WO2022201087A1

WO2022201087A1 - 3'-[(2z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4h-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid and its salts formulation

Info

Publication number: WO2022201087A1
Application number: PCT/IB2022/052704
Authority: WO
Inventors: Mangesh Sadashiv BORDAWEKAR; Kanhaiyalal PATIDAR; Parthkumar PATEL; Alan Edward Royce; Daya D. Verma; Chandrakant VELIP; Shaikh Mohsin Shaikh Hamid
Original assignee: Novartis Ag
Priority date: 2021-03-25
Filing date: 2022-03-24
Publication date: 2022-09-29

Abstract

The present invention relates to an oral pharmaceutical formulation, suitably tablets, suitably capsules, comprising 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (INN name eltrombopag) or a pharmaceutically acceptable salt thereof, wherein the oral pharmaceutical formulation is coated with an enteric coating.

Description

3'-[(2Z)-[l-(3,4-dimethylphenyl)-l,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4- ylidene]hydrazino]-2'-hydroxy-[l,l'-biphenyl]-3-carboxylic acid and its salts formulation

Mi l l) OF nil INVENTION

The present invention relates to an oral pharmaceutical formulation, suitably tablets, suitably capsules, comprising 3'-[(2Z)-[l-(3,4-dimethylphenyl)-l,5-dihydro- 3 -methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[ 1 , 1 '-biphenyl]-3 - carboxylic acid (INN name eltrombopag) or a pharmaceutically acceptable salt thereof, wherein the oral pharmaceutical formulation is coated with an enteric coating. Suitably eltrombopag is in the form of bis-(monoethanolamine) salt (interchangeably referred as “eltrombopag olamine”).

BACKGROUND OF THU INVENTION

3'-{N'-[l-(3,4-dimethylphenyl)-3-methyl-5-oxo-l,5-dihydropyrazol-4- ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid (hereinafter Compound A) is a compound which is disclosed, along with pharmaceutically acceptable salts, hydrates, solvates and esters thereof, as being useful as an agonist of the TPO receptor, particularly in enhancing platelet production and particularly in the treatment of thrombocytopenia, in WO 01/89457, the disclosure of which is hereby incorporated by reference.

Compound eltrombopag bis-(monoethanolamine) is disclosed in WO 03/098002; the disclosure of which is hereby incorporated by reference.

Eltrombopag (US brand Promacta, EU brand Revolade) is currently marketed globally for chronic immune (idiopathic) thrombocytopenia (ITP) and severe aplastic anemia. Both the US and the EU current drug labels contain instructions on avoidance of taking the drug together with food, or closely before or after meal, especially calcium-rich food, for example dairy products. For example on the US label it states “Take PROMACTA on an empty stomach (1 hour before or 2 hours after a meal). Take PROMACTA at least 2 hours before or 4 hours after other medications (e.g., antacids), calcium-rich foods. Similarly on the EMA approved Revolade it states “The tablets should be taken at least two hours before or four hours after any products such as antacids, dairy products (or other calcium containing food products), or mineral supplements containing polyvalent cations (e.g. iron, calcium, magnesium, aluminium, selenium and zinc)”

As reported in Promacta drug label, an open-label, randomized- Sequence, crossover trial was conducted to assess the effect of food on the bioavailability of eltrombopag. A standard high-fat breakfast significantly decreased plasma eltrombopag AUC0-co by approximately 59% and Cmax by 65% and delayed Tmax by 1 hour. The calcium content of this meal may have also contributed to this decrease in exposure. In a second trial, administration of a single 25-mg dose of eltrombopag for oral suspension to adults with a high-calcium, moderate-fat, moderate-calorie meal reduced plasma eltrombopag AUC0-co by 75% (90% Cl:

71%, 88%) and Cmax by 79% (90% Cl: 76%, 82%). Administration of a single 25- mg dose of eltrombopag for oral suspension 2 hours after the high-calcium meal reduced plasma eltrombopag AUC0-co by 47% (90% Cl: 40%, 53%) and Cmax by 48% (90% Cl: 40%, 54%). Administration of a single 25-mg dose of eltrombopag for oral suspension 2 hours before the high-calcium meal reduced plasma eltrombopag AUC0-co by 20% (90% Cl: 9%, 29%) and Cmax by 14% (90% Cl: 2%, 25%).

This is because eltrombopag chelates with polyvalent metals, especially with calcium, and forms insoluble complex. As a result eltrombopag formulation has greatly reduced dissolution rate in the presence of calcium (example 8, WO/2008/136843). Hence eltrombopag has reduced bioavailability in the presence of food, especially calcium-rich food (negative food effect).

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1: 2-stage dissolution test of enteric coated capsule formulation (EXAMPLE 1) as described in EXAMPLE 4.

FIG. 22-stage dissolution test of enteric coated Promacta tablet (EXAMPLE 2) as described in EXAMPLE 5. FIG. 3 Dog PK study on food effect with Promacta, enteric coated Promacta and enteric coated capsule under fasted and fed conditions (FIG. 3 A AUC, FIG. 3B Cmax).

DESCRIPTION OF THE INVENTION

Surprisingly we have found that enteric coated pharmaceutical formulations overcome calcium-rich food induced food effect. Without wishing to be bound by the theory, we speculate that the enteric coating, by preventing the drug from released in stomach, where the calcium or other polyvalent metals concentration is high, postpones the drug dissolution and absorption to small intestine, where the polyvalent metals concentration drops. Consequently the enteric coated pharmaceutical formulations mitigate food effect caused mainly by calcium or other polyvalent metals contained in food.

Thus the present invention relates to an oral pharmaceutical composition comprising 3'-[(2Z)-[l-(3,4-dimethylphenyl)-l,5-dihydro-3-methyl-5-oxo-4H- pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[ 1 , 1 '-biphenyl]-3 -carboxylic acid (eltrombopag), or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical formulation is coated with an enteric coating (pharmaceutical composition of the invention).

In one embodiment the pharmaceutically acceptable salt is monoethanolamine salt. In one embodiment the ratio between eltrombopag and monoethanolamine is 1:1. In one embodiment the ratio between eltrombopag and monoethanolamine is 1:2 (bis-(monoethanolamine)).

