DESC:Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:

By the term “composition” as used herein refers to a solid dosage form suitable for oral administration, such as a tablet, capsule, spheroids, mini-tablets, pellets, granules, pills and the like; preferably, oral tablets.

The singular forms “a,” “an,” and “the” and the like include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes both a single compound and a plurality of different compounds.

The term “about” when used before a numerical designation, e.g., temperature, time, amount, and concentration, including a range, indicates approximations which may vary by ±10%, ±5% or ±1%.

The term “solvate” refers to a complex formed by the combining of Compound A and a solvent.

The terms “substantially amorphous” and “mostly amorphous” refer to amorphous Compound A where a small amount of crystalline Compound A may be present. In some embodiments, the amount of crystalline Compound A is less than about 10%, or less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.2%, or less than about 0.1%.

“Administration” refers to introducing an agent into a patient. A therapeutic amount can be administered, which can be determined by the treating physician or the like. An oral route of administration is preferred for the crystalline forms of compound a described herein. The related terms and phrases “administering” and “administration of”, when used in connection with a compound or pharmaceutical composition (and grammatical equivalents) refer both to direct administration, which may be administration to a patient by a medical professional or by self-administration by the patient, and/or to indirect administration, which may be the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient. In any event, administration entails delivery of the drug to the patient.

“Therapeutically effective amount” or “therapeutic amount” refers to an amount of a drug or an agent that when administered to a patient suffering from a condition, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of the condition in the patient. The therapeutically effective amount will vary depending upon the subject and the condition being treated, the weight and age of the subject, the severity of the condition, the composition or excipient chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can be determined readily by one of ordinary skill in the art. The full therapeutic effect does not necessarily occur by administration of one dose and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. For example, and without limitation, a therapeutically effective amount of an agent, in the context of treating anemia, refers to an amount of the agent that alleviates, ameliorates, palliates, or eliminates one or more symptoms of anemia in the patient.

“Treatment”, “treating”, and “treat” are defined as acting upon a disease, disorder, or condition with an agent to reduce or ameliorate the harmful or any other undesired effects of the disease, disorder, or condition and/or its symptoms. Treatment, as used herein, covers the treatment of a human patient, and includes: (a) reducing the risk of occurrence of the condition in a patient determined to be predisposed to the disease but not yet diagnosed as having the condition, (b) impeding the development of the condition, and/or (c) relieving the condition, i.e., causing regression of the condition and/or relieving one or more symptoms of the condition.

Suitable routes of administration may, for example, include oral, rectal, transmucosal, nasal, or intestinal administration and parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections. The crystalline form or composition thereof may be administered in a local rather than a systemic manner. For example, a crystalline form or composition thereof can be delivered via injection or in a targeted drug delivery system, such as a depot or sustained release formulation. In one embodiment, the route of administration is oral.

The pharmaceutical compositions of the present disclosure may be manufactured by any of the methods well-known in the art, such as by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.

As noted above, the compositions can include one or more pharmaceutically acceptable excipients that facilitate processing of active molecules into preparations for pharmaceutical use.

Present invention relates to a pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, processes for the preparation of the pharmaceutical composition.

Present invention relates to a pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof, one or more pharmaceutically acceptable excipients. where in the pharmaceutical composition is oral solid dosage form.

Present invention relates to a pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients. where in formulations is prepared into powders, granules and tablets, methods for manufacturing and processing the powders, granules and tablets.

Present invention relates to a pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof, one or more pharmaceutically acceptable excipients, wherein the Roxadustat having 10-70% w/w of the composition.

Present invention relates to a process for the preparation of Roxadustat or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients having comparable dissolution properties, content uniformity, stability and equivalent bioavailability w.r.t commercialized Roxadustat dosage form.

Present invention relates to a pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients like diluent, binder, glidant, lubricant, solubilizer, antacid, disintegrant and colorant.

Present invention relates to a pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof, one or more pharmaceutically acceptable excipients, where in the particle size of Roxadustat is less than 250 microns, preferably less than 100 microns, more preferably less than 50 microns.

Present invention relates to a pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof, one or more pharmaceutically acceptable excipients, where in Roxadustat is in the form of crystalline of amorphous form.

The term "composition" or "formulation" or "dosage form" has been employed interchangeably for the purpose of the present invention and mean that it is a pharmaceutical composition which is suitable for administration to a patient or subject.

The subject can be an animal, preferably a mammal, more preferably a human. For the purpose of the present invention terms "immediate release" or "sustained release" or "extended release" or "prolonged release" have been used interchangeably and mean broadly that Roxadustat.

The term “pharmaceutically acceptable” as used herein means that which is useful in preparing a pharmaceutical composition that is generally safe and non-toxic.

The term “excipients” as used herein means a component of a pharmaceutical product that is not an active ingredient such as, for example, fillers, diluents, carriers and the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.

