral pharmaceutical composition according to claim 2, wherein deferasirox has a mean particle size in the range of 0.1 -50µm.

4. The oral pharmaceutical composition according to claim 2, wherein deferasirox has a mean particle size in the range of l-25µm.

5. An oral pharmaceutical composition in the form of a dispersible tablet comprising deferasirox or pharmaceutically acceptable salts thereof, wherein said deferasirox has a mean particle size less than about l00µm and is present in an amount at least 66% by weight based on total weight of said tablet.

6. The oral pharmaceutical composition according to claim I, wherein deferasirox is present in said composition in the range of 66%-86% by weight based on total weight of the composition.

7. An oral pharmaceutical composition in the form of a dispersible tablet comprising deferasirox or pharmaceutically acceptable salts thereof, wherein the pharmaceutically acceptable excipients comprise:

(i) at least one filler/diluent in an amount less than about 20% by weight based on total weight of said tablet;

(ii) at least one disintegrant in an amount of about 10% to 20% by weight based on total weight of said tablet;

(iii) at least one binder in an amount of about 0.5% to 4.5% by weight based on total weight of said tablet;

(iv) at least one surfactant in an amount of about 0.5% to 5% by weight based on total weight of said tablet;

(v) at least one glidant in an amount of about 3% to 15% by weight based on total weight of said tablet; and/or

(vi) at least one lubricant in an amount of about 0.5%-1.5% by weight based on total weight of said tablet.

8. The oral pharmaceutical composition according to claim 7, wherein said filler/diluent is selected from a group comprising lactose, microcrystalline cellulose, dicalcium phosphate, sugar alcohols, dextrates, dextrin, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, starch, pregelatinized starch or a combination thereof.

9. The oral pharmaceutical composition according to claim 7, wherein said disintegrant is selected from a group comprising crospovidone, sodium starch glycolate, maize starch, salts of carboxy methyl cellulose, alginic acid, sodium alginate, guar gum, low-substituted hydroxypropyl cellulose or a combination thereof

10. The oral pharmaceutical composition according to claim 7, wherein said binder is selected from the group comprising starches, hydroxypropyl cellulose, hydroxyethyl cellulose, hypromellose, polyvinylpyrrolidone, gums, gelatin or a combination thereof

11. The oral pharmaceutical composition according to claim 7, wherein said surfactant is selected from the group comprising sodium lauryl sulfate,
quaternary ammonium salts, polysorbates, sorbitan esters, poloxamer, betaines, cetyl alcohol, oleyl alcohol or a combination thereof.

12. The oral pharmaceutical composition according to claim 7, wherein said glidant and lubricant is selected from a group comprising silica, colloidal silica, magnesium stearate, calcium stearate, magnesium trisilicate, talc, sodium stearyl fumarate, glyceryl behenate, hydrogenated castor oil or a combination thereof.

13. A process for the preparation of oral pharmaceutical composition in the form of a dispersible tablet, comprising deferasirox or its pharmaceutically acceptable salts thereof, wherein said process comprises:

(i) wet-granulating deferasirox or its pharmaceutically acceptable salts and at least one intra-granular excipient with a binder solution to form granules;

(ii) drying and optionally milling said granules;

(iii) mixing said granules with at least one extra-granular excipients to form a blend;

(iv) lubricating said blend with at least one lubricant to form the final blend;

(v) compressing said final blend to form a tablet.

14. The oral pharmaceutical composition according to claim 5, wherein the disintegration time of said tablet is of 5 minutes or less.

15. The oral pharmaceutical composition according to any of the preceding claims, for use in the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older.