Formulations Comprising Daprodustat

Abstract

The present disclosure relates to immediate-release tablets of daprodustat having good tensile strength. In other aspects, pharmaceutical uses of the immediate-release tablets and dosing regimens for using the immediate-release tablets are disclosed.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present disclosure relates to daprodustat immediate release tablets having good tensile strength. In other aspects, medical uses of the immediate release tablets and dosing regimens for using the immediate release tablets are disclosed. [Background technology]

[0002] Background of the Invention Tablets must have suitable mechanical strength to prevent shattering or breakage during downstream processing and handling, while ensuring suitable disintegration after oral administration. Assessment of tablet mechanical strength is therefore routinely performed during tablet manufacture as a measure of product robustness.

[0003] The physical properties of the drug and excipients used in tablets significantly affect the mechanical properties of the resulting tablets, including tablet tensile strength. For example, Shah et al. reported the effect of the bulk density of two widely used microcrystalline cellulose preparations on tablet tensile strength and friability (World Journal of Pharmaceutical Research, 2017, 6(10):841-852). The authors reported a correlation between bulk density and tensile strength, and these parameters were inversely proportional to each other. Similarly, a correlation was found between bulk density and friability, and these parameters were also inversely proportional to each other.

[0004] Daprodustat is a prolyl hydroxylase inhibitor currently in development for the treatment of anemia due to chronic kidney disease. A tablet formulation of daprodustat is disclosed in WO 2019 / 052133. There is a need for daprodustat tablets that have sufficient tablet tensile strength to allow for normal storage, distribution, and handling. Summary of the Invention

[0005] In a first aspect, the present invention provides immediate release tablets comprising 1 to 10 mg (measured as the free acid) of daprodustat or a pharmaceutically acceptable salt thereof, having a tablet tensile strength of 1.7 MPa or greater after compression of the tablet core at a pressure in the range of 200 to 290 MPa.

[0006] In a second aspect, the present invention provides an immediate release tablet of the invention for use in therapy, including the treatment of anemia resulting from chronic kidney disease.

[0007] In a third aspect, the present invention provides an immediate release tablet of the present invention for use in treating anemia due to chronic kidney disease, the immediate release tablet being administered once daily at one of the following doses: 1, 2, 4, 6, 8, 10, 12, 16 and 24 mg (dose of the free acid) according to the following dosing regimen: If the hemoglobin concentration is 12 g / dL or higher, daprodustat treatment is discontinued and treatment at the next lower dose is initiated until the hemoglobin concentration is less than 11.5 g / dL; b. If hemoglobin concentration is within the range of ≥9.5 to <11.5 g / dL, the dose is maintained; c. If the hemoglobin concentration is within the range of >11 to ≤11.5 g / dL at two consecutive clinic visits and there has been an increase or no change in hemoglobin concentration since the last visit, the dose will be reduced by one dose step; d. If hemoglobin concentration is within the range of >11.5 to <12 g / dL and there has been a decrease in hemoglobin concentration since the last visit, the dose will be maintained. e. If hemoglobin concentration is within the range of >11.5 to <12 g / dL and there has been an increase or no change in hemoglobin concentration since the last visit, the dose will be reduced by one dose step; f. If the hemoglobin concentration is within the range of ≥9.5 to <10 at two consecutive clinic visits and there has been a decrease or no change in hemoglobin concentration since the last visit, the dose will be increased by one dose step; g. If hemoglobin concentration is within the range of 7.5 to <9.5 g / dL and hemoglobin concentration has increased by 0.5 g / dL or more since the last visit, the dose will be maintained; h. If the hemoglobin concentration is within the range of 7.5 to <9.5 g / dL and there has been a decrease in hemoglobin concentration since the last visit, no change, or an increase of less than 0.5 g / dL, the dose will be increased by one dose step; i. If hemoglobin concentration is less than 7.5 g / dL, the dose is increased by one dose step; j. If the hemoglobin concentration increases by more than 2 g / dL in 4 weeks or if the hemoglobin concentration increases by more than 1 g / dL in 2 weeks, the dose will be reduced by one dose step; k. If the hemoglobin concentration decreases by more than 2 g / dL in 4 weeks or if the hemoglobin concentration decreases by more than 1 g / dL in 2 weeks, the dose will be increased by one dose step. It is administered according to the following.

[0008] In one embodiment, the immediate release tablets of the present invention are administered once daily at one of the following doses: 1, 2, 4, 6, 8, 12, 16, and 24 mg (free acid dose) according to the dosing regimens described herein. [Brief explanation of the drawings]

[0009] [Figure 1] 1 is a scanning electron microscope image of the non-solvated crystalline form of daprodustat free acid. [Figure 2] 1 shows the X-ray powder diffraction pattern of the non-solvated crystalline form of daprodustat free acid. Specific Description of the Invention

[0010] definition Immediate release tablets comprising 1 to 10 mg (measured as the free acid) of daprodustat or a pharmaceutically acceptable salt thereof may be formulated to have the following dissolution criteria: 1. An average of 85% or more of the daprodustat content of the tablets (based on at least 12 tablets) dissolves within 45 minutes in a pH 6.8 buffer or enzyme-free Simulated Intestinal Fluid, USP, using United States Pharmacopeia (USP) Apparatus 2 at a rotation speed of 50 ± 2 rpm and a dissolution volume of 500 ± 5 mL for tablets containing less than 2 mg of daprodustat (measured as the free acid) and 900 ± 9 mL for tablets containing 2 mg or more of daprodustat (measured as the free acid). The tablet contains 1 to 10 mg (measured as the free acid) of daprodustat or a pharmaceutically acceptable salt thereof, which satisfies the above.

