DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“SOLID DISPERSION OF DAPRODUSTAT AND A PROCESS FOR THE PREPARATION THEREOF”

Glenmark Life Sciences Limited
an Indian Company, registered under the Indian Companies Act 1956, and having its registered office at Plot No. 170-172,
Chandramouli Industrial Estate,
Mohol Bazarpeth, Solapur 413213.

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION
The present invention relates to a solid dispersion comprising daprodustat or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The present invention also relates to a process for the preparation of the solid dispersion, a pharmaceutical composition comprising the solid dispersion, and therapeutic use of the solid dispersion.
BACKGROUND OF THE INVENTION
Daprodustat is known by its chemical name N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl]glycine, and is represented by a compound of formula I (the “compound I”),

I
Daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF PHI), is indicated for the treatment of anemia due to chronic kidney disease in adults who have been receiving dialysis for at least four months. Daprodustat tablets, marketed as Jesduvroq®, are manufactured in five strengths, 1 mg, 2 mg, 4mg, 6 mg, and 8 mg, and are to be taken orally once daily and three times weekly.
Daprodustat and its pharmaceutically acceptable salts are described in a published PCT application no. WO 2007150011.
Various polymorphic forms of daprodustat are known in the art. For instance, PCT Publication No. WO 2019052133 discloses Form CS1 and CS9 of daprodustat and PCT Publication No. WO 2020102302 discloses various polymorphs of daprodustat, and processes for the preparation thereof.
As per the Chemistry Review for daprodustat published by the US FDA (the U.S. Food & Drug Administration), this drug substance is classified as BCS class II drug thereby indicating solubility issues associated with it. Poor solubility of a drug substance is one of the major problems in the preparation of oral dosage form containing such drug substance, particularly because poor the rate of solubilisation and absorption of a drug substance, lower will be its bioavailability and pharmacokinetic performance. Therefore, the right approach will be to improve the solubility properties of the drug substance in turn to improve its overall pharmacokinetic profile in order to effectively exert its therapeutic effects. The present invention attempts to provide a solution for the specified problems associated with daprodustat.
SUMMARY OF THE INVENTION
The present invention provides a solid dispersion comprising daprodustat or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier selected from a polymer or a non-polymeric porous material.
The present invention also provides a solid dispersion comprising daprodustat or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier selected from a polymer or a non-polymeric porous material, and at least one surfactant.
The present invention further provides a process for the preparation of a solid dispersion comprising daprodustat or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier selected from a polymer or a non-polymeric porous material; wherein the process comprises the steps of:
a) dissolving daprodustat or a pharmaceutically acceptable salt thereof, in a solvent to obtain a solution or a suspension;
b) adding a pharmaceutically acceptable carrier to the solution or suspension obtained in the step (a) to obtain a reaction mixture; and
c) removing the solvent from the reaction mixture obtained in the step b) to obtain the solid dispersion.
The present invention further provides a process for the preparation of a solid dispersion comprising daprodustat and a pharmaceutically acceptable carrier selected from a polymer or a non-polymeric porous material; wherein the process comprises the steps of:
(i) dissolving daprodustat and a pharmaceutically acceptable carrier in a solvent to obtain a solution or a suspension;
(ii) adding the solution or suspension obtained in the step i) to water to obtain a reaction mixture; and
(iii) removing the solvents from the reaction mixture obtained in the step (ii) to obtain the solid dispersion.
The present invention further provides a pharmaceutical composition comprising the solid dispersion of daprodustat as described herein, and optionally one or more pharmaceutical acceptable excipients selected from a diluent, a disintegrant, a binder, a lubricant, a glidant, a surfactant or a mixture thereof.
The present invention also provides a method for the treatment of anaemia caused due to chronic kidney disease comprising administering a therapeutically effective amount of the solid dispersion of the present invention, or the pharmaceutical composition comprising the solid dispersion, to a patient in need thereof.
The present invention also provides use of the solid dispersion of the present invention or the pharmaceutical composition comprising the solid dispersion in the treatment of anaemia caused due to chronic kidney disease.
These and other aspects of the present invention will be apparent from the following description, and reference to the accompanying drawings.
BRIEF DESCRIPTION OF DRAWINGS
Figure 1 illustrates characteristic XRPD (X-Ray Powder Diffraction) pattern of the solid dispersion of daprodustat as obtained in example 1.
Figure 2 illustrates characteristic XRPD (X-Ray Powder Diffraction) pattern of solid dispersion of daprodustat as obtained in example 2.