In one embodiment the pharmaceutical composition of the invention comprises eltrombopag bis-(monoethanolamine). Other pharmaceutically acceptable salts include but not limited to sodium salt, potassium salt, magnesium salt, ammonia salt, choline salt, N-methyl-D- glucamine salt, 4-(2-hydroxyethyl)morpholine salt, triethanolamine salt, L-lysine salt, piperazine salt, ethylenediamine salt, diethanolamine salt, N,N’- dimethylethanolamine salt, N,N’-dibenzylethylenedamine salt, tert-butylamine salt, tris(hydroxymethyl) amino methane (also named as tromethamine) salt, l-(2- hydroxyethyl)pyrrolidine salt and diethylenetriamine salt.

An enteric coating, also known as gastro-resistant coating is a barrier applied to oral medication that controls the location in the digestive tract where it is absorbed. The term “enteric” refers to the small intestine; therefore, enteric coatings resist breakdown of medication before it reaches the small intestine. Typically the enteric coating remains intact in the acid environment, e.g. pH is below 2, e.g. pH is 1-2, or typically pH is 1.2 to 1.8. Typically the drug release is limited to less than 10%, suitably less than 5%, or suitably less than 1% in the acidic environment when the medication is kept in the acidic medium for several hours.

Typically a two-stage dissolution test, as exemplified in EXAMPLE 3, is used to determine the drug release under acidic pH condition (mimicking the stomach acidity) and under close to neutral to neutral pH condition (mimicking the pH condition of the intestine). Typically the drug release in the first step of the two- stage dissolution test is about less than 10%, suitably less than 7%, suitably less than 5%, suitably less than 3%, suitably less than 1%, normally measured up to one hour, 1.5 hour or suitably 2 hours when the enteric coated formulation is kept in the acidic pH medium, e.g. pH=1.2.

The enteric coating should quickly dissolve as soon as the pH rises above a trigger pH value (trigger pH) and thereby expose the core composition of the medication to the surrounding intestinal fluid. In the second step of the two-stage dissolution test, the dissolved drug should start to be measurable a few minutes after medication is immersed in the second pH medium and the amount of dissolved drug should steadily increase with time, e.g. within about 15, 30, 45, 60, 75, 90 min after the medication is put in the 2^nd pH medium. A typical 2-stage dissolution test result of an enteric coated formulation is depicted in the below figure.

Enteric film-coating polymers are essentially polyacids and typically only dissolve in water above pH=5.0-6.0; these polymers are selected for their ability not only to form robust coatings that adhere strongly to tablet surfaces, but also to permit rapid drug release from dosage form once it passes from the stomach into the small intestine. Thus in one embodiment the enteric coating comprises a polymer which is insoluble in an aqueous medium, wherein the aqueous medium has a pH < 2 ± 0.3, suitably pH < 1.5 ± 0.3, suitably pH between 1±0.3 to 1.5±0.3 or suitably pH at 1.2±0.3. Under this acidic condition, the polymer remains essentially intact and does not dissolve. In one embodiment the enteric coating comprises a polymer which is soluble in an aqueous medium has a pH > 5±0.3, > 5.5±0.3; > 6±0.3, > 6.5±0.3, or > 7±0.3, suitably soluble between 5±0.3 to 7±0.3, soluble between 5±0.3 to 6.5±0.3, soluble between 5.5±0.3 to 6.5±0.3, soluble between 5.5±0.3 to 6.0±0.3, soluble at between 5.5±0.3; 5.5±0.2. Alternatively the polymer is soluble between 6.5±0.3 to 7.0±0.3. In one preferred embodiment the polymer is soluble between 5.5±0.3 to

6.0±0.3, soluble at between 5.5±0.3; 5.5±0.2. The aqueous medium can either be a buffered dissolution medium or a bio relevant simulated intestinal fluid, which is to simulate the fasting and fed conditions of small intestine by adding the appropriate bio-relevant surfactants to the corresponding buffer concentrates.

The term “soluble”, as used herein and hereunder, refers to the property of the polymer to become permeable and dissolve in the medium above trigger pH. Typically, the description of a polymer’s solubility is provided by the polymer manufacture, for example, as shown in table 2 below, Eudragit L 100-55 Soluble in intestinal fluid from pH 5.5.

Suitably polymers to be used as enteric coating includes but not limited the following Cellulose acetate phthalate, Cellulose acetate trimellitate, Polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, Hydroxypropylmethylcellulose acetate succinate, Shellac (esters of aleurtic acid) and methacrylic acid copolymers (Eudragit). Furthermore methacrylic acid copolymers (Eudragit) includes but not limited to Poly (MA - EA) 1:1, Poly (MA - MMA) 1:1; and Poly (MA - MMA) 1 :2 and any combination thereof, wherein MA is methacrylic acid, EA is ethyl acrylate and MMA is methyl methacrylate.

Preferred are the Poly(methacrylic acid-co-methyl methacrylate) polymers that have trigger pH 5.0-7.5, suitably 5.5 to 7. These polymers form the basis of enteric coating formulations used in either organic solvent-based or aqueous coating formulations.

In addition to employing a single polymer in the enteric coating, mixtures of polymers in different proportion can yield a polymer mixture which dissolves at varied pH , for example mixing of Eudragit L 100 and Eudragit SI 00 (Reference - Chapter 1 Enteric Targeting Thorough Enteric Coating, Bianca Brogmann and thomas E Beckert. Book - Drug targeting technology:physical chemical biological methods).

A breakdown of coating systems especially designed for aqueous coating applications is shown in Table 1 below.

Table 1

MA, Methacrylic acid; EA, Ethyl acrylate.

Table 2 below provides the product Eudragit series and their important product characterizations, e.g. their pH dependent solubility, which is an important parameter for a skilled artisan to make decision which polymer to choose, depending where it is preferred the drug to be released from the enteric coated medication.

Table 2

In one embodiment, the polymer is poly (MA - EA) 1:1. In a preferred embodiment the enteric polymer is Eudragit L 100-55. In an another preferred embodiment the enteric polymer is Eudragit L 30 D-55 (formerly Eudragit L 30 D).