[0011] In one embodiment, the dissolution profile of an immediate release tablet comprising 1-10 mg (measured as the free acid) of daprodustat or a pharmaceutically acceptable salt thereof using United States Pharmacopeia (USP) Apparatus 2 under the conditions specified above, compared to a tablet containing the same dose of active pharmaceutical ingredient as described in Example 3, must further exhibit an f2 value of ≧50. In one embodiment, the tablet of Example 3 was compressed using a main compression pressure of 200-290 MPa, more particularly 240-260 MPa, and even more particularly about 250 MPa.

[0012] In the context of the present invention, the term tablet core refers to the entire tablet excluding the coating.

[0013] Tablet tensile strength is a measure of the robustness of a tablet and may be measured by any method known in the art, for example, by using a diametral compression test. In one embodiment, tablet tensile strength (measured in MPa) is determined using the method published by Pitt and Newton (Journal of Materials Science 23, 2723-2728, 1988).

[0014] The term "flow agent" refers to an excipient that can improve the flow of poorly flowing powders. Flow agents include colloidal silicon dioxide, talc, starch, and magnesium stearate. While magnesium stearate is often used as a lubricant, it also increases the flow of poorly flowing powders at concentrations typically used in formulations (addition of up to 4% magnesium stearate has been reported to improve the flow of spray-dried lactose; see Morin and Brians, AAPS PharmSciTech. 2013 Sep; 14(3): 1158-1168).

[0015] In the context of the present invention, a tablet compartment is a portion of the tablet that has the same composition. For example, the granules and the extragranular space can be separate compartments within the tablet. Different layers of a multi-layer tablet can form separate compartments. In addition, the entire monolithic tablet can be a single compartment.

[0016] Active Pharmaceutical Ingredients The tablets of the present invention comprise 1 to 10 mg (measured as the free acid) of daprodustat or a pharmaceutically acceptable salt thereof. Daprodustat is the USAN, INN, and JAN name for the compound N-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine (the IUPAC name for this compound is N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl]glycine). Daprodustat exhibits keto / enol tautomerism. All tautomers of daprodustat, including mixtures thereof, are intended to be encompassed within the scope of the present invention.

[0017] Daprodustat or a pharmaceutically acceptable salt thereof may be prepared according to the process disclosed in WO 2007 / 150011. In one embodiment, the tablet contains 1 to 10 mg of daprodustat free acid.

[0018] In certain embodiments, the daprodustat free acid is: 1) a sharp melting point of 240-242°C as determined by thermogravimetric analysis; and / or 2) Cu K α an X-ray powder diffraction (XRPD) pattern comprising at least five diffraction angles selected from the group consisting of 4.0+ / -0.2, 6.4+ / -0.2, 7.5+ / -0.2, 8.0+ / -0.2, 15.2+ / -0.2, 17.2+ / -0.2, 18.6+ / -0.2, 19.3+ / -0.2, 19.9+ / -0.2, 20.4+ / -0.2, 21.0+ / -0.2, and 24.1+ / -0.2 degrees 2θ when measured using a It is a non-solvated crystalline form characterized by:

[0019] This crystalline form may be prepared according to the methods described in Examples 1 to 4 of WO 2019 / 052133.

[0020] In certain embodiments, the non-solvated crystalline form of daprodustat free acid is Cu K α The compound is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five diffraction angles selected from the group consisting of 4.0+ / -0.2, 6.4+ / -0.2, 7.5+ / -0.2, 8.0+ / -0.2, 15.2+ / -0.2, 17.2+ / -0.2, 18.6+ / -0.2, 19.3+ / -0.2, 19.9+ / -0.2, 20.4+ / -0.2, 21.0+ / -0.2 and 24.1+ / -0.2 degrees 2θ when measured using a 200 kHz X-ray diffraction (XRPD) pattern.

[0021] In certain embodiments, the non-solvated crystalline form of daprodustat free acid is Cu K αand 24.1+ / -0.2 degrees 2θ, as measured using a 200 kHz X-ray powder diffraction (XRPD) pattern comprising at least 6, 7, 8, or 9 diffraction angles selected from the group consisting of 4.0+ / -0.2, 6.4+ / -0.2, 7.5+ / -0.2, 8.0+ / -0.2, 15.2+ / -0.2, 17.2+ / -0.2, 18.6+ / -0.2, 19.3+ / -0.2, 19.9+ / -0.2, 20.4+ / -0.2, 21.0+ / -0.2, ...

[0022] In one embodiment, the non-solvated crystalline form of daprodustat free acid is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least the following diffraction angles 2θ 6.4+ / −0.2, 7.5+ / −0.2, and 8.0+ / −0.2 degrees.

[0023] In one embodiment, the non-solvated crystalline form of daprodustat free acid is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least the following diffraction angles 2θ 6.4+ / −0.2, 7.5+ / −0.2, 8.0+ / −0.2, 17.2+ / −0.2, and 19.3+ / −0.2 degrees.

[0024] In a more specific embodiment, the non-solvated crystalline form of daprodustat free acid is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least the following diffraction angles 2θ 6.4+ / −0.2, 7.5+ / −0.2, 8.0+ / −0.2, 15.2+ / −0.2, 17.2+ / −0.2, and 19.3+ / −0.2 degrees.

