WO2023111187A1

WO2023111187A1 - Pharmaceutical compositions comprising eltrombopag

Info

Publication number: WO2023111187A1
Application number: PCT/EP2022/086171
Authority: WO
Inventors: Javier TORREJÓN NIETO; Luis GÓMEZ COELLO
Original assignee: Galenicum Health, S.L.U
Priority date: 2021-12-15
Filing date: 2022-12-15
Publication date: 2023-06-22

Abstract

The present invention relates to a pharmaceutical composition comprising eltrombopag or any acceptable pharmaceutical salt thereof and a non-reducing disaccharide as diluent. Manufacturing processes of such formulations are also described.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING ELTROMBOPAG

FIELD

STATE OF THE ART

Eltrombopag olamine, 3’-(N’-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1 ,5-dihydropyrazol -4-ylidene]hydrazino}-2’-hydroxy-biphenyl- 3-carboxylic acid - 2-aminoethanol is a nonpeptide haematopoietic receptor agonist, which mimics haematopoietic growth factors, including thrombopoietin (TPO), particularly enhancing platelet production and, thus, is particularly useful in the treatment of thrombocytopenia (see e.g. WO 03/098992 A2 and WO 2008/136843 A1). The process for the synthesis of eltrombopag acid is described in WO 01/89457 A2.

In Europe, eltrombopag olamine is approved under the tradename Revolade®. Revolade® is in tablet form and comprises eltrombopag olamine in an amount corresponding to 12.5 mg, 25 mg, 50 mg, and 75 mg of eltrombopag free acid. The tablet composition of the different strength is not dose proportional.

By and large, eltrombopag olamine undergoes a Maillard reaction with respective pharmaceutically acceptable excipients, such as reducing sugars, e.g. lactose, maltose, glucose, arabinose and fructose. In this reaction, eltrombopag olamine is degraded and forms impurities, which can be measured in the pharmaceutical tablet composition. In order to avoid unacceptable degradation of eltrombopag olamine, WO 2008/136843 A1 teaches to use diluents substantially free of reducing sugars and coordinating metals. In particular, mannitol is used as an excellent diluent. It is known that mannitol is a widely used pharmaceutical diluent where its particular value lies in the fact that it is not hygroscopic and may be used with moisture-sensitive active ingredients such as eltrombopag. Further, granulations containing mannitol have the advantage of being easily dried (Handbook of pharmaceutical excipients, 2016, 8th ed by Pharmaceutical Press, Sheskey).

It would be desirable to have a tablet composition comprising eltrombopag that exhibits excellent stability and be suitable for production on a commercial scale. The composition should also exhibit adequate dissolution and disintegration resulting in a good bioavailability. Furthermore, it would be advantageous if the different tablet strengths can be formulated in a dose proportional manner to require just one single blend.

The above issues have been addressed in the present invention and specific embodiments thereof.

SUMMARY OF THE INVENTION

The first aspect of the present invention is a pharmaceutical composition comprising eltrombopag or any acceptable pharmaceutical salt thereof, and a nonreducing disaccharide as a diluent.

A second aspect of the present invention deals with a process for the preparation of the said pharmaceutical composition.

A third aspect of the present invention provides said pharmaceutical composition for use as a medicament, preferably for use in thrombocytopenia.

DESCRIPTION OF THE INVENTION

It is the object of the present invention to obtain eltrombopag pharmaceutical compositions having good technological properties (flowability, compaction, hardness, disintegration, dissolution, stability and uniformity of content) with good stability, good solubility, good dissolution profiles and resulting in good bioavailability of the pharmaceutical composition. Good dissolution according to the invention is understood as achieving at least a 90% dissolution rate after 60 minutes, since it has been observed that when at least 90% is dissolved after 60 minutes, eltrombopag plasma levels are adequate to achieve a therapeutic effect. Good stability according to the invention is understood so that the physical-chemical characteristics of the product remain stable throughout time.

The inventors have found that using one or more non-reducing disaccharides as diluents, optionally in combination with other diluents, allows the obtaining of such pharmaceutical compositions which can be manufactured on a commercial scale with desirable pharmacokinetic profile and stability. In addition, the different strengths are dose proportional. The inventors have also found out that when non-reducing disaccharides such as trehalose are used in combination with other diluents such as lactose, the dissolution rates of the resulting compositions are improved.