Diluents according to the present invention include but not limited to lactose monohydrate, lactose anhydrous, fructose, dextrose, dextrates, dextrins, mannitol, lactitol, sorbitol, starch, sucrose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, or combinations thereof.

Binders according to the present invention include but not limited to hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, gelatin, ethyl cellulose, polyvinyl alcohol, pregelatinized starch, carboxymethyl cellulose, Polysorbate 80, sodium alginate, microcrystalline cellulose, calcium hydrogen phosphate and the like or combinations thereof.

Disintegrants according to the present invention include but not limited to starches or modified starches such as pregelatinized starch, croscarmellose sodium, crospovidone, sodium starch glycolate, low substituted hydroxypropyl cellulose, hydroxypropyl cellulose, chitosan and the like or combinations thereof.

Surfactants according to the present invention may be selected from anionic, cationic or non- ionic surface-active agents or surfactants. Suitable anionic surfactants include but not limited to carboxylate, sulfonate, and sulfate ions such as sodium lauryl sulfate (SLS), sodium laurate, dialkyl sodium sulfosuccinates particularly bis- (2-ethylhexyl) sodium sulfosuccinate, sodium stearate, potassium stearate, sodium oleate and the like. Suitable cationic surfactants include but not limited to those containing long chain cations, such as benzalkonium chloride, bis-2- hydroxyethyl oleyl amine or the like.

Lubricants and/or glidants according to the present invention include but not limited to colloidal silicon dioxide, stearic acid, magnesium stearate, Syloid XDP, calcium stearate, sodium stearyl fumarate, talc, hydrogenated castor oil, and mixtures thereof.

The term “photostabilizing agent” is an agent that prevents or reduces the photodegradation or photodecomposition of a molecule upon exposure to light (light under ICH condition, sunlight, indoor light, etc.). In other words, the photostabilizing agent functions to prevent or reduce the formation of photodegradation products. Typically, the photostabilizing agent prevents or reduces the photodegradation of the light-sensitive molecule by blocking the exposure of the molecule to light within a wavelength range. Non-limiting examples of photostabilizing agents include pigments, dyes, dye lakes, and the like.
The term “photodegradation” and “photodecomposition” are used interchangeably throughout the disclosure.

The term “effective amount” of a photostabilizing agent refers to the amount of a photostabilizing agent in a pharmaceutical formulation that is sufficient to prevent or reduce the photodegradation of the active pharmaceutical ingredients (API), such that the amount of photodegradation product(s) that is produced is limited to a desired maximum level under specified light conditions. In the embodiments described herein, the effective amount of a photostabilizing agent is the amount sufficient to limit the amount of photodegradation product of Compound A that is produced to a level that is less than about 0.2% w/w Compound A (or 2000 ppm), under ICH conditions. In some embodiments, the effective amount of photostabilizing agent may limit the amount of photodegradation product of Compound A that is produced to a level that is less than about 0.15% w/w Compound A, less than about 0.1% w/w Compound A, or less than 0.05% w/w Compound A. As will be apparent to one skilled in the formulation’s art, the effective amount of a stabilizing agent will vary with the particular agent used. Using the disclosure herein, particularly the analytical methods described in the examples, and the general knowledge in the formulation’s art, one of ordinary skill in the art can readily determine the amount of any particular agent (or combination of agents) that will achieve the level of photo protection (i.e., reduction of the production of photodegradation product) sufficient to limit photodegradation product to the desired maximum level.

The term “photodegradation product” as used herein refers to a new molecule that is formed from Compound A upon exposing Compound A to light. The photodegradation product may be detected by a variety of standard analytical methods (e.g., high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS), gas chromatography (GC), nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FTIR), etc.). In one embodiment, the photodegradation product may be detected and measured by HPLC.

The photostabilizing agent comprises a soluble dye, a dye lake, a pigment or a combination thereof. In one embodiment, the photostabilizing agent comprises titanium dioxide and at least one additional dye. In one embodiment, the dye is selected from the group consisting of a black dye, a blue dye, a green dye, a red dye, an orange dye, a purple dye, a violet dye, a yellow dye, and combinations thereof. In another embodiment, the dye is selected from the group consisting of a black dye, a blue dye, a green dye, a red dye, an orange dye, a yellow dye, and combinations thereof. In yet another embodiment, the dye is selected from the group consisting of a red dye, an orange dye, a yellow dye, and combinations thereof.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, processes for the preparation of the pharmaceutical composition.

In one of the embodiments of the present invention relates to a process for preparation contain sift the microcrystalline cellulose, lactose monohydrate and Roxadustat blend, dry mix the content, prepare the binder solution with povidone and water, granulate the above obtained mixture and co shift croscarmellose sodium, magnesium stearate, lubricate and compress with suitable tools.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, where in the composition is in the form of a tablet or capsule.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients are:

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, where in the composition is prepared by wet granulation, dry granulation method or direct compression.