[0025] In one embodiment, the non-solvated crystalline form of daprodustat free acid is characterized by an X-ray powder diffraction (XRPD) pattern comprising characteristic XRPD peaks at the following 2θ values: 6.4°+ / −0.2°, 7.5°+ / −0.2°, and 7.9°+ / −0.2°. The X-ray powder diffraction pattern may exhibit one or more additional characteristic peaks at the following 2θ values: 17.2°+ / −0.2°, 21.0°+ / −0.2°, 24.0°+ / −0.2°, or 19.3°+ / −0.2°.

[0026] The nonsolvated crystalline form of daprodustat free acid disclosed above has needle-like crystals as shown in FIG. 1. These shapes result in crystals with low bulk density and poor flowability, as described in Example 1. The use of a flow agent to improve powder flow and facilitate formulation is well known in the art. As described in Example 2, the use of a flow agent directly mixed with the nonsolvated crystalline form of daprodustat free acid resulted in tablets with low tensile strength. Example 3 demonstrates that the flow agent can be omitted in the compartment containing the nonsolvated crystalline form of daprodustat free acid, resulting in tablets with good tensile strength and quality.

[0027] tablet In a first aspect, the present invention provides immediate-release tablets comprising 1 to 10 mg (measured as the free acid) of daprodustat or a pharmaceutically acceptable salt thereof, having a tablet tensile strength of 1.7 MPa or greater after compression of the tablet core at a pressure in the range of 200 to 290 MPa. In more specific embodiments, the tablet tensile strength of the tablet core after compression at a pressure in the range of 200 to 290 MPa is 1.75 or greater, 1.8 or greater, 1.9 or greater, or 2.0 MPa or greater. In certain embodiments, the immediate-release tablets comprise 1 to 8 mg (measured as the free acid) of daprodustat or a pharmaceutically acceptable salt thereof. For the avoidance of doubt, the expression "main compression pressure" used in Examples 5 and 6 refers to the pressure used to compress the tablet core.

[0028] In one embodiment, the immediate-release tablet of the invention comprises a compartment containing daprodustat or a pharmaceutically acceptable salt thereof in an amount of up to 5% by weight of the free acid, wherein the compartment does not contain a glidant. In one embodiment, the compartment contains a non-solvated crystalline form of daprodustat free acid.

[0029] In one embodiment, the tablet is a monolithic tablet consisting of a single compartment of uniform composition, which may be film-coated. In one embodiment, the compartment is the tablet core. In another embodiment, the compartment is the entire tablet.

[0030] In an alternative embodiment, the tablet contains granules dispersed in the extragranular space and may be film-coated. The granular and extragranular compositions may be different and may form separate compartments. In one embodiment, the granular compartment is a glidant-free compartment containing daprodustat or a pharmaceutically acceptable salt thereof (e.g., a nonsolvated crystalline form of daprodustat free acid).

[0031] In one embodiment, the intragranular compartment comprises the unsolvated crystalline form of daprodustat free acid, a diluent, a binder, and a disintegrant, and does not include a glidant. For the avoidance of doubt, more than one diluent, binder, or disintegrant may be included. In one embodiment, the intragranular compartment consists of the unsolvated crystalline form of daprodustat free acid, one or more diluents, binders, and disintegrants, and does not include a glidant.

[0032] In one embodiment, the extragranular compartment comprises a diluent, a disintegrant, a lubricant, and optionally a flow agent. For the avoidance of doubt, two or more diluents, disintegrants, lubricants, or flow agents may be included. In one embodiment, the extragranular compartment consists of one or more diluents, disintegrants, lubricants, and optionally a flow agent.

[0033] Suitable diluents include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g., corn starch, potato starch, and pregelatinized starch), cellulose and its derivatives (e.g., microcrystalline cellulose), calcium sulfate, and dicalcium phosphate. In one embodiment, the diluent is not lactose.

[0034] Suitable binders include starch (e.g., corn starch, potato starch, and pregelatinized starch), hypromellose, gelatin, gum arabic, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g., microcrystalline cellulose).

[0035] Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmellose sodium, alginic acid, and sodium carboxymethyl cellulose.

[0036] Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.

[0037] The fluidizing agent may include colloidal silicon dioxide, talc, starch, and magnesium stearate. In one embodiment, the fluidizing agent is colloidal silicon dioxide or magnesium stearate. In one embodiment, the fluidizing agent is silica. In another embodiment, the fluidizing agent is colloidal silicon dioxide.

[0038] In one embodiment, the present invention provides a method for producing a medicament comprising: a) an intragranular component comprising a 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 flow agent; It consists of Immediate release tablets, which may be coated, are provided.

[0039] In a more specific embodiment, the present invention provides a method for treating a cancer cell comprising: a) a crystalline form of non-solvated daprodustat free acid and an intragranular component consisting of 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 flow agent; It consists of Immediate release tablets, which may be coated, are provided.

[0040] A coating may be applied to the tablet core. An example of a commercially available coating is "OPADRY OY-S-28876 WHITE." Color coatings are also commercially available.

[0041] In one embodiment, the immediate release tablet contains up to 76% by weight of intragranular ingredients based on the weight of the uncoated tablet.