Definitions

As used in the present disclosure, the following words, phrases, and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

All percentages are expressed by weight (w/w) unless specifically noted otherwise.

Disclosed compositions of the present invention may comprise eltrombopag free base or any acceptable pharmaceutically salts and can include further active ingredients in the same or in a separate composition. Preferably the active ingredient refers to eltrombopag olamine (bis-monoethanolamine) salt.

Eltrombopag or pharmaceutically acceptable salts thereof can be in a crystalline or non-crystalline solid form.

The term "diluent" as used herein refers to pharmaceutically acceptable excipients which are added to the bulk volume of the active ingredient making up the solid composition. As a result, the size of the solid composition increases, which makes its size suitable for handling. In the present invention, the terms “diluent” and “filler” are considered equivalent. As used herein, "disintegrant" means a substance or a mixture of substances added to a tablet to facilitate its breakup or disintegration after administration.

As used herein, "lubricant" means a substance that reduces friction between the composition of the present invention and the surfaces of the apparatus used to compact the composition into a compressed form.

As used herein, "binder" means a substance that imparts cohesive properties to a formulation. Binders ensure that tablets, powders, granules and others can be formed by the required mechanical strength

FIRST ASPECT

In a first aspect, the present invention relates to a pharmaceutical composition comprising eltrombopag or any acceptable pharmaceutical salt thereof, and a nonreducing disaccharide as diluent. Preferably, the non-reducing disaccharide is selected from sucrose or trehalose or mixtures thereof. More preferably, the diluent is selected from trehalose.

The pharmaceutical composition of the present invention can further include other diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sorbitol, compressible sugar, microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, fructose, kaolin, mannitol, lactitol, maltose, isomaltose, xylitol, inositol, starch, calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, sodium alginate, magnesium carbonate, magnesium oxide, poloxamers, polyethylene oxide, hydroxypropyl methyl cellulose and mixtures thereof. Different types of microcrystalline cellulose may be suitable for use in the formulations described herein. Examples of microcrystalline cellulose include Avicel® types: PH101 , PH102, PH103, PH105, PH 112, PH113, PH200, PH301 , and other types of microcrystalline cellulose, such as silicified microcrystalline cellulose (SMCC). Preferably, the other diluents are selected from calcium phosphate dibasic, calcium phosphate tribasic, microcrystalline cellulose, lactose, lactose monohydrate, anhydrous lactose, mannitol, sorbitol, magnesium carbonate, maltose, isomaltose, xylitol, starch and mixtures thereof. More preferably, the other diluents are selected from microcrystalline cellulose, lactose, lactose monohydrate, anhydrous lactose, mannitol, sorbitol, xylitol, magnesium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, or mixtures thereof. Even more preferably the other diluents are selected from lactose, lactose monohydrate, anhydrous lactose, calcium phosphate, microcrystalline cellulose or mixtures thereof.

Diluents are frequently used in an amount ranging from 15 wt% to 75 wt% weight of the formulation.

In a preferred embodiment of the first aspect of the present invention, the pharmaceutical composition comprises eltrombopag, trehalose and lactose. In a further preferred embodiment, the composition further comprises calcium phosphate. In an even further preferred embodiment, the pharmaceutical composition comprises: eltrombopag olamine, trehalose and lactose.

In a preferred embodiment of the first aspect of the invention, the lactose content with respect to the total weight of the tablet is at least 1 %. In a preferred embodiment of the first aspect of the present invention, the said pharmaceutical composition further comprises at least one disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium croscarmellose, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, starch and sodium alginate. Preferably, the at least one disintegrant is selected from croscarmellose, sodium croscarmellose, crospovidone, low-substituted hydroxypropyl cellulose, starch, sodium starch glycolate, carmellose and mixtures thereof. More preferably, the disintegrant is selected from sodium starch glycolate, sodium croscarmellose or mixtures thereof.

Disintegrants are frequently used in an amount ranging from 1 wt% to 25 wt% by weight of the formulation, preferably from 5 wt% to 20 wt%.

