Tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde

Abstract

Provided herein are high strength/high drug load tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (“Compound 1”), dispersible tablets comprising Compound 1, processes of manufacturing such tablets, and methods for treating patients with the tablets. Compound 1 is useful for treating hematological disorders such as sickle cell disease, pulmonary disease such as idiopathic pulmonary fibrosis, and hypoxia and hypoxemia conditions.

1 .- 45 . (canceled) 
     
     
         46 . A dispersible tablet comprising:
 (i) about 30% to about 70% by weight of Compound 1 of formula:   
       
         
           
           
               
               
           
         
         (ii) filler; 
         (iii) disintegrant; 
         (iv) glidant; and 
         (v) a lubricant; 
         wherein the percentage by weight is relative to the total weight of the tablet. 
       
     
     
         47 . A dispersible tablet comprising:
 (i) about 30% to about 70% by weight of Compound 1 of formula:   
       
         
           
           
               
               
           
         
         (ii) a filler; 
         (iii) a disintegrant; 
         (iv) a glidant; 
         (v) a lubricant; 
         (vi) a surfactant; and 
         (vii) optionally a binder; 
         wherein the amount of disintegrant to filler is in a ratio of about 1:28, and wherein the percentage by weight is relative to the total weight of the tablet. 
       
     
     
         48 . A tablet comprising:
 (i) about 30% to about 70% by weight of Compound 1 of formula:   
       
         
           
           
               
               
           
         
         (ii) a filler; 
         (iii) less than about 2% by weight of disintegrant; 
         (iv) a glidant; 
         (v) a lubricant; 
         (vi) a surfactant; and 
         (vii) optionally a binder; 
         wherein the amount of disintegrant to filler is in a ratio of about 1:28 and wherein the percentage by weight is relative to the total weight of the tablet. 
       
     
     
         49 . A dispersible tablet comprising:
 (i) 60%±5% by weight of crystalline Compound 1 of formula:   
       
         
           
           
               
               
           
         
         wherein crystalline Compound 1 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° 20); 
         (ii) about 20% to about 35% by weight of microcrystalline cellulose; 
         (iii) about 1% to about 2% by weight of croscarmellose sodium; 
         (iv) less than about 2% by weight of colloidal silicon dioxide; 
         (v) about 1% to about 5% by weight of magnesium stearate; 
         (vi) a sweetener; 
         (vii) a flavoring agent; and 
         (viii) a coloring agent; 
         wherein the percentage by weight is relative to the total weight of the tablet and wherein the dispersible tablet disintegrates in a liquid in less than 1 minute. 
       
     
     
         50 . A method of treating sickle cell disease in a patient, wherein the method comprises administering to the patient one or more of a dispersible tablet of  claim 46 . 
     
     
         51 .- 57 . (canceled) 
     
     
         58 . The dispersible tablet of  claim 46 , comprising:
 (i) about 50% to about 70% by weight of Compound 1;   (ii) about 20% to about 35% by weight of filler;   (iii) about 1% to about 2% by weight of disintegrant;   (iv) less than about 2% by weight of glidant; and   (v) about 1% to about 5% by weight of lubricant.   
     
     
         59 . The dispersible tablet of  claim 58 , further comprising:
 (vi) a sweetener;   (vii) a flavoring agent; and   (viii) a coloring agent.   
     
     
         60 . The dispersible tablet of  claim 46 , comprising:
 (i) about 50% to about 70% by weight of Compound 1;   (ii) about 20% to about 35% by weight of filler;   (iii) about 1% to about 2% by weight of disintegrant;   (iv) less than about 2% by weight of glidant;   (v) about 1% to about 5% by weight of lubricant;   (vi) optionally about 1% to about 3% by weight of sweetener;   (vii) optionally about 0.2% to about 1.5% by weight of flavoring agent; and   (viii) optionally about 0.1% to about 1% by weight of coloring agent.   
     
     
         61 . The dispersible tablet of  claim 60 , wherein the filler is microcrystalline cellulose. 
     
     
         62 . The dispersible tablet of  claim 60 , wherein the disintegrant is croscarmellose sodium. 
     