[0042] In one embodiment, the immediate release tablet comprises an intragranular compartment and an extragranular compartment, a. The intragranular components are: i. 1 to 10 mg of a non-solvated crystalline form of daprodustat free acid; ii. about 5% by weight of hypromellose; iii. about 1.5% by weight of croscarmellose sodium; and iv. mannitol and microcrystalline cellulose in a weight ratio of about 2.2 to about 3.6; comprising b. The extragranular ingredients comprise, based on the total weight of the extragranular ingredients, the following: i. about 12% by weight of croscarmellose sodium; ii. about 4% by weight of magnesium stearate; iii. about 1.5% colloidal silica; and iv. mannitol and microcrystalline cellulose in a weight ratio of about 2; The compound comprises:

[0043] In certain embodiments, the tablet comprises about 1, 2, or 4 mg of daprodustat and has a core tablet weight of about 150 mg. In another embodiment, the tablet comprises about 6, 8, or 10 mg of daprodustat and has a core tablet weight of about 300 mg. In another embodiment, the tablet comprises about 6 or 8 mg of daprodustat and has a core tablet weight of about 300 mg. The tablets described herein may optionally be film-coated.

[0044] In one embodiment, the immediate release tablet is lactose-free.

[0045] Medical uses The immediate-release tablets of the present invention may be used in therapy, more specifically, in the treatment of anemia. In certain embodiments, the immediate-release tablets of the present invention may be used to treat anemia due to chronic kidney disease (also known as renal anemia), anemia in cancer patients undergoing chemotherapy (including myelosuppressive therapy or platinum-containing chemotherapy), anemia in HIV-infected patients treated with zidovudine, and anemia due to rheumatoid arthritis. In one embodiment, the immediate-release tablets of the present invention may be administered to patients undergoing elective orthopedic surgery.

[0046] Thus, in one embodiment, the present invention provides an immediate release tablet of the present invention for use in therapy.

[0047] In another embodiment, the present invention provides an immediate-release tablet of the present invention for use in a method for treating anemia resulting from chronic kidney disease.

[0048] In yet another embodiment, the present invention provides the use of daprodustat or a pharmaceutically acceptable salt thereof in the manufacture of an immediate release tablet of the present invention for use in the treatment of anemia due to chronic kidney disease.

[0049] In another embodiment, the present invention provides a method for treating anemia due to chronic kidney disease in a subject in need thereof, comprising administering to the subject an immediate-release tablet of the present invention.

[0050] Preferably, the subject is a mammal, hi certain embodiments, the subject is a human.

[0051] In more specific embodiments, the subject with anemia due to chronic kidney disease may be undergoing dialysis (e.g., hemodialysis or peritoneal dialysis). In another embodiment, the subject may be iron deficient (TSAT 20% or less and / or serum ferritin 100 ng / ml or less) and may be undergoing additional iron replacement therapy.

[0052] In a further embodiment, the present invention provides a dosing regimen for treating anemia due to chronic kidney disease, aiming to maintain hemoglobin within the range of 10-12 g / dL and provide a safe increase in hemoglobin levels below this range. Dosage is modified based on hemoglobin levels determined at clinical visits. Hemoglobin levels may be measured by known methods (e.g., HemoCue).

[0053] In one aspect, the present invention provides a dosing regimen for treating anemia due to chronic kidney disease in a patient, wherein an immediate-release tablet of the present invention is administered once daily at a dose of 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 12 mg, 16 mg, or 24 mg, and the dose is increased or decreased by one dose step based on the patient's hemoglobin concentration to maintain the patient's hemoglobin concentration within the range of 10 to 12 g / dL. In one embodiment, the dose is increased or decreased by one dose step based on the patient's hemoglobin concentration to maintain the patient's hemoglobin concentration within the range of 10 to 11 g / dL. In one embodiment, the dose is increased or decreased by one dose step based on the patient's hemoglobin concentration to maintain the patient's hemoglobin concentration at a target of 10 g / dL.

[0054] In certain embodiments, the patient's hemoglobin level is monitored at least once every three months. In more specific embodiments, the patient's hemoglobin level is monitored monthly or every four weeks. One skilled in the art will understand that the frequency of monitoring can increase once treatment is initiated and can decrease once the patient's hemoglobin level stabilizes within the target range (10-12 g / dL, or 10-11 g / dL, or 10 g / dL).

[0055] In embodiments where the patient's hemoglobin level rises rapidly (eg, above 2.0 g / dL within 4 weeks), the dose is reduced by one dose step or discontinued.

[0056] In embodiments where the patient's hemoglobin concentration exceeds the upper limit of the target range, administration is discontinued and treatment resumed at the next lower dose level until the hemoglobin concentration is within the target range.

[0057] Clinical judgment is also important in increasing and decreasing the dose. In embodiments where the patient is over the target range and at risk for thromboembolism (e.g., if the patient has had a stroke), the dose is decreased by one dose step or discontinued. In embodiments where the patient exhibits symptoms of anemia, the dose is increased by one dose step.

[0058] In one embodiment, the patient is not undergoing dialysis, hi another embodiment, the patient is undergoing dialysis (e.g., hemodialysis or peritoneal dialysis).

[0059] In embodiments where the patient is not on dialysis and has not been previously treated with an erythropoiesis-stimulating agent, the starting dose for the immediate-release tablets of the present invention is 4 mg once daily (if the patient's hemoglobin level is less than 9.0 g / dL) or 2 mg once daily (if the patient's hemoglobin level is 9.0 g / dL or greater). In embodiments where the patient is not on dialysis and is being switched from an erythropoiesis-stimulating agent, the starting dose for the immediate-release tablets of the present invention is 4 mg once daily. In embodiments where the patient is on dialysis, the starting dose for the immediate-release tablets of the present invention is 4 mg once daily.