In a preferred embodiment, the pharmaceutical composition comprises at least one lubricant. Examples of lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, mixtures of magnesium stearate with sodium lauryl sulfate, talc, stearic acid, waxes, glycerides, light mineral oil, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycols, alkyl sulfates, or sodium benzoate and mixtures thereof . Preferably, the at least one lubricant is selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, talc, stearic acid and sodium stearyl fumarate. More preferably, the lubricant is selected from magnesium stearate.

Lubricants are frequently used from 0.25 wt% to 10 wt% by weight of the formulation.

In a preferred embodiment, the pharmaceutical composition optionally comprises at least one binder. Examples of binders suitable for use in the present invention include: cellulose derivatives (such as carboxymethyl cellulose and salts thereof, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and ethyl cellulose), polyvinylpyrrolidone, povidone, polyethylene glycol, waxes, water, alcohol, magnesium aluminum silicate, and bentonites or mixtures thereof.

Binders are frequently used from 0 wt% to 15 wt% by weight of the formulation.

In another preferred embodiment, the pharmaceutical composition of the invention is free from a binder.

In another preferred embodiment of the first aspect of the invention, eltrombopag or any pharmaceutical acceptable salts thereof is micronized. In a preferred embodiment, eltrombopag or any pharmaceutical acceptable salts thereof has a particle size volume distribution with a D90 less than 200 pm, preferably less than 150 pm, more preferably from less than 100 pm. The particle size volume distribution is analysed by laser diffraction spectroscopy using a Malvern Mastersizer 3000 particle size analyzer.

In another embodiment of the present invention, the pharmaceutical composition is a tablet or a capsule, preferably a tablet.

In a preferred embodiment, the tablet composition is film coated with a coating agent, preferably comprising one or more pharmaceutically acceptable polymers, optionally one or more pharmaceutically acceptable plasticizers, and optionally one or more pharmaceutically acceptable pigments.

The one or more polymer agents of the pharmaceutically acceptable coating agent are preferably selected from one or more of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyethylene glycol, polyethylene glycol-polyvinyl alcohol graftpolymer, and polysorbate. The one or more pigments are preferably selected from the group of titanium dioxide, aluminum lakes, and iron oxides

Such coating agents may optionally further comprise one or more additional adjuvants such as a detackifier, flow aid, surfactant, and secondary film-forming polymer. Examples of optional detackifiers include lecithin, stearic acid, mineral oil, modified derivatized starch, tapioca dextrin, and polyethylene glycol. Examples of optional secondary film-forming polymers include sodium alginate, propylene glycol alginate, and polyvinylpyrrolidone. Examples of optional surfactants include dioctyl sodium sulfosuccinate and polysorbate 80. Examples of optional flow aids include talc, fumed silica, bentonite, hydrogenated vegetable oils, stearines, and waxes.

More preferably, the coating agent comprises is selected from hypromellose, macrogol 400, polysorbate 80 and titanium dioxide (commercially available as Opadry® White), or hypromellose, macrogol 400, titanium dioxide, iron oxide yellow and iron oxide red (commercially available as Opadry® Brown), or hypromellose, macrogol 400, titanium dioxide, iron oxide red and iron oxide black (commercially available as Opadry® Brown).

Each of the embodiments of the present invention described herein may be combined with one or more other embodiments of the present invention described herein that are not inconsistent with the embodiment(s) with which it is combined.

SECOND ASPECT

In a second aspect, the present invention relates to a process for the manufacture of a pharmaceutical composition of the first aspect.

Pharmaceutical compositions of the present invention may be manufactured in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing the active compounds into preparations which can be used pharmaceutically. Such conventional manufacturing techniques are, for instance, mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

One conventional manufacturing techniques for the preparation of the formulation of the present invention is compression. Another conventional manufacturing techniques for the preparation of the formulation of the present invention is granulation.

The term "granulation" includes dry and wet granulation techniques. The term "wet granulation" refers to any process comprising the steps of addition of a liquid to the powder starting materials, preferably kneading, and drying to yield a solid dosage form. The term "dry granulation" refers to any process that comprises compacting the powder, usually either by slugging or with a roller compactor, and preferably milling the compacted powder to obtain the granules. No liquid is employed for the dry granulation.

