FORMULATION COMPRISING DAPRODUSTAT
The present disclosure relates to an immediate release tablet of daprodustat having good tensile strength. In other aspects, medical uses of the immediate release tablet and dosage regimens for using the immediate release tablet are disclosed.
1 . An immediate release tablet comprising from 1 to 10 mg (measured as the free acid) daprodustat or a pharmaceutically acceptable salt thereof which has a tablet tensile strength of greater than or equal to 1.7 MPa following compaction of the tablet core at a pressure in the range of 200 to 290 MPa.
2 . An immediate release tablet according to claim 1 , wherein the tablet tensile strength is greater than or equal to 1.75 MPa following compaction of the tablet core at a pressure in the range of 200 to 290 MPa.
3 . An immediate release tablet according to claim 1 wherein said daprodustat or a pharmaceutically acceptable salt thereof is a crystalline form of non-solvated daprodustat free acid characterised by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.4+/−0.2, 7.5+/−0.2 and 8.0+/−0.2 degrees 2θ.
4 . An immediate release tablet according to claim 3 , wherein the tablet comprises a compartment containing the crystalline form of non-solvated daprodustat free acid in an amount up to 5% based on the weight of the free acid, where the compartment does not contain a glidant.
5 . An immediate release tablet according to claim 4 , wherein the compartment is the entire tablet core.
6 . An immediate release tablet according to claim 4 , wherein the compartment is a granule within the tablet.
7 . An immediate release tablet according to claim 6 which tablet consists of:
a) intragranular components comprising the crystalline form of non-solvated daprodustat free acid, a diluent, a binder and a disintegrant; and
b) extragranular components comprising a diluent, a disintegrant, a lubricant, and optionally a glidant;
wherein the tablet is optionally coated.
8 . An immediate release tablet according to claim 7 , which tablet consists of:
a) intragranular components consisting of the crystalline form of non-solvated daprodustat free acid and one or more diluents, one or more binders and one or more disintegrants; and
b) extragranular components comprising a diluent, a disintegrant, a lubricant, and optionally a glidant;
wherein the tablet is optionally coated.
9 . An immediate release tablet according to claim 8 , wherein the tablet contains up to 76% by weight of intragranular components based on the weight of the uncoated tablet.
10 . An immediate release tablet according to claim 4 , wherein the glidant is colloidal silicon dioxide.
11 . An immediate release tablet according to claim 8 , wherein:
i. the intragranular components comprise:
i. 1 to 10 mg of the crystalline form of non-solvated daprodustat free acid;
ii. about 5 wt % hypromellose;
iii. about 1.5 wt % croscarmellose sodium; and
iv mannitol and microcrystalline cellulose in a weight ratio from about 2.2 to about 3.6;
ii. the extragranular components comprise, based on the total weight of the extragranular components:
i. about 12 wt % croscarmellose sodium;
ii. about 4 wt % magnesium stearate;
iii. about 1.5% colloidal silica; and
iv. mannitol and microcrystalline cellulose in a weight ratio of about 2.
12 . An immediate release tablet according to claim 11 , wherein the tablet comprises about 1, 2 or 4 mg daprodustat and has a core tablet weight of about 150 mg.
13 . An immediate release tablet according to claim 11 , wherein the tablet comprises about 6 or 8 mg daprodustat and has a core tablet weight of about 300 mg.
14 . An immediate release tablet according to claim 12 , wherein the tablet is film-coated.
15 . An immediate release tablet according to claim 13 , wherein the tablet does not comprise lactose.
16 - 27 . (canceled)
28 . A method for the treatment of anemia due to chronic kidney disease in a subject in need thereof, comprising administering to said subject the immediate release tablet according to claim 1 .
29 . A method according to claim 28 , wherein the subject is receiving dialysis.
30 . A method according to claim 28 , wherein the subject is iron deficient and wherein the subject additionally receives supplemental iron therapy.
31 . A method according to claim 28 , wherein the immediate release tablet of the invention is administered once daily at a dose of either 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 12 mg, 18 mg or 24 mg and wherein the dose is increased or decreased by one dose step based on the haemoglobin concentration of the patient to maintain the haemoglobin concentration of the patient within the range 10-11 g/dL.
32 . A method according to claim 31 , wherein the patient is not on dialysis.
33 . A method according to claim 32 wherein the starting dose for the immediate release tablet is 4 mg once daily (where the patient has previously been treated with an erythropoiesis stimulating agent, or where the patient has not previously been treated with an erythropoiesis stimulating agent and has a haemoglobin concentration of <9/0 g/dL) or 2 mg once daily (where the patient has not previously been treated with an erythropoiesis stimulating agent and has a haemoglobin concentration of ≥9.0 g/dL).
34 . A method according to claim 28 , wherein the immediate release tablet is administered three times per week at a dose of either 2 mg, 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, 36 mg or 48 mg and wherein the dose is increased or decreased by one dose step based on the haemoglobin concentration of the patient to maintain the haemoglobin concentration of the patient within the range 10-11 g/dL.
35 . A method according to claim 34 , wherein the patient is on dialysis.
36 . A method according to claim 35 , wherein the starting dose is 8, 12, 16 or 24 mg three times per week.
37 . A method according to claim 31 , wherein the haemoglobin concentration of the patient is monitored at least once every three months.
38 . A method according to claim 34 , wherein the haemoglobin concentration of the patient is monitored at least once every three months.
39 . A method according to claim 37 , wherein when there is an increase in haemoglobin concentration of the patient exceeding 2.0 g/dL within 4 weeks, the dose is reduced by one dose step or interrupted.
40 . A method according to claim 38 , wherein when there is an increase in haemoglobin concentration of the patient exceeding 2.0 g/dL within 4 weeks, the dose is reduced by one dose step or interrupted.