[0060] In one aspect, the present invention provides a dosing regimen for treating anemia due to chronic kidney disease in a patient undergoing dialysis, wherein an immediate-release tablet of the present invention is administered three times per week at a dose of 2 mg, 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, 32 mg, or 48 mg, and the dose is increased or decreased by one dose step based on the patient's hemoglobin concentration to maintain the patient's hemoglobin concentration within the range of 10 to 12 g / dL. In one embodiment, the dose is increased or decreased by one dose step based on the patient's hemoglobin concentration to maintain the patient's hemoglobin concentration within the range of 10 to 11 g / dL.

[0061] In certain embodiments, the patient's hemoglobin level is monitored at least once every three months. In more specific embodiments, the patient's hemoglobin level is monitored monthly or every four weeks. One skilled in the art will understand that monitoring can be more frequent once treatment is initiated and can be less frequent once the patient's hemoglobin level stabilizes within the target range (10-12 g / dL, or 10-11 g / dL).

[0062] In embodiments where the patient's hemoglobin level rises rapidly (eg, above 2.0 g / dL within 4 weeks), the dose is reduced by one dose step or discontinued.

[0063] In embodiments where the patient's hemoglobin concentration exceeds the upper limit of the target range, administration is discontinued and treatment resumed at the next lower dose level until the hemoglobin concentration is within the target range.

[0064] Clinical judgment is also important in increasing and decreasing the dose. In embodiments where the patient is over the target range and at risk for thromboembolism (e.g., if the patient has had a stroke), the dose is decreased by one dose step or discontinued. In embodiments where the patient exhibits symptoms of anemia, the dose is increased by one dose step.

[0065] In one embodiment, the starting dose for the immediate release tablets of the present invention is 8, 12, 16, or 24 mg three times per week.

[0066] A dosing regimen for treating anemia due to chronic kidney disease to maintain hemoglobin levels within the range of 10-11 g / dL is provided, wherein the immediate release tablets of the present invention are administered once daily at one of the following doses: 1, 2, 4, 6, 8, 10, 12, 16, and 24 mg (free acid dose): a) If the hemoglobin concentration is 12 g / dL or greater, daprodustat treatment is discontinued until the hemoglobin concentration is less than 11.5 g / dL, and treatment is initiated at the next lower dose; b) if hemoglobin concentration is within the range of ≥9.5 to <11.5 g / dL, the dose is maintained; c) If the hemoglobin concentration is within the range of >11 to ≤11.5 g / dL at two consecutive clinic visits and there has been an increase or no change in hemoglobin concentration since the last visit, the dose will be reduced by one dose step; d) If hemoglobin concentration is within the range of >11.5 to <12 g / dL and there has been a decrease in hemoglobin concentration since the last visit, the dose will be maintained. e) If the hemoglobin concentration is within the range of >11.5 to <12 g / dL and there has been an increase or no change in hemoglobin concentration since the last visit, the dose will be reduced by one dose step; f) If the hemoglobin concentration is within the range of ≥9.5 to <10 at two consecutive clinic visits and there has been a decrease or no change in hemoglobin concentration since the last visit, the dose will be increased by one dose step; g) if hemoglobin concentration is within the range of 7.5 to <9.5 g / dL and hemoglobin concentration has increased by 0.5 g / dL or more since the last visit, the dose will be maintained; h) If the hemoglobin concentration is in the range of 7.5 to <9.5 g / dL and there has been a decrease in hemoglobin concentration since the last visit, no change, or an increase of <0.5 g / dL, the dose will be increased by one dose step; i) If hemoglobin concentration is less than 7.5 g / dL, the dose is increased by one dose step; j) If there is an increase in hemoglobin concentration of more than 2 g / dL in 4 weeks or if there is an increase in hemoglobin concentration of more than 1 g / dL in 2 weeks, the dose will be reduced by one dose step; and k) If there is a decrease in hemoglobin concentration of more than 2 g / dL in 4 weeks or a decrease in hemoglobin concentration of more than 1 g / dL in 2 weeks, the dose will be increased by one dose step.

[0067] In one embodiment, the immediate release tablets of the present invention are administered once daily at one of the following doses: 1, 2, 4, 6, 8, 12, 16, and 24 mg (free acid dose) according to the dosing regimens described herein.

[0068] In one embodiment, the present invention provides an immediate release tablet of the present invention for use in treating anemia due to chronic kidney disease, wherein the immediate release tablet of the present invention is administered once daily at one of the following doses: 1, 2, 4, 6, 8, 10, 12, 16, and 24 mg (dosage of the free acid) according to the dosing regimen as described herein. In a more specific embodiment, the present invention provides an immediate release tablet of the present invention for use in treating anemia due to chronic kidney disease, wherein the immediate release tablet of the present invention is administered once daily at one of the following doses: 1, 2, 4, 6, 8, 12, 16, and 24 mg (dosage of the free acid) according to the dosing regimen as described herein.