Once the granules are obtained, they can be compressed, optionally with other pharmaceutical excipients such as lubricants, into tablets. Alternatively, the granules can be filled into capsules.

In an embodiment of the second aspect, the present invention relates to a process for the manufacture of a pharmaceutical composition comprising eltrombopag or any acceptable pharmaceutical salt thereof and a non-reducing disaccharide as diluent, comprising the following steps:

(i) weighing, sieving and mixing eltrombopag with a non-reducing diluent and, optionally, other pharmaceutically acceptable excipients, and

(ii) compressing the mixture obtained in step (i) to form a tablet

(iii) optionally, coating the resulting tablet of step (ii).

In another embodiment, the present invention relates to a process for the manufacture of a pharmaceutical composition comprising eltrombopag or any acceptable pharmaceutical salt thereof and a non-reducing disaccharide as diluent, comprising the following steps:

(i) weighing, sieving and mixing eltrombopag with a non-reducing diluent and optionally other pharmaceutically acceptable excipients, and

(ii) optionally, granulating the mixture obtained in step (i)

(iii) encapsulating the mixture obtained in step (i) or the granules obtained in step (ii)

In another embodiment, the present invention relates to a process for the manufacture of a pharmaceutical composition comprising eltrombopag or any acceptable pharmaceutical salt thereof and a mixture of a non-reducing disaccharide and lactose as diluents, comprising the following steps:

(i) weighing, sieving and mixing eltrombopag with a non-reducing diluent, lactose and optionally other pharmaceutically acceptable excipients, and

(ii) optionally, granulating the mixture obtained in step (i)

(iii) encapsulating the mixture obtained in step (i) or the granules obtained in step

(ii)

(ii) optionally, granulating the mixture obtained in step (i)

(ii) optionally, compacting the mixture obtained in step (i),

(iii) granulating the mixture obtained in step (i) or the compacted mixture obtained in step (ii),

(iv) optionally, mixing the granules obtained in step (iii) with at least one pharmaceutically acceptable excipient, and

(v) compressing the granules obtained in step (iii) or the mixture obtained in step

(iv) to form a tablet

(vi) optionally coating the resulting tablet of step (v)

In another embodiment, the present invention relates to a process for the manufacture of a pharmaceutical composition comprising eltrombopag or any acceptable pharmaceutical salt thereof, and a mixture of lactose and a non-reducing disaccharide as diluents, comprising the following steps:

(i) weighing, sieving and mixing eltrombopag with lactose, a non-reducing diluent and optionally other pharmaceutically acceptable excipients, and

(ii) optionally, compacting the mixture obtained in step (i),

(iv) to form a tablet

(vi) optionally coating the resulting tablet of step (v)

(ii) optionally, compacting the mixture obtained in step (i),

(iv) mixing the granules obtained in step (iii) with lactose and at least one pharmaceutically acceptable excipient, and

(v) compressing the granules obtained in step (iii) or the mixture obtained in step (iv) to form a tablet

(vi) optionally coating the resulting tablet of step (v)

(i) weighing, sieving and mixing eltrombopag with trehalose and optionally other pharmaceutically acceptable excipients, and

(ii) granulating the mixture obtained in step (i) (iii) optionally, mixing the granules obtained in step (iii) with at least one pharmaceutically acceptable excipient, and

(iv) compressing the granules obtained in step (ii) or the mixture obtained in step (iii) to form a tablet

(v) optionally coating the resulting tablet of step (iv)

IN A THIRD ASPECT

In a third aspect, the present invention relates to the use of the pharmaceutical composition of the first aspect as a medicament. Preferably, for use in treating thrombocytopenia, for use in enhancing platelet production, for use in treating adult chronic immune (idiopathic) thrombocytopenic purpura (ITP) splenectomised patients who are refractory to other treatments (e.g. corticosteroids, immunoglobulins), for use in adult non-splenectomised patients where surgery is contraindicated, for use in adult patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy and for use in patients with acquired severe aplastic anaemia (SAA) who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for haematopoietic stem cell transplantation.