In one of the embodiments of the present invention relates to a process for the preparation of Roxadustat or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients having comparable dissolution properties, content uniformity, stability and equivalent bioavailability w.r.t commercialized Roxadustat dosage form.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the Roxadustat having 10-70% w/w of the composition.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the particle size of Roxadustat is less than 250 microns, preferably less than 100 microns, more preferably less than 50 microns.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the Roxadustat is in the form of crystalline of amorphous form.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof, one or more pharmaceutically acceptable excipients like diluent, fillers, disintegrating, binder, glidant, lubricant, solubilizer, antacid, disintegrant and colorant.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof, one or more pharmaceutically acceptable excipients, where in the coating does not contain photo stabilizing agent titanium di oxide.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof, one or more pharmaceutically acceptable excipients, where in the coating layer contain photo stabilizing agent is iron oxide.
In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof, one or more pharmaceutically acceptable excipients, where in the coating contain photo stabilizing agent titanium di oxide, Lecithin (Soy), polyethylene glycol, polyvinyl alcohol, talc, allura red ac aluminium lake.

In one of the embodiments of the present invention relates to a pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof, one or more pharmaceutically acceptable excipients, where in the composition does not contain coating material.

Examples:
Example 1:
S. No. Ingredients mg/Tablet % w/w
20 mg 50 mg 70 mg 100 mg 150 mg
Intragranular
1 Roxadustat 20.00 50.00 70.00 100.00 150.00 25.00
2 Lactose Monohydrate 42.60 106.50 149.10 213.00 319.50 53.25
3 Microcrystalline cellulose PH 101 9.12 22.80 31.92 45.60 68.40 11.40
Binder
4 Povidone K 30 3.60 9.00 12.60 18.00 27.00 4.50
5 Purified water q.s. q.s. q.s. q.s. q.s. NA
Extra granular
6 Croscarmellose Sodium 4.00 10.00 14.00 20.00 30.00 5.00
7 Magnesium stearate/
Calcium stearate 0.68 1.70 2.38 3.40 5.10 0.85
Total weight of uncoated tablets 80.00 200.00 280.00 400.00 600.00 100.00
Film coating
8 Opadry II Red 85G550037* 4.00 8.00 8.4 12.00 18.00 --
9 Purified water q.s. q.s. q.s. q.s. q.s. q.s.
Total weight of coated tablet 84.00 208.00 288.40 412.00 618.00 --

Coating material Composition – Lecithin (Soy), Polyethylene glycol, Polyvinyl Alcohol, Talc, Titanium Di oxide, FD&C Red #40/Allura Red Ac Aluminium Lake.

1. Sifting:
I. sift the Microcrystalline cellulose PH 101 and Lactose Monohydrate through #30 mesh .
II. co-sift Roxadustat API and step 1 Blend through 30 # mesh.
2. Dry mixing : Load the step II Dry mix in Rapid Mixer Granulator and mix for 10 minutes at impeller slow speed and Chopper off.
3. Binder preparation: Add required quantiry of Purified water and kept under stirring, to that add weighed quantity of Povidone K 30 under stirring upto clear solution was formed.
4. Granulation: Granulate the step 2 with step 3 Binder solution to attain desired granules and dried to attain desired %LOD and all the dried granules passes through 30# mesh.
5. Extragranular agents: Sift Croscarmellose sodium through 40# mesh and blend with step 4 in asuitable blender upto 10 minutes.
6. Sift Magnesium stearate through 60# mesh.
7. Lubrication: Blend the step 5 materials with step 6 for 5 mins.
8. Compression: Compress the above blend by using suitable punches.

Example 2:
Manufacturing Formula:
S. No. Ingredients mg/Tablet % w/w
20 mg 50 mg 70 mg 100 mg 150 mg
Intragranular
1 Roxadustat 20.00 50.00 70.00 100.00 150.00 25.00
2 Lactose Monohydrate 42.60 106.50 149.10 213.00 319.50 53.25
3 Microcrystalline cellulose PH 101 9.12 22.80 31.92 45.60 68.40 11.40
Binder
4 Povidone K 30 3.60 9.00 12.60 18.00 27.00 4.50
5 Purified water q.s. q.s. q.s. q.s. q.s. NA
Extra granular
6 Croscarmellose Sodium 4.00 10.00 14.00 20.00 30.00 5.00
7 Magnesium stearate/
Calcium stearate 0.68 1.70 2.38 3.40 5.10 0.85
Total weight of uncoated tablets 80.00 200.00 280.00 400.00 600.00 100.00
Film coating
8 Opadry II Red 85G550037* 4.00 8.00 8.4 12.00 18.00 --
9 Purified water q.s. q.s. q.s. q.s. q.s. q.s.
Total weight of coated tablet 84.00 208.00 288.40 412.00 618.00 --