[0069] In one embodiment, the present invention provides the use of daprodustat or a pharmaceutically acceptable salt thereof in the manufacture of an immediate release tablet of the present invention for use in treating anemia due to chronic kidney disease, wherein the immediate release tablet of the present invention is administered once daily at one of the following doses: 1, 2, 4, 6, 8, 10, 12, 16, and 24 mg (dosage of the free acid) according to the dosing regimen as described herein. In a more specific embodiment, the present invention provides the use of daprodustat or a pharmaceutically acceptable salt thereof in the manufacture of an immediate release tablet of the present invention for use in treating anemia due to chronic kidney disease, wherein the immediate release tablet of the present invention is administered once daily at one of the following doses: 1, 2, 4, 6, 8, 12, 16, and 24 mg (dosage of the free acid) according to the dosing regimen as described herein.

[0070] In another aspect, the present invention provides a dosing regimen for treating anemia due to chronic kidney disease in a patient undergoing dialysis, wherein an immediate-release tablet of the present invention is administered three times a week at a dose of 2 mg, 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, 32 mg, or 48 mg (free acid dose), the dose being increased or decreased by one dose step based on the patient's hemoglobin concentration to maintain the patient's hemoglobin concentration within the range of 10 to 12 g / dL. In one embodiment, the dose being increased or decreased by one dose step based on the patient's hemoglobin concentration to maintain the patient's hemoglobin concentration within the range of 10 to 11 g / dL.

[0071] In certain embodiments, the patient's hemoglobin level is monitored at least once every three months. In more specific embodiments, the patient's hemoglobin level is monitored monthly or every four weeks. One skilled in the art will understand that the frequency of monitoring can increase once treatment is initiated and can decrease once the patient's hemoglobin level stabilizes within the target range (10-12 g / dL or 10-11 g / dL).

[0072] In embodiments where the patient's hemoglobin level rises rapidly (eg, above 2.0 g / dL within 4 weeks), the dose is reduced by one dose step or discontinued.

[0073] In one embodiment, the starting dose for the immediate release tablets of the present invention is 8, 12, 16, or 24 mg three times per week.

[0074] A dosing regimen for treating anemia due to chronic kidney disease to maintain hemoglobin levels within the range of 10-11 g / dL is provided, wherein the immediate release tablets of the present invention are administered three times per week at a dose of either 2 mg, 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, 32 mg, or 48 mg (free acid dose): a) If the hemoglobin concentration is 12 g / dL or greater, daprodustat treatment is discontinued until the hemoglobin concentration is less than 11.5 g / dL, and treatment is initiated at the next lower dose; b) if hemoglobin concentration is within the range of ≥9.5 to <11.5 g / dL, the dose is maintained; c) If the hemoglobin concentration is within the range of >11 to ≤11.5 g / dL at two consecutive clinic visits and there has been an increase or no change in hemoglobin concentration since the last visit, the dose will be reduced by one dose step; d) If hemoglobin concentration is within the range of >11.5 to <12 g / dL and there has been a decrease in hemoglobin concentration since the last visit, the dose will be maintained. e) If the hemoglobin concentration is within the range of >11.5 to <12 g / dL and there has been an increase or no change in hemoglobin concentration since the last visit, the dose will be reduced by one dose step; f) If the hemoglobin concentration is within the range of ≥9.5 to <10 at two consecutive clinic visits and there has been a decrease or no change in hemoglobin concentration since the last visit, the dose will be increased by one dose step; g) if hemoglobin concentration is within the range of 7.5 to <9.5 g / dL and hemoglobin concentration has increased by 0.5 g / dL or more since the last visit, the dose will be maintained; h) If the hemoglobin concentration is within the range of 7.5 to <9.5 g / dL and there has been a decrease in hemoglobin concentration since the last visit, no change, or an increase of <0.5 g / dL, the dose will be increased by one dose step; i) If hemoglobin concentration is less than 7.5 g / dL, the dose is increased by one dose step; j) If there is an increase in hemoglobin concentration of more than 2 g / dL in 4 weeks or if there is an increase in hemoglobin concentration of more than 1 g / dL in 2 weeks, the dose will be reduced by one dose step; and k) If there is a decrease in hemoglobin concentration of more than 2 g / dL in 4 weeks or a decrease in hemoglobin concentration of more than 1 g / dL in 2 weeks, the dose will be increased by one dose step.

[0075] In one embodiment, the present invention provides an immediate release tablet of the present invention for use in the treatment of anemia due to chronic kidney disease in patients undergoing dialysis, wherein the immediate release tablet of the present invention is administered at one of the following doses (free acid dose): 2 mg, 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, 32 mg, or 48 mg three times a week according to the dosing regimen as described herein.

[0076] In one embodiment, the present invention provides the use of daprodustat or a pharmaceutically acceptable salt thereof in the manufacture of an immediate release tablet of the present invention for use in the treatment of anemia due to chronic kidney disease in patients undergoing dialysis, wherein the immediate release tablet of the present invention is administered at one of the following doses (free acid dose): 2 mg, 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, 32 mg, or 48 mg, three times a week, according to the dosing regimen as described herein.

[0077] For the avoidance of doubt, it is noted that any particular dose may be administered in a single tablet or in multiple tablets, for example an 8 mg dose may be administered as one 8 mg tablet, or two 4 mg tablets, or four 2 mg tablets, or eight 1 mg tablets.