Each of the aspects and embodiments of the present invention described herein may be combined with one or more aspects and embodiments of the present invention.

EXAMPLES

The examples, which are incorporated and form part of the specification, merely illustrate certain embodiments of the present invention and should not be construed as limiting the invention. They are meant to serve to explain specific modes of the present invention to those skilled in the art

All examples of the invention have been carried out by using a particle size volume distribution D90 of 15 microns and a particle size volume distribution D90 of 60 microns. The different tested particle sizes did not impact the stability or the dissolution profile results. Example 1

Wet granulated tablets comprising eltrombopag olamine and the ingredients in Table 1 were prepared.

Table 1

As a general procedure, the ingredients trehalose, microcrystalline cellulose and povidone were blended with eltrombopag olamine and then wet-granulated (in a high- shear wet-granulator) with purified water. The wet-granule mass was wet-milled, then dried in a fluid-bed dryer and the dried granules were milled. Then extragranular ingredients (microcrystalline cellulose and sodium starch glycolate) were separately weighed, screened and blended with the granules. Magnesium stearate was added and blended with the mixture. The blend was compressed.

This composition showed good stability and dissolution rate.

Example 2 Wet granulated tablets comprising eltrombopag olamine and the ingredients in

Table 2 were prepared.

Table 2

As a general procedure, the ingredients sodium croscarmellose, trehalose and anhydrous lactose were blended with eltrombopag olamine and then wet-granulated (in a high-shear wet-granulator) with purified water. The wet-granule mass was wet-milled, then dried in a fluid-bed dryer and the dried granules were milled.

Then extragranular ingredients (anhydrous lactose, calcium phosphate, microcrystalline cellulose and sodium starch glycolate) were separately weighed, screened and blended with the granules. Magnesium stearate was added and blended with the mixture. The blend was compressed.

This composition showed good stability and dissolution rate.

Example 3 Wet granulated tablets comprising eltrombopag olamine and the ingredients in

Table 3 were prepared.

Table 3

Then extragranular ingredients (anhydrous lactose, microcrystalline cellulose and sodium starch glycolate) were separately weighed, screened and blended with the granules. Magnesium stearate was added and blended with the mixture. The blend was compressed.

This composition showed good stability and dissolution rate.

Example 4

Wet granulated tablets comprising eltrombopag olamine and the ingredients in Table 4 were prepared.

Table 4

As a general procedure, the ingredients sodium croscarmellose, mannitol and microcrystalline cellulose were blended with eltrombopag olamine and then wet- granulated (in a high-shear wet-granulator) with purified water. The wet-granule mass was wet-milled, then dried in a fluid-bed dryer and the dried granules were milled.

Then extragranular ingredients (microcrystalline cellulose and sodium starch glycolate) were separately weighed, screened and blended with the granules. Magnesium stearate was added and blended with the mixture. The blend was compressed.

Example 5 - Comparative example

Figure 1 shows dissolution profiles of compositions from Example 3 and Example

4 which have been carried out at pH 6.8 (phosphate buffer) using a USP Type II apparatus, 50 rpm, 37°C in a 900 mL medium. Assay analyzed by HPLC.

Composition from Example 3, comprising trehalose and lactose, shows a faster dissolution profile at 5, 10 and 15 minutes, which is therapeutically beneficial for the patients under treatment.

Example 6 - Comparative example

Compositions from Example 3 and 4 were manufactured and placed under temperature stress conditions at 50°C for 15 and 30 days.

SUBSTITUTE SHEET (RULE 26) Figure 2 shows dissolution profiles of compositions from Example 3 and Example 4 which have been carried out at pH 6.8 (phosphate buffer) using a USP Type II apparatus, 50 rpm, 37°C in a 900 mL medium. Assay analyzed by HPLC.

Composition from Example 3 shows a greater stability under temperature stress conditions. After 15 and 30 days, the dissolution rate at 15 minutes remains at approximately 80%, whereas example 4 composition drops to approximately 60% after 15 days and approximately 50% after 30 days.

Example 7 - Comparative example

Composition from Example 1 was manufactured and placed under temperature stress conditions at 50°C for 15 and 30 days.