Figure 3 illustrates characteristic XRPD (X-Ray Powder Diffraction) pattern of solid dispersion of daprodustat as obtained in example 3.
Figure 4 illustrates characteristic XRPD (X-Ray Powder Diffraction) pattern of daprodustat as obtained in example 4.
Figure 5 illustrates characteristic XRPD (X-Ray Powder Diffraction) pattern of daprodustat as obtained in example 5.
Figure 6 illustrates characteristic XRPD (X-Ray Powder Diffraction) pattern of daprodustat as obtained in example 6.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides a solid dispersion comprising daprodustat or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier selected from a polymer or a non-polymeric porous material.
As used herein the term "solid dispersion" refers to a system in a solid state comprising at least two components, and in the context of the present invention, one of the components is daprodustat or a pharmaceutically acceptable salt thereof, which is dispersed throughout the other component, and the other component is a pharmaceutically acceptable carrier selected from a polymer or a non-polymeric porous material, and optionally a surfactant.
As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, excipients, carrier, compositions or dosage forms which will be considered by a prudent medical practitioner, suitable for administration to humans and animals without excessive toxicity, irritation, allergic response or other complications commensurate with a reasonable benefit/risk ratio.
As used herein, the term “pharmaceutically acceptable carrier” refers to both polymers and non-polymeric excipients, and combinations thereof, capable of dissolving or molecularly dispersing daprodustat or a pharmaceutically acceptable salt thereof. In the context of the present invention, the term “non-polymeric excipients” refers to “non-polymeric porous materials”.
As used herein, the term “pharmaceutically acceptable salts” in reference to daprodustat encompasses the pharmaceutically acceptable salts referred to in the published PCT application no. WO 2007150011. Representative examples of pharmaceutically acceptable salts of daprodustat includes hydrochloride, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, lactate, phthalate, oxalate, succinate, benzoate, stearate, ascorbate, palmitate, oleate, pyruvate, malonate, laurate, glutarate, glutamate, methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate, benzenesulfonate (besylate), and toluenesulfonate (tosylate). A person of skill in the art would understand that these pharmaceutically-acceptable salts of daprodustat can be prepared by separately reacting the compound in its free acid or free base form with a suitable acid.
As used herein, the term “about” refers to any value which lies within the range defined by a number up to 10% of the value.
As used herein, the abbreviation w/w denotes weight by weight of the total contents.
In an embodiment, the daprodustat contained in the solid dispersion of the present invention is in a crystalline form or an amorphous form.
In an embodiment, the pharmaceutically acceptable carrier used in the solid dispersion of the present invention is a polymer.
In an embodiment, the polymer is selected from homopolymers or copolymers of N-vinyl lactams, cellulose derivatives, polyalkylene oxides, polyacrylates, polymethacrylates, vinyl acetate polymers, polyacrylamides, polyvinyl alcohol, oligo- or polysaccharides, polyhydroxyalkylacrylates, polyhydroxyalkyl-methacrylates, copolymers of methyl methacrylate and acrylic acid, polyethylene glycols (PEGs), or a mixture thereof.
In another embodiment, the polymer is selected from a homopolymer or a copolymer of N-vinyl lactams selected from polyvinylpyrrolidone (PVP), polyvinylpolypyrrolidone (crospovidone), polyvinylcaprolactam or a mixture thereof. Examples of commercially available polyvinylpyrrolidone (PVP) include PVP K17, PVP K25, PVP K30, PVP K90, and the like.
In yet another embodiment, the polymer is a cellulose derivative selected from methylcellulose, ethylcellulose, propylcellulose, carboxymethyl cellulose, methyl cellulose adipate, hydroxypropyl cellulose; 5-carboxypent-1-yl hydroxypropyl cellulose, methyl 5-carboxypentyl cellulose, ethyl 5-carboxypentyl cellulose, cellulose acetate propionate, cellulose acetate butyrate, carboxymethyl cellulose acetate butyrate, hydroxypropylmethyl cellulose, cellulose acetate adipate, cellulose acetate phthalate, cellulose acetate suberate, cellulose acetate adipate hydroxyethyl ester, cellulose acetate adipate propionate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate, hydroxypropylmethyl cellulose acetate succinate, or a mixture thereof.
In another further embodiment, the polymer is polyalkylene oxides selected from polyethylene oxide, polypropylene oxide, copolymers of poly(ethylene oxide) and poly(propylene oxide), or a mixture thereof.
In another embodiment, the polymer is a polyacrylate or polymethacrylate selected from acrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl methacrylate copolymers, butyl methacrylate/2-dimethylaminoethyl methacrylate copolymers, poly (hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates, or a mixture thereof. Commercially available polymethacrylates are sold under the trade name Eudragit®. In the context of the present invention, the polymethacrylates are alternatively referred to as “Eudragit polymers”. Examples of Eudragit polymers include Eudragit L12,5; Eudragit L100; Eudragit EPO; Eudragit L 100-55; Eudragit L 30 D-55; Eudragit L 100; Eudragit S 12, 5P; Eudragit S 12,5; Eudragit S 100; Eudragit FS 30D; Eudragit RL 12,5; Eudragit RL100; Eudragit RS 100; Eudragit RS PO; Eudragit RS 30D, and the like.