The enteric coating normally further comprises plasticizer. Plasticizers typically reduce the glass transition temperature and impart flexibility to the polymeric film. At glass transition, the polymer changes from a tough, rigid, inflexible, and brittle material into one that is softer, and more pliable. These latter properties are of great value in film coating, and thus it is beneficial to match the glass transition temperature of the final coating system to the coating conditions that will be used. For most coating systems, it is desirable that the glass transition temperature of that system be optimized for the coating process conditions used. For aqueous polymer dispersions (or latexes), it is desired that such optimization is achieved for appropriate coalescence of the coating. Typical plasticizers used include but are not limited to following classes, polyhydric alcohol (e.g. Propylene glycol, glycerol, polyethylene glycol), Acetate esters (e.g. glyceryl triacetate, triethyl citrate (TEC), acetyl triethyl citrate), phthalate esters (e.g. diethyl phthlate), glycerides (e.g. acetylated monoglycerides), oils (e.g. castor oil, mineral oil). In one embodiment the plasticizer is selected from a group consisting of propylene glycol, Polyethylene glycols and Triethyl citrate. In one embodiment the plasticizer is Tri ethyl citrate.

The choice of plasticizer can also be dictated by excipient companies based upon their work on their polymers and selected plasticizers, as exemplified in Table 2

The enteric coating normally further comprises anti-sticky/ Anti-tacking agent. These agents avoid tackiness and agglomeration of the tablets during coating. Anti-tacking agents used typically include but not limited to, talc, magnesium stearate, kaolin, silicon dioxide and glycerol monostearate. Concentration of the them can vary, talc is normally used in range of 25-100% (% based on dry polymer), while normally 5-20% (% based on dry polymer) of Glycerol monostearate is used. In one embodiment the anti-tacking agent is talc. In one embodiment the anti tacking agent is Glycerol monostearate.

Besides choosing the proper polymer for enteric coating. Enteric coating should also have a certain degree of thickness so that polymer film do not dissolve (swell) and remain impermeable to acidic environment for several hours. Typically this can be achieved by coating the layer of polymer film over the core tablet to a thickness of about 5 to 60 pm, suitably 10 to 50 pm, suitably 20-40 pm. Alternatively, the enteric protection could be rendered by coating the polymer layer of about 0.5-15 mg/cm², suitably about 1-10 mg/cm²’ suitably 2-7 mg/cm² on the core. Typically the weight of the enteric coating should be at least 5% of the total weight of the pharmaceutical formulation of the invention (including the weight of the enteric coating), suitable between about 7% to 15%, suitably between 8 to 14%, suitable between 9 to 13%, suitable 9 to 12% of the total weight of the pharmaceutical formulation of the invention.

To apply an enteric coating to a core pharmaceutical composition is within the common general knowledge of a skilled person in the field. Before enteric polymer coating over the core tablets, generally a layer of seal or sub coat is applied. Purpose of seal coating is to provide protection to the core of tablet and prevent migration of ingredients to core. This also helps in giving a uniform surface on which functional coating of an enteric polymer can form. Enteric coating polymers are acidic and can have interaction with drug present in the core. To avoid these interactions sub coat or seal coat is recommended using but not limited to cellulosic polymers like HPMC and HPC. Following this an enteric polymer coating is applied. Typically, irrespective of coating material, coating process invariably involves the deposition of thin layer of polymer by means of a spray of aqueous or organic coating suspension/solution on top of a rotating tablet bed. The film is dried by passing hot air through the tablet bed and residual solvent/water is removed to leave a thin film on tablet core. Enteric coated capsule is normally commercially available, for example Vcaps® Enteric Capsules from Evonik, or QualiV S from Qualicaps. In one preferred embodiment the capsule is sealed by banding, preferably with a polymer according to the present invention. The purpose of banding is to prevent or to reduce the acid ingress. Suitably the banding polymer is the same polymer used in enteric coating.

The pharmaceutical composition releases less than 10%, suitably less than 7%, suitably less than 5%, suitably less than 3%, suitably less than 1% of eltrombopag in a dissolution test performed in an aqueous medium at an acidic pH, e.g. a pH < 2 ± 0.3, suitably pH at 1.2±0.3, most suitably pH at 1.2±0.15, when measured up to one hour, up to 1.5 hour or most suitably up to 2 hours.

The enteric coating quickly dissolves when pH rises over the trigger pH and thus the pharmaceutical composition releases measurable amount of eltrombopag in a dissolution test, for example at least 20% or at least 50% or at least 70% of eltrombopag within 15 minutes after the pharmaceutical composition of the invention is immersed in an aqueous medium having pH above 5.5±0.3, e.g. at pH6.8±0.3. Under such condition, the amount of dissolved eltrombopag should steadily increase with time, e.g. within the 15, 30, 45, 60, 75, 90 min.

Example 3 describes the two-stage dissolution test for assessing the drug release from the pharmaceutical composition of the invention. Preferably low amount of surfactant, e.g. Tween 80, typically 0.1 to 1.0, e.g. 0.5%v/v is added to the dissolution medium to facilitate the dissolution of eltrombopag.

In one embodiment the pharmaceutical composition of the invention comprises at least one or more excipients.

Suitably, the at least one or more pharmaceutically acceptable excipients include a diluent (also known as filler or bulking agent) and/or a binder and/or a lubricant and/or a disintegrant and/or glidiant. Those skilled in the art will recognize that a given material may provide one or more functions in the tablet formulation, although the material is usually included for a primary function. Diluents provide bulk, for example, in order to make the tablet a practical size for processing. Diluents may also aid processing, for example, by providing improved physical properties such as flow, compressibility, and tablet hardness. Because of the relatively high percentage of diluent and the amount of direct contact between the diluent and the active compound in the typical pharmaceutical formulation, the interaction of the diluent with the active compound is of particular concern to the formulator. Examples of diluents suitable for general use include: water-soluble fillers and water-insoluble fillers, such as calcium phosphate (e.g., di and tri basic, hydrated or anhydrous), calcium sulfate, calcium carbonate, magnesium carbonate, kaolin, spray dried or anhydrous lactose, cellulose (e.g., microcrystalline cellulose, powdered cellulose), pregelatinized starch, starch, lactitol, mannitol, sorbitol, maltodextrin, powdered sugar, compressible sugar, sucrose, dextrose, and inositol. The diluents that do not contain polyvalent metals and diluents that are non-reducing sugars are suitable for tablets of the current invention. Suitable diluents for use in this invention include microcrystalline cellulose, powdered cellulose, pregelatinized starch, starch, lactitol, mannitol, sorbitol, and maltodextrin. Unsuitable diluents include calcium phosphate (e.g., di and tri basic, hydrated or anhydrous), calcium sulfate, calcium carbonate, magnesium carbonate, kaolin, and spray dried or lactose. In one embodiment the diluent is not lactose. In one embodiment of the present invention, the diluent is composed of one or both of Mannitol and microcrystalline cellulose.