[0078] It is clear that dose adjustments involve increasing or decreasing the daprodustat dose by one dose step at a time. Those receiving the highest (maximum) dose of daprodustat who require an increase will maintain the same dose, while those receiving the lowest dose of daprodustat who require a decrease will discontinue daprodustat treatment. [Example]

[0079] Example 1: Characterization of the non-solvated crystalline form of daprodustat free acid Nonsolvated crystalline forms of daprodustat free acid may be prepared as described in Examples 1-4 of WO 2019 / 052133 and exhibit characteristic XRPD peaks at 2θ values ​​of 6.4°+ / -0.2°, 7.5°+ / -0.2°, and 7.9°+ / -0.2°. The X-ray powder diffraction pattern may exhibit one or more additional characteristic peaks at 2θ values ​​of 17.2°+ / -0.2°, 21.0°+ / -0.2°, 24.0°+ / -0.2°, or 19.3°+ / -0.2°.

[0080] XRPD analysis of the non-solvated crystalline form of daprodustat free acid was performed on a Philips X'Pert Pro diffractometer, scanning samples using the parameters shown in Table 1.

[0081] [Table 1]

[0082] The sample was placed in a zero-background silicon sample holder and gently flattened using a glass slide.

[0083] The XRPD pattern is shown in Figure 2. The peaks identified in this pattern are listed in Table 2.

[0084] [Table 2]

[0085] The flowability of the non-solvated crystalline form of daprodustat free acid was determined in accordance with United States Pharmacopoeia Chapter 616 (USP <616> The compressibility index was calculated based on the bulk density and tapped density measurements of the powder using the bulk density and tapped density measurement method of the Japanese Patent Laid-Open Publication No. 2002-200504. A compressibility index of more than 25 indicates poor flowability, while a compressibility index of less than 15 indicates good flowability.

[0086] The compressibility index is calculated as 100 x (1 - bulk density / tapped density).

[0087] The compressibility index of the unsolvated crystalline form of daprodustat free acid is greater than 65, indicating very poor flowability and very low bulk density (less than 0.2 g / mL).

[0088] Comparative Example 2 - Tablets with glidant in the daprodustat-containing compartment A tablet formulation of the nonsolvated crystalline form of daprodustat free acid containing a glidant in the granulation can be prepared as follows: The tablet core comprises granules and extragranular components. Granules are prepared by adding daprodustat, mannitol, microcrystalline cellulose, hypromellose 2910, croscarmellose sodium, and colloidal silicon dioxide to a high-shear granulator. The powders are blended under high shear for at least 5 minutes, and granulation is carried out while spraying at least 26% w / w purified water for a water addition time of at least 7 minutes and a wet massing time of at least 2 minutes. The wet granules are dried in a fluid-bed dryer at a product temperature of at least 38°C to a target moisture content of 2% w / w or less. The granules are dry-milled to standardize the granule size distribution. The milled granules are further blended with the extragranular components mannitol, microcrystalline cellulose, and croscarmellose sodium. Magnesium stearate is added and the resulting mixture is compressed into tablet cores using a rotary tablet press under the following conditions and using a compression pressure ranging from 180 to 370 MPa: Tablet shape / size: Round, biconvex tablet / diameter 7 mm (4 mg dose or less); diameter 9 mm (6 mg dose or more) Compression speed: at least 40,000 tablets / hour

[0089] The composition of the tablets is provided in Table 3.

[0090] [Table 3]

[0091] Example 3 - Tablets with glidant outside the daprodustat-containing compartment A tablet formulation of the nonsolvated crystalline form of daprodustat free acid containing a glidant in the extragranular matrix can be prepared as follows: The tablet core comprises granules and extragranular components. Granules are prepared by adding daprodustat, mannitol, microcrystalline cellulose, hypromellose 2910, and croscarmellose sodium to a high-shear granulator. The powders are blended under high shear for at least 5 minutes, and granulation is carried out while spraying at least 26% w / w purified water for a water addition time of at least 7 minutes and a wet massing time of at least 2 minutes. The wet granules are dried in a fluid-bed dryer at a product temperature of at least 38°C to a target moisture content of 2% w / w or less. The granules are dry-milled to standardize the granule size distribution. The milled granules are further blended with the extragranular components mannitol, microcrystalline cellulose, croscarmellose sodium, and the glidant colloidal silicon dioxide. Magnesium stearate is added and the resulting mixture is compressed into tablet cores using a rotary tablet press under the following conditions using a compression pressure in the range of 180-370 MPa: Tablet shape / size: Round, biconvex tablet / diameter 7 mm (4 mg or less); diameter 9 mm (6 mg or more) Compression speed: at least 40,000 tablets / hour

[0092] The composition of the tablets is provided in Table 4.

[0093] [Table 4]

[0094] Example 4 - Tablets without glidant A glidant-free tablet formulation of the nonsolvated crystalline form of daprodustat free acid may be prepared as follows: The milled granules of Example 3 are blended with the extragranular ingredients mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. To achieve the same target core tablet weight, the levels of extragranular mannitol and microcrystalline cellulose are adjusted while maintaining the same ratio, taking into account the omission of the glidant colloidal silicon dioxide. The resulting mixture is compressed into tablet cores using a rotary tablet press under the following conditions, using a compression pressure ranging from 180 to 370 MPa. Tablet shape / size: Round, biconvex tablet / diameter 7 mm (4 mg or less); diameter 9 mm (6 mg or more) Compression speed: at least 40,000 tablets / hour

[0095] Example 5 - Measurement of tablet tensile strength Tablet tensile strength is measured on the tablet cores using the method published by Pitt and Newton (Journal of Materials Science 23, 2723-2728, 1988). The results at various compression pressures for the tablets of Examples 2, 3 and 4 are shown in Table 5.