In another further embodiment, the polymer is a vinyl acetate polymer selected from copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate (also known as partially saponified “polyvinyl alcohol”), or a mixture thereof.
In yet another further embodiment, the polymer is an oligo- or polysaccharides selected from carrageenans, galactomannans, xanthan gum, cyclodextrin or hyaluronic acid.
In an embodiment, the pharmaceutically acceptable carrier used in the solid dispersion of the present invention is a non-polymeric porous material.
In an embodiment, the non-polymeric porous material is selected from mesoporous silica, colloidal silica, calcium silicate, magnesium silicate aluminosilicate (zeolite), or magnesium aluminosilicate.
In an embodiment, the present invention provides a solid dispersion comprising daprodustat and a pharmaceutically acceptable carrier selected from polyvinyl pyrrolidone (PVP), polyvinylpolypyrrolidone (crospovidone), polyvinyl pyrrolidone-vinyl acetate copolymer (PVP VA), polyethylene glycol, ethyl cellulose, methyl cellulose, cyclodextrin, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose acetate succinate(HPMC-AS), hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropylmethyl cellulose succinate (HPMCS), Eudragit polymer, mesoporous silica, colloidal silica, magnesium aluminosilicate, or a mixture thereof.
In an embodiment, the present invention provides a solid dispersion comprising daprodustat and a polymer selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate or hydroxypropylmethyl cellulose acetate succinate.
In another embodiment, the present invention provides a solid dispersion comprising daprodustat and a polymer selected from hydroxypropylmethyl cellulose (HPMC), or hydroxypropylmethyl cellulose acetate succinate (HPMC-AS) or a mixture thereof.
In yet another embodiment, the present invention provides a solid dispersion comprising daprodustat and a polymer selected from polyvinyl pyrrolidone (PVP), polyvinylpolypyrrolidone (crospovidone), or a mixture thereof.
In an embodiment, the present invention provides a solid dispersion comprising daprodustat and Eudragit polymer as the pharmaceutically acceptable carrier.
In yet another embodiment, the present invention provides a solid dispersion comprising daprodustat and cyclodextrin as the pharmaceutically acceptable carrier.
In another further embodiment, the present invention provides a solid dispersion comprising daprodustat and a non-polymeric porous material selected from mesoporous silica, colloidal silica, magnesium aluminosilicate or a mixture thereof.
In an embodiment, as may be combined with any of the preceding paragraphs, the solid dispersion of the present invention comprising daprodustat and a pharmaceutically acceptable carrier, further comprises a surfactant.
In an embodiment, as may be combined with any of the preceding paragraphs, the surfactant used in the solid dispersion of the present invention is selected from polysorbate 20 (Tween® 20), polysorbate 80 (Tween® 80), sorbitan monolaurate (Span 20®), Sorbitan monooleate (Span 80®), sodium docusate, sodium lauryl sulfate, poloxamers or a mixture thereof.
In an embodiment, as may be combined with any of the preceding paragraphs, the ratio of daprodustat to the pharmaceutically acceptable carrier ranges from about 1: 0.5 to about 1:10 [w/w].
In an embodiment, as may be combined with any of the preceding paragraphs, the ratio of daprodustat to the pharmaceutically acceptable carrier ranges from about 1: 1 to about 1:5 [w/w].
The solid dispersion comprising daprodustat and a pharmaceutically acceptable carrier, with or without surfactant as described in one or more embodiments of the present invention may be an amorphous solid dispersion.
In an embodiment, the present invention provides a solid dispersion comprising daprodustat and an Eudragit polymer, wherein the solid dispersion is characterised by the X-ray powder diffraction pattern substantially as shown in Figure 1.
In another embodiment, the present invention provides a solid dispersion comprising daprodustat and an Eudragit polymer, wherein the solid dispersion is characterised by X-ray powder diffraction pattern (XRPD) having peaks at about 4.01, 6.41, 7.49, 7.98, 15.12, 15.83 and 17.14 9 ±0.2 degrees two theta.
In an embodiment, the present invention provides a solid dispersion comprising daprodustat and mesoporous silica, wherein the solid dispersion is characterised by the X-ray powder diffraction pattern substantially as shown in Figure 2.
In another embodiment, the present invention provides a solid dispersion comprising daprodustat and mesoporous silica, wherein the solid dispersion is characterised by X-ray powder diffraction pattern (XRPD) having peaks at about 4.43, 5.61, 15.05, 18.57 and 20.17±0.2 degrees two theta.
In an embodiment, the present invention provides a solid dispersion comprising daprodustat and hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), wherein the solid dispersion is characterised by the X-ray powder diffraction pattern substantially as shown in Figure 3.
In another embodiment, the present invention provides a solid dispersion comprising daprodustat and hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), wherein the solid dispersion is characterised by X-ray powder diffraction pattern (XRPD) having peaks at about 4.43, 5.56, 7.58, 8.38, 8.95, 15.15 and 20.50 ±0.2 degrees two theta.