Binders impart cohesive properties to the powdered material. Examples of binders suitable for use in the present invention include: starch (e.g., paste, pregelatinized, mucilage), gelatin, sugars (e.g., sucrose, glucose, dextrose, molasses, lactose, dextrin, xylitol, sorbitol), polymethacrylates, natural and synthetic gums (e.g., acacia, alginic acids and salts thereof such as sodium alginate, gum tragacanth, Irish moss extract, panwar gum, ghatti gum, guar gum, zein), cellulose derivatives [such as carboxymethyl cellulose and salts thereof, methyl cellulose (MC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC) and ethyl cellulose (EC)], polyvinylpyrrolidone, Veegum, larch arabogalactan, polyethylene glycol, waxes, water, alcohol, magnesium aluminum silicate, and bentonites. In one embodiment the binder is a reducing sugar. In one embodiment the binder is not lactose and glucose. In one embodiment the binder is not lactose. In one embodiment of the present invention, the binder comprises polyvinylpyrrolidone (PVP).

Lubricants are generally used to enhance processing, for example, to prevent adhesion of the formulation material to manufacturing equipment, reduce interparticle friction, improve rate of flow of the formulation, and/or assist ejection of the formulations from the manufacturing equipment. Examples of lubricants suitable for use in the present invention include: talc, stearates (e.g., magnesium stearate, calcium stearate, zinc stearate, palmitostearate), stearic acid, hydrogenated vegetable oils, glyceryl behanate, polyethylene glycol, ethylene oxide polymers (e.g., CARBOWAXes), liquid paraffin, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, and silica derivatives (e.g., colloidal silicon dioxide, colloidal silica, pyrogenic silica, and hydrated sodium silicoaluminate). In one embodiment of the present invention, the lubricant comprises magnesium stearate.

Disintegrants are employed to facilitate breakup or disintegration of the formulation after administration. Examples of disintegrants suitable for use in the present invention include: starches, celluloses, gums, crosslinked polymers, and effervescent agents, such as corn starch, potato starch, pregelatinized starch, modified corn starch, croscarmellose sodium, crospovidone, sodium starch glycolate, Veegum HV, methyl cellulose, microcrystalline cellulose, cellulose, modified cellulose gum (e.g., Ac-Di-Sol R), agar, bentonite, montmorillonite clay, natural sponge, cation exchange resins, ion exchange resins (e.g., polyacrin potassium), alginic acid and alginates, guar gum, citrus pulp, carboxymethylcellulose and salts thereof such as sodium lauryl sulfate, magnesium aluminum silicate, hydrous aluminum silicate, sodium bicarbonate in admixture with an acidulant such as tartaric acid or citric acid. In one embodiment of the present invention, the disintegrant is sodium starch glycolate. In one embodiment the disintegrant is crospovidone. In one embodiment the disintegrant is croscarmellose sodium. In one embodiment the pharmaceutical composition of the invention comprises or alternatively consists essentially of or consists of diluent, binder, disintegrant and lubricant.

In one embodiment the pharmaceutical composition of the invention comprises or alternatively consists essentially of or consists of one or two diluent, one binder, one disintegrant and one lubricant.

In one embodiment the pharmaceutical composition of the invention comprises or alternatively consists essentially of or consists of one diluent, one binder, one disintegrant and one lubricant.

In the foregoing embodiments, the diluent is suitably a combination of mannitol and microcrystalline cellulose, the non-reducing sugar is suitably mannitol, the binder is suitably polyvinylpyrolidone, the lubricant is suitably magnesium stearate, and the disintegrant is suitably sodium starch glycolate.

In one embodiment the pharmaceutical composition of the invention substantially free from or free from a reducing sugar.

Oral dosage form is meant to be taken orally, typically as instructed by the medicine manufacturer. Common oral dosage form includes but not limited to solid dosage form such as tablets, capsules, pellets, lozenges, granules and powders and liquid dosage form such as syrup. In one embodiment the pharmaceutical composition of the invention is in the form of an enteric coated tablet. In one embodiment the pharmaceutical composition of the invention is in the form of enteric coated granules.

In one embodiment the one or more excipient is a surfactant, preferably vitamin E TPGS.

In one embodiment the weight of eltrombopag is not more than 30%, suitably from 5% to 25%, suitably from 5 to 20% of the total weight of eltrombopag and vitamin E TPGS. The term “weight of eltrombopag” as used in the context of the present invention refers to the weight of the free acid form, unless indicated otherwise. By way of example, formulation in Example 1 consists of 95.6mg of eltrombopag bis-monoethanolaime, corresponding to 75mg of eltrombopag, 358.2mg of vitamin E TPGS and 23.8mg of vitamin E, then the weight of eltrombopag of the total weight of eltrombopag and vitamin E TPGS is 17.3% (75/(75+358.2)). In contrast, %w/w, As used in the tables of the Examples, indicates each components’ weight percentage of the weight of the total composition. For example ETB115 95.6mg is the 20% of eltrombopag bis-olamine of a total of 477.6 mg of the composition (drug load, 95.6/477.6=20%). The weight of the anti-oxidant of the total weight of the pharmaceutical composition is 5.0% (23.8/477.6=5%).

In one embodiment vitamin E TPGS is the only surfactant in the pharmaceutical composition of the invention.