[0096] [Table 5]

[0097] Example 6 - Alternative tablet formulation without glidant An alternative tablet formulation containing 0.5 mg to 100 mg of the nonsolvated crystalline form of daprodustat free acid and no glidant may be prepared as follows: Granules are prepared by adding daprodustat, mannitol, microcrystalline cellulose, hypromellose 2910, and croscarmellose sodium to a high-shear granulator. The powders are blended under high shear for at least 5 minutes, and granulation is carried out while spraying at least 25% w / w purified water for a water addition time of at least 4 minutes and a wet massing time of at least 1 minute. The wet granules are dried to a target moisture content in a fluid-bed dryer. The granules are dry-milled to standardize the granule size distribution. The milled granules are further blended with the extragranular ingredients croscarmellose sodium, optionally mannitol, and optionally microcrystalline cellulose. Magnesium stearate is added and the resulting mixture is compressed into tablet cores using a rotary tablet press to produce round, regular concave tablets of 7.5 mm diameter (less than 5 mg) and 10 mm diameter (greater than 5 mg).

[0098] The tablet compositions are provided in Tables 6 and 7.

[0099] [Table 6]

[0100] [Table 7]

[0101] Tablet tensile strength is measured on the tablet cores using the method published by Pitt and Newton (Journal of Materials Science 23, 2723-2728, 1988). The tablet tensile strength of these formulations is in the range of 1.71 to 2.27 MPa.

Claims

1. 1. An immediate-release tablet comprising 1 to 10 mg (measured as the free acid) of daprodustat or a pharmaceutically acceptable salt thereof, wherein the tablet core has a tablet tensile strength of 1.7 MPa or greater after compression at a pressure in the range of 200 to 290 MPa, wherein the daprodustat or pharmaceutically acceptable salt thereof is the crystalline form of the unsolvated daprodustat free acid characterized 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; the tablet comprises glidant-free granules containing the crystalline form of non-solvated daprodustat free acid in an amount of up to 5% based on the weight of the free acid; The tablet a. below: i. 1-10 mg of a non-solvated crystalline form of daprodustat free acid; ii. 5% by weight of hypromellose; iii. 1.5% by weight of croscarmellose sodium; and iv. mannitol and microcrystalline cellulose in a weight ratio of 2.2 to 3.6; an intragranular component comprising: b. Based on the total weight of the extragranular ingredients, the following: i. 12% by weight of croscarmellose sodium; ii. 4% by weight of magnesium stearate; iii. 1.5% colloidal silica; and iv. Mannitol and microcrystalline cellulose in a weight ratio of 2; An extragranular component comprising It consists of The tablet may be coated. Immediate-release tablets.

2. 2. The immediate release tablet of claim 1, wherein the tablet core has a tablet tensile strength of 1.75 MPa or greater after compression at a pressure in the range of 200 to 290 MPa.

3. An immediate-release tablet as described in claim 1 or 2, containing up to 76% by weight of intragranular components based on the weight of the uncoated tablet.

4. An immediate release tablet according to any one of claims 1 to 3, comprising 1, 2 or 4 mg of daprodustat and having a core tablet weight of 150 mg.

5. 4. The immediate release tablet according to any one of claims 1 to 3, comprising 6 or 8 mg of daprodustat and having a core tablet weight of 300 mg.

6. 6. The immediate release tablet of claim 4 or 5, which is film coated.

7. 7. The immediate release tablet of any one of claims 1 to 6, which is lactose-free.

8. 8. The immediate release tablet of any one of claims 1 to 7 for use in treating anemia resulting from chronic kidney disease in a subject.

9. 9. The immediate release tablet of claim 8, wherein the subject is undergoing dialysis.

10. 10. The immediate release tablet of claim 8 or 9, wherein the subject is iron deficient and the subject is receiving additional iron replacement therapy.

11. 9. The immediate-release tablet of claim 8, wherein the immediate-release tablet is administered once daily at a dose of either 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 12 mg, 16 mg, or 24 mg, and the dose is increased or decreased by one dose step based on the patient's hemoglobin level to maintain the patient's hemoglobin level within the range of 10 to 11 g / dL.

12. 12. The immediate release tablet of claim 11, wherein the patient is not on dialysis.

13. 13. The immediate-release tablet of claim 12, wherein the starting dose for the immediate-release tablet is 4 mg once daily (if the patient has been previously treated with an erythropoiesis-stimulating agent, or if the patient has not been previously treated with an erythropoiesis-stimulating agent and has a hemoglobin concentration less than 9.0 g / dL) or 2 mg once daily (if the patient has not been previously treated with an erythropoiesis-stimulating agent and has a hemoglobin concentration equal to or greater than 9.0 g / dL).

14. 9. The immediate-release tablet of claim 8, 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, 32 mg, or 48 mg, and the dose is increased or decreased by one dose step based on the patient's hemoglobin level to maintain the patient's hemoglobin level within the range of 10-11 g / dL.

15. 15. The immediate release tablet of claim 14, wherein the patient is undergoing dialysis.

16. 16. The immediate release tablet of claim 15, wherein the starting dose for the immediate release tablet is 8, 12, 16, or 24 mg three times a week.

17. 17. The immediate release tablet of any one of claims 11 to 16, wherein the patient's hemoglobin level is monitored at least once every three months.

18. 18. The immediate-release tablet of any one of claims 11 to 17, wherein the dose is reduced by one dose step or discontinued if the patient's hemoglobin level rises above 2.0 g / dL within four weeks.

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