In an embodiment, the present invention provides crystalline daprodustat, wherein the crystalline form is characterised by X-ray powder diffraction pattern (XRPD) substantially as shown in Figure 4.
In another embodiment, the present invention provides a crystalline daprodustat, wherein the crystalline form is characterised by X-ray powder diffraction pattern (XRPD) having peaks at about 6.02, 6.82, 15.28, 15.67, 18.60, 27.12, 27.52 and 28.01 ±0.2 degrees two theta.
In one embodiment, the present invention provides crystalline daprodustat, wherein the crystalline form is characterised by X-ray powder diffraction pattern substantially as shown in Figure 4, and is having characteristic X-ray powder diffraction pattern (XRPD) peaks at about 6.02, 6.82, 15.28, 15.67, 18.60, 27.12, 27.52 and 28.01 ±0.2 degrees two theta.
In an embodiment, the present invention provides crystalline daprodustat, wherein the crystalline form is characterised by X-ray powder diffraction pattern substantially as shown in Figure 5.
In one embodiment, the present invention provides crystalline daprodustat, wherein the crystalline form is characterised by X-ray powder diffraction pattern having peaks at about 4.85, 6.85, 15.3, 18.70 and 27.78 ±0.2 degrees two theta.
In one embodiment, the present invention provides crystalline daprodustat, wherein the crystalline form is characterised by X-ray powder diffraction pattern substantially as shown in Figure 5, and is having characteristic X-ray powder diffraction pattern (XRPD) peaks at about 4.85, 6.85, 15.3, 18.70 and 27.78 ±0.2 degrees two theta.
In one embodiment, the present invention provides amorphous daprodustat, substantially as shown in Figure 6.
In an aspect, the present invention also provides a process for the preparation of a solid dispersion comprising daprodustat and a pharmaceutically acceptable carrier selected from a polymer or a non-polymeric porous material; wherein the process comprises the steps of:
a) dissolving daprodustat in a solvent to obtain a solution or a suspension;
b) adding a pharmaceutically acceptable carrier to the solution or suspension obtained in the step (a) to obtain a reaction mixture; and
c) removing the solvent from the reaction mixture obtained in the step b) to obtain the solid dispersion.
In one embodiment, the solvent used in the step (a) of the above process, may be selected from the group consisting of (C1-C6)alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and the like; halogenated hydrocarbons such as methylene dichloride, ethylene dichloride, chloroform and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1-4-dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; dimethyl sulfoxide (DMSO); hydrocarbons such as hexane, heptane, toluene, xylene and the like; N-methyl pyrrolidinone (NMP), water or a mixture thereof.
In an embodiment, the step (a) involving dissolving daprodustat in a solvent is carried out at a temperature ranging from about 20°C to about 35°C.
In an embodiment, the reaction mixture obtained in the step (b) may be stirred for a suitable time. The stirring time may range from about 5 minutes to about 15 hours, or longer.
In an embodiment, the step (b) of the above process further comprises the step of adding a surfactant to the reaction mixture containing daprodustat and a pharmaceutically acceptable carrier selected from a polymer or a non-polymeric porous material.
In another embodiment, the step (b) of the above process further comprises the step of adding a surfactant, wherein the surfactant is added together with the pharmaceutically acceptable carrier selected from a polymer or a non-polymeric porous material to the solution or suspension obtained in the step (a).
In an embodiment, in the step (b) of the above process, the pharmaceutically acceptable carrier selected from a polymer or a non-polymeric porous material is dissolved in a solvent prior to addition to the solution or suspension of the step (a).
In an embodiment, in the step (b) of the above process, the pharmaceutically acceptable carrier selected from a polymer or a non-polymeric porous material, and the surfactant are dissolved in a solvent prior to addition to the solution or suspension of the step (a).
In an embodiment, the solvent used for dissolving the pharmaceutically acceptable carrier selected from a polymer or a non-polymeric porous material and/or the surfactant may be selected from the solvents as described in respect of the step (a) of the above process.
In one embodiment, in the step (c) of the above process the solvent is removed by methods selected from the group consisting of evaporation, distillation, filtration and spray drying.
In an embodiment, the polymer or the non-polymeric porous material used in the step (b) of the above process as described in any of the preceding embodiments related to the the polymers, and/or the non-polymeric porous material.
In an embodiment, the surfactant used in the step (b) of the above process is selected from the surfactants described in any of the preceding embodiments.
In an aspect, the present invention also provides a process for the preparation of a solid dispersion comprising daprodustat and a pharmaceutically acceptable carrier selected from a polymer or a non-polymeric porous material; wherein the process comprises the steps of:
(i) dissolving daprodustat and a pharmaceutically acceptable carrier in a solvent to obtain a solution or a suspension;