In one embodiment the one or more excipient is an anti-oxidant. Suitably the anti-oxidant includes but not limited to Vitamin E, Butylhydroxytoluol (BHT), Butylhydroxyanisol (BHA), Propyl gallate, ascorbyl palmitate, ascorbic acid, EDTA and sodium metabisulfite or a mixture thereof.

In one embodiment the weight of the anti-oxidant is not more than 10%, suitably not more than 7%, suitably not more than 5%, suitably not more than 3%, suitably not more than 1%, of the total weight of the pharmaceutical composition.

In one embodiment the anti-oxidant is EDTA.

In one embodiment the pharmaceutical composition of the invention comprises, consists essentially of or consists of vitamin E TPGS and EDTA. Preferably this composition is in the form of an enteric coated capsule.

In one embodiment the pharmaceutical composition consists essentially of or consists of eltrombopag or a pharmaceutically acceptable salt thereof, vitamin E TPGS and at least one anti-oxidant. In one embodiment the pharmaceutical composition consists of eltrombopag, vitamin E TPGS and only one anti-oxidant. In one embodiment the anti-oxidant is not more than 10%, suitably not more than 7%, suitably not more than 5%, of the total weight of the pharmaceutical composition.

In one embodiment the anti-oxidant is selected from a list consisting of Vitamin E, Butylhydroxytoluol (BHT), Butylhydroxyanisol (BHA), Propyl gallate, ascorbyl palmitate, ascorbic acid, EDTA and sodium metabisulfite or a mixture of. There exists trace amount of vitamin E (about 1.5%) in vitamin E TPGS of GMP standard. This amount of vitamin E is generally regarded as impurities unless otherwise specified in this application.

In one preferred embodiment the anti-oxidant is EDTA.

In one embodiment the pharmaceutical composition comprises eltrombopag or a pharmaceutically acceptable salt thereof, vitamin E TPGS and EDTA. In one embodiment the pharmaceutical composition consists essentially of or consists of eltrombopag, vitamin E TPGS and EDTA.

In aspect the present invention provides a process of making the pharmaceutical composition of the invention by melting the at least one surfactant, e.g. vitamin E TPGS, and incorporating eltrombopag and filling the molten mass into the enteric coated capsules which upon cooling forms a semi-solid in the capsule. Preferably the capsule is further sealed by banding with an enteric polymer.

The oral dosage form, suitable tablets, capsules or granules, suitably capsules, containing the pharmaceutical composition of the present invention typically comprise at least about 5mg or at least about lOmg of eltrombopag, suitably at least about lOmg of eltrombopag per dosage form. The oral dosage form, suitable tablets, capsules or granules, suitably capsules, containing the pharmaceutical formulation of the present invention typically comprise at most about 200mg, 150mg, lOOmg or 75mg, suitably at most about 75mg of eltrombopag per dosage form. In one embodiment the pharmaceutical composition comprises about lOmg to about lOOmg of eltrombopag, or about lOmg to 75mg, or about 5mg to 75mg of eltrombopag per dosage form. Preferred embodiments of such dosage form comprises about 12.5mg, 25mg, 50mg, 75mg, lOOmg or 125mg of eltrombopag.

In another preferred embodiment, due to the increased bioavailability of eltrombopag in the pharmaceutical composition of the present invention, the oral dosage form comprises less amount of eltrombopag but is bioequivalent sto the corresponding 12.5mg, 25mg, 50mg, 75mg, lOOmg or 125mg of the commercial Promacta doses, respectively. In one embodiment the pharmaceutical composition of the present invention comprises about 9mg, about 17.5mg, about 19.5mg, about 35mg, about 39mg, about 52.5mg and about 58.5mg of eltrombopag, based on the weight of eltrombopag free acid.

In one embodiment the pharmaceutical composition of the present invention, preferably in oral dosage form, suitably tablets, capsules or granules, suitably capsules, is substantially free of, preferably free of, polyvalent metals and/or that is substantially free of reducing sugars.

By the term “polyvalent metal” and “polyvalent metals” and derivatives thereof, as used herein is meant a metal or a metal containing excipient, suitably a diluent, or metal containing tablet coating material, which forms a complex, such as a chelate complex, in the presence of eltrombopag olamine. Examples of such metals include: aluminum, calcium, copper, cobalt, gold, iron, magnesium, manganese and zinc.

By the term “reducing sugar” as used herein is meant a sugar or sugar containing excipient, suitably a diluent, which reacts with eltrombopag or a pharmaceutical acceptable salt thereof, suitably eltrombopag olamine, to form a Maillard product when admixed together. Examples of such reducing sugars include: lactose, maltose, glucose, arabinose and fructose.

In one aspect it provides the pharmaceutical composition of the invention for use in the treatment of thrombocytopenia, especially chronic idiopathic thrombocytopenic purpura, aplastic anemia, and acute radiation syndrome (ARS).

In one embodiment the pharmaceutical composition of the invention is for use in the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

In one embodiment the pharmaceutical composition of the invention is for use in combination with standard immunosuppressive therapy for treatment in the first-line treatment of adult and pediatric patients 2 years and older with severe aplastic anemia. In one embodiment the pharmaceutical composition of the invention is for use in the treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy.

In one aspect it provides a method of treating thrombocytopenia comprising administering to a subject in need thereof a therapeutically effective amount of eltrombopag or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition of the present invention.

In one aspect it provides a method of treating earlier thrombocytopenia, especially thrombocytopenia naive subject or subject has not received Corticosteroids treatment, comprising administering to a subject in need thereof a therapeutically effective amount of eltrombopag or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition of the present invention. In one embodiment the pharmaceutical composition of the present invention is used for as first line treatment of thrombocytopenia.

In one aspect it provides a method of treating chemotherapy induced thrombocytopenia (CIT) comprising administering to a subject in need thereof a therapeutically effective amount of eltrombopag or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition of the present invention.

In one aspect it provides a method of treating low-risk MDS comprising administering to a subject in need thereof a therapeutically effective amount of eltrombopag or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition of the present invention.