Coating material Composition – Lecithin (Soy), Polyethylene glycol, Polyvinyl Alcohol, Talc, Calcium Carbonate, Calcium hydrogen phosphate, FD&C Red #40/Allura Red Ac Aluminium Lake

1. Sifting:
III. sift the Microcrystalline cellulose PH 101 and Lactose Monohydrate through #30 mesh .
IV. co-sift Roxadustat API and step 1 Blend through 30 # mesh.
2. Dry mixing : Load the step II Dry mix in Rapid Mixer Granulator and mix for 10 minutes at impeller slow speed and Chopper off.
3. Binder preparation: Add required quantiry of Purified water and kept under stirring, to that add weighed quantity of Povidone K 30 under stirring upto clear solution was formed.
4. Granulation: Granulate the step 2 with step 3 Binder solution to attain desired granules and dried to attain desired %LOD and all the dried granules passes through 30# mesh.
5. Extragranular agents: Sift Croscarmellose sodium through 40# mesh and blend with step 4 in asuitable blender upto 10 minutes.
6. Sift Magnesium stearate through 60# mesh.
7. Lubrication: Blend the step 5 materials with step 6 for 5 mins.
8. Compression: Compress the above blend by using suitable punches.

Example -3:
S. No. Ingredients mg/Tablet % w/w
20 mg 50 mg 70 mg 100 mg 150 mg
Intragranular
1 Roxadustat 20.00 50.00 70.00 100.00 150.00 25.00
2 Lactose Monohydrate 42.60 106.50 149.10 213.00 319.50 53.25
3 Microcrystalline cellulose PH 101 9.12 22.80 31.92 45.60 68.40 11.40
Binder
4 Povidone K 30 3.60 9.00 12.60 18.00 27.00 4.50
5 Purified water q.s. q.s. q.s. q.s. q.s. NA
Extra granular
6 Croscarmellose Sodium 4.00 10.00 14.00 20.00 30.00 5.00
7 Magnesium stearate 0.68 1.70 2.38 3.40 5.10 0.85
Total weight of uncoated tablets 80.00 200.00 280.00 400.00 600.00 100.00

1. Sifting:
I. sift the Microcrystalline cellulose PH 101 and Lactose Monohydrate through #30 mesh .
II. co-sift Roxadustat API and step 1 Blend through 30 # mesh.
2. Dry mixing : Load the step II Dry mix in Rapid Mixer Granulator and mix for 10 minutes at impeller slow speed and Chopper off.
3. Binder preparation: Add required quantiry of Purified water and kept under stirring, to that add weighed quantity of Povidone K 30 under stirring upto clear solution was formed.
4. Granulation: Granulate the step 2 with step 3 Binder solution to attain desired granules and dried to attain desired %LOD and all the dried granules passes through 30# mesh.
5. Extragranular agents: Sift Croscarmellose sodium through 40# mesh and blend with step 4 in asuitable blender upto 10 minutes.
6. Sift Magnesium stearate through 60# mesh.
7. Lubrication: Blend the step 5 materials with step 6 for 5 mins.
8. Compression: Compress the above blend by using suitable punches.
,CLAIMS:1) A oral pharmaceutical composition comprising Roxadustat or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the composition contain 10-70% w/w of the Roxadustat from the total weight of the composition.

2) The oral pharmaceutical composition as claimed in claim 1, wherein the composition contain one or more pharmaceutically acceptable excipients are diluent, fillers, disintegrating, binder, glidant, lubricant, solubilizer, antacid, disintegrant and colorant.

3) The oral pharmaceutical composition as claimed in claim 1, wherein the composition contains one or more pharmaceutically acceptable excipients are lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, magnesium stearate or calcium stearate.

4) The oral pharmaceutical composition as claimed in claim 1, wherein the composition is an oral tablet or capsule pharmaceutical dosage form.

5) The oral pharmaceutical composition as claimed in claim 1, wherein the composition is prepared by wet granulation or dry granulation or direct compression method.

6) The oral pharmaceutical composition as claimed in claim 1, wherein the composition contain particle size is less than 500 microns, preferably less than 300 microns, more preferably less than 100 microns.

7) The oral pharmaceutical composition as claimed in claim 1, wherein the composition may or may not contain film coating material.

8) The process for preparation of pharmaceutical composition as claimed in claim 1, where in the process involved in the steps sift the inactive ingredients with Roxadustat or its salts dry mix the content prepare the binder solution by adding povidone perform the granulation with the obtained substance to attain desired granules, perform the extra granulation, lubricate, compress the blend with suitable punches.

9) The pharmaceutical composition as claimed in claim 1, wherein the composition is used for the treatment of symptomatic anemia associated with chronic kidney disease (CKD).