(ii) adding the solution or suspension obtained in the step (i) to water to obtain a reaction mixture; and
(iii) removing the solvent from the reaction mixture obtained in the step (ii) to obtain the solid dispersion.
In one embodiment, the solvent used in the step (i) of the above process, may be selected from the solvents as described in the preceding embodiment in respect of the step (a).
In one embodiment, the solvent used in the step (i) of the above process, may be selected from methylene dichloride, ethylene dichloride, chloroform, diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1-4-dioxane, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate, acetone, ethyl methyl ketone, methyl isobutyl ketone or a mixture thereof.
In another embodiment, the solvent used in the step (i) of the above process, may be selected from diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane or a mixture thereof.
In the above process for the preparation of the solid dispersion, the temperature at which the step (i) involving dissolving daprodustat in a solvent is carried out may depend on the specific solvent used.
In an embodiment, the step (i) involving dissolving daprodustat in a solvent is carried out at a temperature ranging from about 20°C to about 60°C.
In an embodiment, the step (i) involving dissolving daprodustat in a solvent is carried out at a temperature ranging from about 40°C to about 50°C.
In another embodiment, the step (i) of the above process further comprises the step of adding a surfactant.
In an embodiment, the surfactant may be added together with the pharmaceutically acceptable carrier selected from a polymer or a non-polymeric porous material in the step (i).
In an embodiment, the surfactant may be added to the solution or suspension obtained in the step (i).
In an embodiment, the reaction mixture obtained in the step (ii) may be stirred for a suitable time. The stirring time may range from about 3 minutes to about 15 hours, or longer.
The stirring time may range from about 3 minutes to about 5 hours.
In an embodiment, in the step (ii) of the above process, the surfactant is dissolved in a solvent prior to addition to the solution or suspension of the step (i).
In an embodiment, the solvent used for dissolving the surfactant may be selected from the solvents as described in respect of the step (a) of the above process.
In one embodiment, in the step (iii) of the above process the solvent is removed by methods selected from the group consisting of evaporation, distillation, filtration and spray drying.
In an embodiment, the pharmaceutically acceptable carrier used in the step (i) of the above process is a polymer which is as described in any of the preceding embodiments related to the polymers per se.
In an embodiment, the pharmaceutically acceptable carrier used in the step (i) of the above process is a non-polymeric porous material which is as described in any of the preceding embodiments related to the non-polymeric porous material per se.
In an embodiment, the surfactant when used in the step (i) or the step (ii) of the above process is selected from the surfactants described in any of the preceding embodiments.
In an aspect, the present invention provides a pharmaceutical composition comprising the solid dispersion as described in any of the preceding embodiments related to the solid dispersion, and optionally one or more pharmaceutical acceptable excipients selected from a diluent, a disintegrant, a binder, a lubricant, a glidant, a surfactant or a mixture thereof.
In an embodiment, the present invention provides a pharmaceutical composition comprising the solid dispersion, wherein the solid dispersion is present in 50 to 80 % w/w.
In an embodiment, the present invention provides a pharmaceutical composition comprising the solid dispersion, wherein the solid dispersion is obtained by the processes for the preparation of the solid dispersion as described herein.
In another embodiment, the pharmaceutical composition comprising the solid dispersion is in solid oral dosage form selected from a tablet or a capsule.
In one aspect, the present invention relates to a method for the treatment of anaemia caused due to chronic kidney disease comprising administering a therapeutically effective amount of the solid dispersion of the present invention, or the pharmaceutical composition comprising the solid dispersion, to a patient in need thereof.
In another aspect, the present invention relates to use of the solid dispersion of the present invention or the pharmaceutical composition comprising the solid dispersion in the treatment of anaemia caused due to chronic kidney disease.
Daprodustat used in the solid dispersion of the present invention has a chemical purity greater than 95% w/w as measured by High-performance liquid chromatography (HPLC).
Daprodustat used in the solid dispersion of the present invention has a chemical purity greater than 99% w/w as measured by HPLC.
In one embodiment, the present invention provides pharmaceutical compositions comprising a solid dispersion of daprodustat obtained by the processes herein described, having a D50 and D90 particle size of less than about 150 microns, preferably less than about 100 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns.
In one embodiment, the present invention pharmaceutical compositions comprising a solid dispersion of daprodustat obtained by the processes herein described, having D90 particle size of less than about 16 microns and D50 particle size of less than about 8 microns.