Figure 3 shows dissolution profiles of composition from Example 1 which have been carried out at pH 6.8 (phosphate buffer) using a USP Type II apparatus, 50 rpm, 37°C in a 900 mL medium. Assay analyzed by HPLC.

As can be seen, the dissolution rate remains the same after temperature stress conditions. This shows an improvement in stability over composition from Example 4 (comprising mannitol) placed under stress conditions and analyzed in Example 6.

Impurities were analysed by HPLC. The area corresponding to the eltrombopag olamine and of the major peaks, if any, was determined. The percentage of impurities was calculated by comparing the areas of the measured peaks with those obtained from the standard.

SUBSTITUTE SHEET (RULE 26)

Claims

1. A pharmaceutical composition comprising eltrombopag or any acceptable pharmaceutical salt thereof and a non-reducing disaccharide as diluent.

2. The pharmaceutical composition according to claim 1 wherein the nonreducing disaccharide is trehalose or sucrose or mixtures thereof.

3. The pharmaceutical composition according to claim 2 wherein the nonreducing disaccharide is trehalose.

4. The pharmaceutical composition according to any of the preceding claims further comprising at least one disintegrant.

5. The pharmaceutical composition according to claim 4 wherein the at least one disintegrant is selected from croscarmellose, sodium croscarmellose, crospovidone, low- substituted hydroxypropyl cellulose, starch, sodium starch glycolate, carmellose and mixtures thereof.

6. The pharmaceutical composition according to any of the preceding claims further comprising at least one lubricant.

7. The pharmaceutical composition according to claim 6 wherein the at least one lubricant is selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, talc, stearic acid and sodium stearyl fumarate.

8. The pharmaceutical composition according to any of the preceding claims wherein Eltrombopag or any acceptable pharmaceutical salt thereof has a particle size volume distribution D90 of less than 200 microns.

9. The pharmaceutical composition according to claim 8 wherein Eltrombopag or any acceptable pharmaceutical salt thereof has a particle size volume distribution D90 of less than 100 microns.

10. The pharmaceutical composition according to any of the preceding claims, further comprising lactose, more preferably anhydrous lactose.

11. The pharmaceutical composition according to the preceding claim, wherein the amount of lactose is at least 1%.

12. The pharmaceutical composition according to any of the preceding claims manufactured by wet granulation wherein the binder consists of water.

13. The pharmaceutical composition according to any of the preceding claims which is in the form of a capsule or a tablet.

14. The pharmaceutical composition according to the preceding claim which is in the form of a tablet.

15. A process for the manufacture of a pharmaceutical composition according to any of the preceding claims comprising the steps of:

(ii) compressing the mixture obtained in step (i) to form a tablet

(iii) optionally, coating the resulting tablet of step (ii).

16. A process for the manufacture of a pharmaceutical composition according to any of the claims 1 to 14 comprising the steps of:

(i) weighing, sieving and mixing eltrombopag with trehalose and, optionally, other pharmaceutically acceptable excipients, and

(ii) compressing the mixture obtained in step (i) to form a tablet

(iii) optionally, coating the resulting tablet of step (ii).

17. A process for the manufacture of a pharmaceutical composition according to any of the claims 1 to 14 comprising the steps of:

(i) weighing, sieving and mixing eltrombopag with trehalose, lactose and, optionally, other pharmaceutically acceptable excipients, and

(ii) compressing the mixture obtained in step (i) to form a tablet

(iii) optionally, coating the resulting tablet of step (ii).

18. A process for the manufacture of a pharmaceutical composition according to any of the claims 1 to 14 comprising the steps of:

(ii) optionally, compacting the mix obtained in step (i),

(vi) optionally coating the resulting tablet of step (v).

19. A process according to the preceding claim wherein a binder is used in step iii.

20. A process according to the preceding claim wherein the binder consists of water.

21. The pharmaceutical composition according to any of the claims 1 to 14 for use as a medicament.

22. The pharmaceutical composition according to any of the claims 1 to 14 for use in the treatment of immune thrombocytopenia (ITP), thrombocytopenia in patients with chronic hepatitis C virus (HCV) and/or severe aplastic anaemia (SAA).