DOSING REGIMENS FOR 2-HYDROXY-6-((2-(1-ISOPROPYL-1H-PYRAZOL-5-YL)PYRIDIN-3-YL)METHOXY)BENZALDEHYDE
Provided herein are methods for treating sickle cell disease, comprising administering to a subject 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)-methoxy)benzaldehyde (Compound 1), or a polymorph thereof, in certain dosing regimens.
1 . A method for treating sickle cell disease in a patient comprising administering to the patient Compound 1:
wherein the compound is administered in a dose of from about 500 mg/day to about 1500 mg/day.
2 . The method of claim 1 , wherein the compound is administered in a dose of from about 600 mg/day to about 900 mg/day.
3 . The method of claim 1 , wherein the compound is administered in a dose of about 600 mg/day.
4 . The method of claim 1 , wherein the compound is administered in a dose of about 900 mg/day, or about 1200 mg/day, or about 1500 mg/day.
5 . The method of claim 1 , wherein the compound is administered in a dose of 600 mg/day.
6 . The method of claim 1 , wherein the compound is administered in a dose of 900 mg/day, 1200 mg/day or 1500 mg/day.
7 . The method of claim 1 , wherein the compound is administered once daily.
8 . The method of claim 5 , wherein the compound is administered once daily.
9 . The method of claim 6 , wherein the compound is administered once daily.
10 . The method of claim 1 , wherein Compound 1 is a crystalline ansolvate form characterized by at least two X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ).
11 . The method of claim 10 , wherein the crystalline ansolvate form is characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ).
12 . The method of claim 10 , wherein the crystalline ansolvate form is characterized by X-ray powder diffraction peaks (Cu Kα radiation) at 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ).
13 . The method of claim 10 , wherein the crystalline ansolvate form of Compound 1 is substantially free of Form I and/or Form N; wherein Form I is characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 12.82°, 15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82° and 26.44°2θ (each ±0.2°2θ); and wherein Form N is characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 11.65°, 11.85°, 12.08°, 16.70°, 19.65° and 23.48°2θ (each ±0.2°2θ).
14 . The method of claim 5 , wherein Compound 1 is a crystalline ansolvate form that is characterized by at least two X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ).
15 . The method of claim 14 , wherein the crystalline ansolvate form is characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ).
16 . The method of claim 14 , wherein the crystalline ansolvate form is characterized by X-ray powder diffraction peaks (Cu Kα radiation) at 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ).
17 . The method of claim 14 , wherein the crystalline ansolvate form of Compound 1 is substantially free of Form I and/or Form N; wherein Form I is characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 12.82°, 15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82° and 26.44°2θ (each ±0.2°2θ); and wherein Form N is characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 11.65°, 11.85°, 12.08°, 16.70°, 19.65° and 23.48°2θ (each ±0.2°2θ).
18 . The method of claim 6 , wherein Compound 1 is a crystalline ansolvate form that is characterized by at least two X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ).
19 . The method of claim 18 , wherein the crystalline ansolvate form is characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ).
20 . The method of claim 18 , wherein the crystalline ansolvate form is characterized by X-ray powder diffraction peaks (Cu Kα radiation) at 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ).
21 . The method of claim 18 , wherein the crystalline ansolvate form of Compound 1 is substantially free of Form I and/or Form N; wherein Form I is characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 12.82°, 15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82° and 26.44°2θ (each ±0.2°2θ); and wherein Form N is characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 11.65°, 11.85°, 12.08°, 16.70°, 19.65° and 23.48°2θ (each ±0.2°2θ).
22 . A capsule dosage form comprising:
(i) from about 65% to about 93% w/w of Compound 1; and
(ii) from about 2% to about 10% w/w a binder;
wherein w/w is relative to the total weight of the formulation, excluding the weight of the capsule.
23 . The capsule dosage form of claim 22 , further comprising from about 2% to about 10% a disintegrant.
24 . The capsule dosage form of claim 22 , further comprising from about 2% to about 10% a disintegrant and about 2% to 35% a filler.
25 . A capsule dosage form comprising:
(i) from about 65% to about 86% w/w of Compound 1;
(ii) from about 2% to about 6% w/w a binder;
(iii) from about 6% to about 25% w/w a filler;
(iv) from about 2% to 6% w/w a disintegrant; and
(iv) from about 0.5% to about 1.5% w/w a lubricant;
wherein w/w is relative to the total weight of the formulation, excluding the weight of the capsule.
26 . The capsule dosage form of claim 25 comprising:
(i) from about 65% to about 86% w/w of Compound 1;
(ii) from about 2% to about 6% w/w a binder;
(iii) from about 3.5% to about 25% w/w an insoluble filler, or 2.5% to 25% w/w of soluble filler, or 2.5% to 25% of a combination of soluble or insoluble filler;
(iv) from about 2% to 6% w/w a disintegrant; and
(iv) from about 0.5% to about 1.5% w/w a lubricant.
27 . The capsule dosage form of claim 26 comprising:
(i) about 86% w/w of Compound 1;
(ii) about 4% w/w a binder;
(iii) about 3.5% w/w an insoluble filler and 2.5% w/w of soluble filler;
(iv) about 3.5% w/w a disintegrant; and
(iv) about 0.5% w/w a lubricant.
28 . The capsule dosage form of claim 27 comprising:
(i) 85.71% w/w of Compound 1;
(ii) 4% w/w a binder;
(iii) 3.64% w/w an insoluble filler and 2.65% w/w of soluble filler;
(iv) 2.65% w/w a disintegrant; and
(iv) 0.5% w/w a lubricant.
29 . The capsule dosage form of claim 27 wherein:
Compound 1 is a crystalline ansolvate form that is characterized by at least two X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ);
the binder is hypromellose;
the insoluble filler is microcrystalline cellulose;
the soluble filler is lactose monohydrate;
the disintregrant is croscarmellose sodium; and
the lubricant is magnesium stearate.
30 . The capsule dosage form of claim 29 wherein the capsule contains 300 mg: 5% of Compound 1, wherein compound 1 is a crystalline ansolvate form that is characterized by at least two X-ray powder diffraction peaks (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2°2θ); wherein the crystalline ansolvate form is substantially free of Form I and/or N; wherein Form I is characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 12.82°, 15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82° and 26.44°2θ (each ±0.2°2θ); and wherein Form N is characterized by at least three X-ray powder diffraction peaks (Cu Kα radiation) selected from 11.65°, 11.85°, 12.08°, 16.70°, 19.65° and 23.48°2θ (each ±0.2°2θ).