     
         63 . The dispersible tablet of  claim 60 , wherein the glidant is colloidal silicon dioxide. 
     
     
         64 . The dispersible tablet of  claim 60 , wherein the lubricant is magnesium stearate. 
     
     
         65 . The dispersible tablet of  claim 60 , wherein the sweetener is sucrose, xylitol, maltitol, mannitol, sorbitol, sucralose, sodium saccharin, acesulfame potassium, or aspartame. 
     
     
         66 . The dispersible tablet of  claim 46 , comprising:
 (i) about 50% to about 70% by weight of Compound 1;   (ii) about 20% to about 35% by weight of microcrystalline cellulose;   (iii) about 1% to about 2% by weight of croscarmellose sodium;   (iv) less than about 2% by weight of colloidal silicon dioxide;   (v) about 1% to about 5% by weight of magnesium stearate;   (vi) optionally about 1% to about 3% by weight of sweetener;   (vii) optionally about 0.2% to about 1.5% by weight of flavoring agent; and   (viii) optionally about 0.1% to about 1% by weight of coloring agent.   
     
     
         67 . The dispersible tablet of  claim 66 , wherein the tablet comprises Compound 1 in an amount of about: 300 mg, 450 mg, 600 mg, 750 mg, 900 mg, 1200 mg, or 1500 mg. 
     
     
         68 . The dispersible tablet of  claim 66 , wherein the tablet comprises Compound 1 in an amount of about 300 mg. 
     
     
         69 . The dispersible tablet of  claim 46 , wherein the amount of disintegrant to filler is in a ratio of about 1:28. 
     
     
         70 . A dispersible tablet comprising:
 (i) 60%±5% by weight of Compound 1 of formula:   
       
         
           
           
               
               
           
         
         (ii) 20% to 35% by weight of microcrystalline cellulose; 
         (iii) 1% to 2% by weight of croscarmellose sodium; 
         (iv) less than 2% by weight of colloidal silicon dioxide; 
         (v) 1% to about 5% by weight of magnesium stearate; 
         (vi) a sweetener; 
         (vii) a flavoring agent; and 
         (viii) a coloring agent; 
         wherein the percentage by weight is relative to the total weight of the tablet. 
       
     
     
         71 . The dispersible tablet of  claim 70 , wherein Compound 1 is in a crystalline ansolvate form characterized by X-ray powder diffraction peaks (Cu Kα radiation) at 13.37°, 14.37°, 19.95° and 23.92° 2θ (each ±0.2° 20). 
     
     
         72 . A dispersible tablet comprising:
 (i) an intragranular component comprising:
 (a) about 58% by weight of Compound 1 of formula: 
   
       
         
           
           
               
               
           
         
         
           (b) about 26% by weight of microcrystalline cellulose; 
           (c) about 1% by weight of croscarmellose sodium; 
           (d) about 1.5% by weight of magnesium stearate; 
           (e) about 0.5% by weight of colloidal silicon dioxide; and 
         
         (ii) an extragranular component comprising:
 (a) about 8% by weight of microcrystalline cellulose; 
 (b) about 0.25% by weight of croscarmellose sodium; 
 (c) about 0.8% by weight of magnesium stearate; 
 (d) about 2.5% by weight of sucralose; 
 (e) about 0.2% by weight of colloidal silicon dioxide; 
 
         wherein the percentage by weight is relative to the total weight of the tablet. 
       
     
     
         73 . The dispersible tablet of  claim 72 , wherein Compound 1 is in a crystalline ansolvate form characterized by X-ray powder diffraction peaks (Cu Kα radiation) at 13.37°, 14.37°, 19.95° and 23.92° 2θ (each ±0.2° 20). 
     
     
         74 . The dispersible tablet of  claim 72 , wherein the extragranular component further comprises artificial grape flavor. 
     
     
         75 . The dispersible tablet of  claim 72 , wherein the extragranular component further comprises iron oxide pigment. 
     
     
         76 . The method of  claim 50 , wherein the dispersible tablet is dispersed in a liquid prior to its administration to the patient.