The term “therapeuticallyeffective amount" and derivatives thereof, means that amount of a drug or active ingredient that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term “therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. The pharmaceutical composition of the invention is capable of mitigating the food effect on eltrombopag, i.e. mitigating the reduction of bioavailability in the presence of food, especially calcium-rich food.

In one embodiment the pharmaceutical composition of the invention, taken with a high-calcium, moderate-fat, moderate-calorie meal in a human subject, the plasma eltrombopag AUC0-co is not reduced by more than about 30%, preferably not reduced by more than about 20%, 15%, 10%, 5%, compared to taken without a meal, e.g. on an empty stomach. A standard high-calcium, moderate-fat, moderate- calorie meal contains about 372 calories ± 20% , about 9 g ± 10 % fat, and about 448 mg ± 10% calcium. Preferably a standard high-calcium, moderate-fat, moderate-calorie meal contains about 372 calories, about 9 g fat, and about 448 mg calcium. In one preferred embodiment plasma eltrombopag AUC0-co is not reduced by more than 20% when the pharmaceutical composition is taken with a high- calcium, moderate-fat, moderate-calorie meal.

A trend was observed in dog study that the pharmaceutical formulation of the invention, when taken with low fat/high calcium diet, exhibited a slightly higher level of AUC0-co, compared to taken without a meal, e.g. on an empty stomach.

Thus in one embodiment the pharmaceutical composition of the invention, taken with a high-calcium, moderate-fat, moderate-calorie meal in a human subject, the plasma eltrombopag AUC0-co is increased by about at least 20%, suitably increased by at least 15%, 10%, 5%, compared to taken without a meal, e.g. on an empty stomach. Suitably the increase is not more than 25%, not more than 15%, not more than 10%. Suitable the increase is between 5% to 10%.

In one embodiment the pharmaceutical composition of the invention, taken with a high-calcium, moderate-fat, moderate-calorie meal in a human subject, the plasma eltrombopag Cmax is not reduced by more than about 30%, preferably not reduced by more than about 20%, 15%, 10%, 5%, compared to taken without a meal, e.g. on an empty stomach. In one preferred embodiment plasma eltrombopag Cmax is not reduced by more than 20% when the pharmaceutical composition is taken with a high-calcium, moderate-fat, moderate-calorie meal.

In one embodiment the pharmaceutical composition of the invention, taken with a high-calcium, moderate-fat, moderate-calorie meal in a human subject, the plasma eltrombopag Cmax is increased by about at least 10%, suitably increased by 5%, compared to taken without a meal, e.g. on an empty stomach. Suitably the increase is not more than 20%, not more than 10%. Suitable the increase is between 5% to 10%.

In one embodiment the pharmaceutical composition of the invention, when taken with a high-calcium, moderate-fat, moderate-calorie meal in a human subject, the plasma eltrombopag AUC0-co is within about 80% and about 125%, suitably within about 80% and about 100%, suitable within about 80% and about 90%, alternatively and suitably within about 100% and about 110%, of the AUC0-co taken without a meal, e.g. on an empty stomach. In one embodiment the pharmaceutical composition of the invention, when taken with a high-calcium, moderate-fat, moderate-calorie meal in a human subject, the plasma eltrombopag Cmax is within about 80% and about 125%, suitably within about 80% and about 100%, suitable within about 80% and about 90%, alternatively and suitably within about 100% and about 110%, of the Cmax taken without a meal, e.g. on an empty stomach.

As used herein, the term “about” in relation to a numerical value x means, for example, +/-10%, suitably +/- 5%, +1-2%.

In one embodiment there is no requirement to take the pharmaceutical composition “on an empty stomach (1 hour before or 2 hours after a meal)” and/or “ at least 2 hours before or 4 hours after other medications (e.g., antacids), calcium- rich foods and/or ” in the drug label of the medicine containing the pharmaceutical composition of the invention.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples, therefore, are to be construed as merely illustrative and not a limitation of the scope of the present invention. EXAMPLES EXAMPLE 1

Enteric coated capsules comprising vit E TPGS and eltrombopag

Capsules comprising eltrombopag olamine and Vitamin E TPGS shown in Table 3 were prepared. Table 3

*75mg is free acid equivalent

* As used in the tables of the Examples, %w/w indicates each components’ weight percentage of the total composition. For example ETB115 95.7 mg is the 20% of eltrombopag bis-olamine of a total of 477.6 mg of the composition (drug load).

Capsules were prepared as follows: VitE TPGS is first melted at 60-70°C in a suitable container. Then compound is added and continuously mixed with a homogenizer. Aliquots equivalent to the fill weight are filled into the body of Vcaps Enteric (Capsugel^®) size 0 capsules and allowed to cool to room temp. HPMC AS LF (solubility above pH 5.5) ethanol solution was used for banding the capsules. Banding solution was applied at the junction of cap and body using an applicator twice with an intermittent drying. EXAMPLE 2

Enteric coated Promacta tablet

75mg Promacta tablet in Table 4 was enteric coated with Eudragit L100 55. Table 4

Coating solution was prepared in two steps. Briefly, in first step 30% w/v Eudragit LI 00-55 dispersion was prepared using overhead stirrer and neutralized using sodium hydroxide. In second step, talc was homogenized in water and triethyl citrate was added to it and homogenization was continued for 10 min. The prepared dispersion was then added to the Eudragit L100-55 dispersion and mixed using overhead stirrer. The final dispersion was sieved through 0.5 mm sieve to make the final coating solution. Formula for the preparation of the coating solution is as shown in the Table 5.

Table 5 Eudragit LI 00-55 coating solution preparation

Step Component Quantity (gm) Dry substance (gm)

1 - Preparation of Eudragit L100-55 300 300 Eudragit L100-55 1 N NaOH 100 4 dispersion

600 _

Total 1000 304

2 - Preparation of Eudragit L100-55 600 180 final coating solution dispersion TEC 18.00 18.00 Talc 45.05 45.05 Water 957.0

Total (gm) 1620.1 243.05 Coating solution was stirred continuously during the coating operation. Coating process was performed following common general procedure. Practically, 10.15%w/w of coating was achieved with the initial Promacta^® tablet weight of 364 mg.

