Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde

Abstract

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.

What is claimed is: 
     
         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 focal of Compound 1 is substantially free of Form I and/or Form N; wherein Form 1 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 fou 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).