Examples:
General methods:
X-Ray Powder Diffraction (XRPD) (Instrumental settings) :
The measurements were performed on Philips X-Ray Diffractometer model XPERT-Empyrean (PANalytical) Detector: pixel[1] using Cu lamp with type and wavelength of the X-ray radiation: K-a1 1.54060[Å], K-a2 1.5444[Å]under the following conditions: The measurements were carried out with a Pre Automatic module programmable divergence slit and anti-scatter Slit (Offset 0.00°); Generator settings: 40 mA/45 kV, tube current 40 mAmp Time per step: 50s, Step size: , 0.013 Peak width 2.00 and start angle (o) 2.0 and End angle: 50.0; Scan type: continuous; measurement performed at 25°C. The XRPD instrument is calibrated using NIST SRM 6-40E silicon standard and NIST SRM 1976 Alumina.
Sample preparation: Take an adequate amount of the sample to fill the sample holder using back-loading technique. Then load the sample holder between the X-ray optics-path and scan using the above described parameters. Integrate the obtained powder X-ray diffraction profiles using X’Pert HighScore Plus Software.

Example 1: Preparation of a solid dispersion of daprodustat with Eudragit
Daprodustat (1 g) was dissolved in a mixture of methanol (2 ml) and methylene dichloride (18 ml) at a temperature ranging from 20°C to 30°C to obtain a solution. Eudragit (2 g) was added to the clear solution, and further stirred for about 5 min to about 10 min to get a clear solution. The solution was then subjected to distillation under vacuum at a temperature ranging from 40°C to 45°C to obtain the solid dispersion. Yield: 2.9 gm.