Table 6 Enteric coated Promacta^® tablet formulation

Sr. no Components Composition per unit Composition per unit

1%) 75 mg (mg/unit)

1 Promacta film coated tablet 75 mg¹ 90.91 364.00

2 Eudragit L 100-55 4.17 16.690

3 Sodium hydroxide 0.06 0.223

4 Triethyl citrate 1.39 5.563

5 Talc 3.48 13.924

6 Water q.s. q.s.

Total 100.0 400.4

EXAMPLE 3

2 stage dissolution by HPLC

Dissolution conditions Paddle method according to Ph. Eur. 2.9.3 “Dissolution for Solid Dosage Forms” or USP <711> “Dissolution” Determination by HPLC.

Speed of rotation 75 + 3 rpm

Test medium (Acid Stage, pH 1.2 HC1 Buffer (0.1M HC1) Stage- 1)

Test medium (Buffer Stage, 0.5%v/v Tween 80 mM potassium phosphate pH 6.8 Stage-2)

Volume of test medium 900 mL

(Stage- 1, Acid Stage) Volume of test medium 900 mL

(Stage-2, Buffer Stage) Temperature 37.0 ± 0.5°C

Column Phenomenex Prodigy C8 or equivalent

Length 150 mm, internal diameter 4.6 mm, particle size 5 pm

Mobile Phase 0.1%TFA in Water: Acetonitrile (20:80, v/v) (Isocratic) Flow rate 1.0 ml/min

Detector wavelength 412nm Injection volume 10 pi of the test and reference solutions

Procedure

Test solution - Acid stage Acid Stage (Stage-1), pH 1.2 HC1 buffer

This test can be carried out by an automated dissolution test system. In dissolution profiles, Samples are required to collect at 60 and 120minutes. At each time point, withdraw 1.5 mL of the solution and immediately filter through a Pall Acrodisc PSF GxF/Glass 1 pm Automated Certified syringe filters or ROBY25/GF55 glass fiber filter 0.7 pm. Collect the test solution into a HPLC vial. Do not replace the medium volume removed.

Test Solution - buffer stage Buffer Stage (Stage-2), 0.5% v/vTween 80 in 50mM Potassium Phosphate pH 6.8

After completion of Acid stage dissolution. Replace the acid stage medium (Stage- 1) with buffer stage pre-heated medium (Buffer Stage media, Stage-2). And continue the test with an automated dissolution test system. In dissolution profiles, Samples are required to collect at 135, 150, 165, 180, 195 and 210minutes (Infinity at 200rpm). At each time point, withdraw 1.5 mL of the solution and immediately filter through a Pall Acrodisc PSF GxF/Glass 1 pm Automated Certified syringe filters or ROBY25/GF55 glass fiber filter 0.7 pm. Collect the test solution into a HPLC vial. Do not replace the medium volume removed. Note: Sampling time for profile generation may be adapted based on project need. Time point in buffer stage are calculated in addition to the time of acid stage e.g. 120min

UV-VIS spectrophotometer (424 nm) is an alternative method instead of HPLC to determine dissolution.

Reference solution This corresponds to 0.088 mg/mL as free acid of ETB115.

EXAMPLE 4 Two-stage test of enteric coated capsule formulation

Enteric coated capsule of EXAMPLE 1 was subjected to two-stage dissolution test described in EXAMPLE 3, except 0.5%v/v Tween is not present in the pH 6.8 Phosphate Buffer. Enteric capsule shells exhibited good acid resistance, and showed about 75% drug release in buffer stage by the end of 210 min (infinity time point). The incomplete drug dissolution in buffer stage was hypothesized to be due to ingress of acid inside the capsule shell during the acid phase. Hence, it was decided to band the enteric capsules to reduce the acid ingress. Banding improved the dissolution by ~ 10-15 % (FIG. 1)

EXAMPLE 5

Dissolution test of enteric coated tablet formulation Dissolution test of the enteric tablets of EXMPLE 2 was performed according to EXAMPLE 3 and the results are shown in FIG. 2. EXAMPLE 6

Dog PK study on food effect on enteric coated formulations

Objective of the Dog PK study was to determine the effect of enteric coating of Promacta tablets, VCaps capsules/Vcaps enteric capsules on the PK under fed and fasted conditions. The study design is as mentioned in the table below.

6 groups of male beagle dogs, 6 dogs per group, were fed 75mg of eltrombopag in the form of Promacta tablet uncoated, enteric coated Promacta tablet and enteric coated capsule (ETB115-ORA-0069 composition) under fasted or fed conditions. In the fasted groups animals were fasted overnight through approximately 7 hours postdose. In the fed groups animals were fasted from standard lab diet overnight through approximately 7 hours postdose. Approximately 50 grams of supplemental low fat/high calcium diet (approximately 425 mg of calcium per 50 grams diet) was provided approximately 30 minutes prior to dose administration. The AUC and Cmax were measured after dose administration.

The results of the study is summarized in FIG. 3A and 3B.

The small sample size as well as the high degree of variability in the PK results made it impossible to draw clear conclusions. However some trends were still observed: while uncoated Promacta tablets indeed showed reduced exposure both in reduced AUC and reduced Cmax under fed conditions, enteric coating or enteric capsules could mitigate or even slightly reverse the food effect both in AUC and in Cmax. In the case of enteric capsule formulation, the mitigation effect is not entirely due to the presence of vitamin E TPGS as the uncoated capsules still had some degree of food effect both in AUC and in Cmax under fed conditions (data not shown).

EXAMPLE 7 Food effect study in health volunteers

The effect of food, high and low in calcium content, on the pharmacokinetics of eltrombopag after administration of enteric coated capsule or tablet comprising eltrombopag olamine will be investigated. The treatment will consist of single oral doses administered in a fasted state, and in various fed conditions: high-fat high- calorie (HFHC) high-calcium meal, HFHC low-calcium meal, high-fat low-calorie (HFLC) low-calcium meal. Subjects will undergo 4 treatment periods with a washout of 7 to 10 days between 2 consecutive doses. The primary objective is to evaluate the effect of food, high or low in calcium, on eltrombopag pharmacokinetics, including but not limited to the measure of AUC, Tmax and Cmax.