Example 2: Preparation of a solid dispersion of daprodustat with mesoporous silica.
Daprodustat (1 g) was dissolved in a mixture of methanol (2 ml) and methylene dichloride (18 ml) at a temperature ranging from 20°C to 30°C to obtain a solution. Mesoporous silica (2 g) was added to the clear solution, and further stirred for about 5 min to about 10 min to get a clear solution. The solution was then subjected to distillation under vacuum at a temperature ranging from 40°C to 45°C to obtain the solid dispersion.
Yield: 2.9 gm.

Example 3: Preparation of a solid dispersion using daprodustat with HPMC-AS
Daprodustat (1 g) was dissolved in a mixture of methanol (2 ml) and methylene dichloride (18 ml) at a temperature ranging from 20°C to 30°C to obtain a solution. Hydroxypropyl methyl cellulose acetate succinate (HPMC-AS) (1 g) was added to the clear solution, and further stirred to get a clear solution. The solution was then subjected to distillation under vacuum at a temperature ranging from 40°C to 45°C to obtain the solid dispersion.
Yield: 1.8 gm.

Example 4: Preparation of a crystalline daprodustat using spray drying technique
Daprodustat (1 g) was dissolved in a mixture of methanol (2 ml) and methylene dichloride (18 ml) at a temperature ranging from 20°C to 30°C to obtain a solution. The solution was fed into a preheated flask under vacuum at a temperature ranging from 50°C to 55°C to obtain a solid.
Yield: 9 gm.

Example 5: Preparation of a crystalline daprodustat by evaporation
Daprodustat (1 g) was dissolved in a mixture of methanol (2ml) and methylene dichloride (18 ml) at a temperature ranging from 20°C to 30°C to obtain a solution. The solution was evaporated under vacuum at a temperature ranging from 50° to 55°C to obtain a solid.
Yield: 9 gm.