Claims

WHAT IS CLAIMED IS:

1. An oral pharmaceutical composition comprising 3'-[(2Z)-[l-(3,4- dimethylphenyl)-l,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4- ylidene]hydrazino]-2'-hydroxy-[ 1 , 1 '-biphenyl]-3 -carboxylic acid (eltrombopag), or a pharmaceutically acceptable salt thereof, wherein the oral pharmaceutical formulation is coated with an enteric coating.

2. The oral pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt is bis-(monoethanolamine).

3. The oral pharmaceutical composition of any one of the preceding claims, wherein the enteric coating comprises a polymer which is substantially insoluble in an aqueous medium, wherein the aqueous medium has a pH < 2 ± 0.3.

4. The oral pharmaceutical composition of claim 3, wherein the polymer is soluble in an aqueous medium, wherein the aqueous medium has a pH > 5±0.3.

5. The oral pharmaceutical composition of claim 4, wherein the aqueous medium has a pH between 5.5±0.3 to 7±0.3.

6. The oral pharmaceutical composition of any one of the claims 3 to 5, wherein the polymer is selected from a group consisting of Cellulose acetate phthalate, Cellulose acetate trimellitate, Polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, Hydroxypropylmethylcellulose acetate succinate, Shellac (esters of aleurtic acid) and methacrylic acid copolymers (Eudragit) or any combination thereof.

7. The oral pharmaceutical composition of claim 6, wherein methacrylic acid copolymers (Eudragit) is selected from the list consisting of Poly (MA - EA) 1 : 1 , Poly (MA - MMA) 1 : 1 ; and Poly (MA - MMA) 1 :2, wherein MA is methacrylic acid, EA is ethyl acrylate and MMA is methyl methacrylate. Poly(methacrylic acid-co-methyl methacrylate) 5.5-7.0

8. The oral pharmaceutical composition of claim 7, wherein methacrylic acid copolymers (Eudragit) is Poly (MA - EA) 1:1.

9. The oral pharmaceutical composition of any one of the claims 3 to 8, wherein the polymer is Eudragit L30D.

10. The oral pharmaceutical composition of any one of the claims 3 to 8, wherein the polymer is Eudragit L100-55.

11. The oral pharmaceutical composition of any one of the preceding claims, wherein the total weight of the enteric coating is at least about 7% of the total weight of the pharmaceutical composition, wherein the total weight of the pharmaceutical composition includes the total weight of the enteric coating.

12. The oral pharmaceutical composition of any one of the preceding claims, wherein the total weight of the enteric coating is between about 8% to about 14% of the total weight of the pharmaceutical formulation of the invention, wherein the total weight of the pharmaceutical composition includes the total weight of the enteric coating.

13. The oral pharmaceutical composition of any one of the preceding claims, wherein eltrombopag is not released more 10% within 60 minutes in a dissolution test performed at pH=1.2 ± 0.5.

14. The oral pharmaceutical composition of any one of the preceding claims, wherein eltrombopag is not released more 10% within 2 hours in a dissolution test performed at pH=1.2 ± 0.5.

15. The oral pharmaceutical composition of any one of the preceding claims, wherein eltrombopag is released at least 20% within 15 min in a dissolution test performed at pH 6.8 ± 0.5.

16. The oral pharmaceutical composition of any one of the preceding claims, wherein eltrombopag is released at least 50% within 15 min in a dissolution test performed at at pH 6.8 ± 0.5.

17. The oral pharmaceutical composition of any one of the claims 13 to 17, wherein the dissolution test is a two-stage dissolution test as described in EXAMPLE 3.

18. The oral pharmaceutical composition of any one of the preceding claims comprising at least one or more excipients.

19. The oral pharmaceutical composition of claim 18, wherein the at least one or more excipients is one or more diluent, wherein the diluent is free from polyvalent metals.

20. The oral pharmaceutical composition of claim 19, wherein the one or more diluent is selected from the group consisting of microcrystalline cellulose and mannitol.

21. The oral pharmaceutical composition of any one of the claims 18 to 20, wherein the at least one or more excipient is a disintegrant.

22. The oral pharmaceutical composition of claim 21, wherein the disintegrant is selected from a group consisting of CMC or PYPP.

23. The oral pharmaceutical composition of any one of the claims 18 to 23, wherein the at least one or more excipient is a binder.

24. The oral pharmaceutical composition of claim 23, wherein the binder is povidone.

25. The oral pharmaceutical composition of any one of the claims 18 to 24 comprising or consisting essentially of eltrombopag, one or two diluent, one binder, one disintegrant, one lubricant.

26. The oral pharmaceutical composition of any one of the preceding claims substantially free from or free from a reducing sugar.

27. The oral pharmaceutical composition of any one of the preceding claims in the form of a tablet.

28. The oral pharmaceutical composition of claim 18, wherein the one or more excipient is vitamin E TPGS.

29. The oral pharmaceutical composition of claim 28, wherein the weight of eltrombopag is not more than 30% of the total weight of eltrombopag and vitamin E TPGS.

30. The oral pharmaceutical composition of claim 28 or 29 further comprising EDTA.

31. An oral pharmaceutical composition consisting essentially of or consisting of eltrombopag, or a pharmaceutically acceptable salt thereof, vitamin E TPGS and EDTA, wherein the pharmaceutical composition is coated with an enteric coating.

32. The oral pharmaceutical composition according to any one of the claims 28 to 31 in the form of a capsule.

33. The oral pharmaceutical composition of claim 32, wherein the capsule is sealed by banding, preferably with the same polymer used in enteric coating according to any one of the claims 3 to 10.

34. The oral pharmaceutical composition according to any one of the preceding claims, wherein plasma eltrombopag AUC0-co taken with a high-calcium, moderate-fat, moderate-calorie meal is within about 80% and about 125% within of the AUC0-co taken on an empty stomach.

35. The oral pharmaceutical composition according to any one of the preceding claims, wherein plasma eltrombopag Cmax taken with a high-calcium, moderate-fat, moderate-calorie meal is within about 80% and about 125% within of the Cmax taken on an empty stomach.