Example 6: Preparation of an amorphous daprodustat by evaporation
Daprodustat (3 g) was dissolved in a mixture of methanol (270 ml) and methylene dichloride (30 ml) at a temperature ranging from 20°C to 30°C to obtain a solution. Hydroxypropyl methyl cellulose acetate succinate (HPMC-AS) (1 g) was added to the clear solution at a temperature ranging from 20°C to 30°C, and further stirred for about 5 min to about 10 min to get a clear solution. The solution was distilled under vacuum at a temperature ranging from 40°C -45°C to obtain a solid.
Yield:5.8 gm.

,CLAIMS:1. A solid dispersion comprising daprodustat or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier selected from a polymer or a non-polymeric porous material.

2. The solid dispersion of claim 1, wherein daprodustat or a pharmaceutically acceptable salt thereof, is in a crystalline form or an amorphous form.

3. The solid dispersion of claim 1 or claim 2, wherein the pharmaceutically acceptable carrier is a polymer selected from homopolymers or copolymers of N-vinyl lactams, cellulose derivatives, polyalkylene oxides, polyacrylates, polymethacrylates (Eudragit polymers), vinyl acetate polymers, polyacrylamides, polyvinyl alcohol, oligo- or polysaccharides, polyhydroxyalkylacrylates, polyhydroxyalkyl-methacrylates, copolymers of methyl methacrylate and acrylic acid, polyethylene glycols (PEGs), or a mixture thereof.

4. The solid dispersion of any one of claims 1, 2 and 3, wherein the polymer is a Eudragit polymer.

5. The solid dispersion of any one of claims 1, 2, and 3, wherein the polymer is selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate, hydroxypropylmethyl cellulose acetate succinate, or a mixture thereof.

6. The solid dispersion of claim 1 or claim 2, wherein the pharmaceutically acceptable carrier is a non-polymeric porous material selected from mesoporous silica, colloidal silica, calcium silicate, magnesium silicate, aluminosilicate (zeolite) or magnesium aluminosilicate.

7. The solid dispersion as claimed in any one of the preceding claims 1 to 6, wherein the ratio of daprodustat to the pharmaceutically acceptable carrier ranges from about 1: 0.5 to about 1:10 [w/w].

8. The solid dispersion as claimed in in any one of the preceding claims 1 to 7, wherein the solid dispersion further comprises a surfactant selected from polysorbate 20 (Tween® 20), polysorbate 80 (Tween® 80), sorbitan monolaurate (Span 20®), Sorbitan monooleate (Span 80®), sodium docusate, sodium lauryl sulfate, poloxamers or a mixture thereof.

9. A process for the preparation of a solid dispersion comprising daprodustat and a pharmaceutically acceptable carrier; wherein the process comprises the steps of:
a) dissolving daprodustat in a solvent to obtain a solution or a suspension;
b) adding a pharmaceutically acceptable carrier to the solution or suspension obtained in the step (a) to obtain a reaction mixture; and
c) removing the solvent from the reaction mixture obtained in the step b) to obtain the solid dispersion.

10. A process for the preparation of a solid dispersion comprising daprodustat and a pharmaceutically acceptable carrier; wherein the process comprises the steps of:
(i) dissolving daprodustat and a carrier in a solvent to obtain a solution or a suspension;
(ii) adding the solution or suspension obtained in the step (i) to water to obtain a reaction mixture; and
(iii) removing the solvent from the reaction mixture obtained in the step (ii) to obtain the solid dispersion.

11. A process for the preparation of the solid dispersion as claimed in claim 9 or claim 10, wherein the process further comprises a step of adding a surfactant.

12. The process as claimed in claim 9 or claim 10, wherein in the step (iii), the solvent is removed by a method selected from the group consisting of evaporation, distillation, filtration and spray drying.