Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid and administration thereof

Abstract

A pharmaceutical composition comprising Compound 1, (3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid), and at least one excipient selected from: a filler, a diluent, a disintegrant, a surfactant, a binder, a glidant and a lubricant, the composition being suitable for oral administration to a patient in need thereof to treat a CFTR mediated disease such as Cystic Fibrosis. Methods for treating a patient in need thereof include administering an oral pharmaceutical formulation of Compound 1 to the patient.

1 .- 55 . (canceled) 
     
     
         56 . A tablet for oral administration comprising:
 a. 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) Form I wherein the Compound 1 Form I is present in an amount ranging from 25 mg to 250 mg;   b. a filler;   c. a diluent;   d. a disintegrant;   e. a surfactant;   f a lubricant; and   g. a binder;   wherein the binder is polyvinylpyrrolidone.   
     
     
         57 . A tablet for oral administration comprising:
 a. Compound 1 Form I wherein the Compound 1 Form I is present in an amount ranging from 25 mg to 250 mg;   b. a filler;   c. a disintegrant;   d. a surfactant;   e. a lubricant; and   f. a binder;   wherein the disintegrant is croscarmellose sodium.   
     
     
         58 . A tablet for oral administration comprising:
 a. Compound 1 Form I wherein the Compound 1 Form I is present in an amount ranging from 25 mg to 250 mg;   b. a filler;   c. a disintegrant;   d. a surfactant;   e. a lubricant; and   f. a binder;   wherein the surfactant is sodium lauryl sulfate and is present in an amount of 0.6 wt % to 2 wt % by weight of the tablet.   
     
     
         59 . A tablet for oral administration comprising:
 a. Compound 1 Form I wherein the Compound 1 Form I is present in an amount ranging from 25 mg to 250 mg;   b. a filler;   c. a disintegrant;   d. a surfactant;   e. a lubricant; and   f. a binder;   wherein Compound 1 Form I is present in an amount of 30 to 70 wt % by weight of the tablet; and   wherein the tablet further comprises an additional therapeutic agent which is N-(5-hydroxy-2,4-ditert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide.   
     
     
         60 . The tablet as claimed in  claim 56 , wherein the tablet further comprises an additional therapeutic agent which is N-(5-hydroxy-2,4-ditert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide. 
     
     
         61 . The tablet as claimed in  claim 57 , wherein the tablet further comprises an additional therapeutic agent which is N-(5-hydroxy-2,4-ditert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide. 
     
     
         62 . The tablet as claimed in  claim 58 , wherein the tablet further comprises an additional therapeutic agent which is N-(5-hydroxy-2,4-ditert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide. 
     
     
         63 . The tablet as claimed in  claim 56 , wherein Compound 1 Form I is present in an amount of 30 to 70 wt % by weight of the tablet. 
     
     
         64 . The tablet as claimed in  claim 63 , wherein Compound 1 Form I is present in the tablet in an amount of 30 to 60 wt % by weight of the tablet. 
     
     
         65 . The tablet as claimed in  claim 56 , wherein the disintegrant is croscarmellose sodium. 
     
     
         66 . The tablet as claimed in  claim 56 , wherein the surfactant is sodium lauryl sulfate and is present in an amount of 0.6 wt % to 2 wt % by weight of the tablet. 
     
     
         67 . The tablet as claimed in  claim 56 , wherein the Compound 1 Form I is present in the tablet in an amount of 200 mg. 
     
     
         68 . The tablet as claimed in  claim 56 , wherein the filler is selected from cellulose, modified cellulose, sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose, cellulose acetate, microcrystalline cellulose, dibasic calcium phosphate, sucrose, lactose, corn starch, potato starch, and any combination thereof. 
     
     
         69 . The tablet as claimed in  claim 68 , wherein the filler is microcrystalline cellulose (MCC) and is present in the tablet in an amount ranging from 20 wt % to 55 wt % by weight of the tablet. 
     
     
         70 . The tablet as claimed in  claim 56 , wherein the disintegrant is croscarmellose sodium and is present in the tablet at a concentration of 2.5 to 6 wt % by weight of the tablet. 
     
     
         71 . The tablet as claimed in  claim 56 , wherein the polyvinylpyrrolidone is present at a concentration of 1 to 8 wt % by weight of the tablet. 
     
     
         72 . The tablet as claimed in  claim 56 , wherein the lubricant is selected from magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil, and any combination thereof. 
     
     
         73 . The tablet as claimed in  claim 72 , wherein the lubricant is magnesium stearate and is present at a concentration of 0.15 to 4.5 wt % by weight of the tablet. 
     
     
         74 . The tablet as claimed in  claim 56 , wherein the tablet further comprises a colorant. 
     
     
         75 . The tablet as claimed in  claim 56 ,
 wherein the surfactant is sodium lauryl sulfate and is present in an amount of 0.6 wt % to 2 wt % by weight of the tablet; and   wherein the tablet further comprises an additional therapeutic agent which is N-(5-hydroxy-2,4-ditert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide.   
     
     
         76 . The tablet as claimed in  claim 56 ,
 wherein the polyvinylpyrrolidone is present at a concentration of 1 to 8 wt % by weight of the tablet;   wherein the disintegrant is croscarmellose sodium; and   wherein the surfactant is sodium lauryl sulfate and is present in an amount of 0.6 wt % to 2 wt % by weight of the tablet.   
     
     
         77 . The tablet as claimed in  claim 56 ,
 wherein the filler is microcrystalline cellulose (MCC) and is present in the tablet in an amount of 25 to 50 wt % by weight of the tablet;   wherein the disintegrant is croscarmellose sodium and is present in the tablet at a concentration of 2.5 to 6 wt % by weight of the tablet;   wherein the surfactant is sodium lauryl sulfate at a concentration of 0.6 to 2 wt % by weight of the tablet;   wherein the lubricant is magnesium stearate at a concentration of 0.15 to 4.5 wt % by weight of the tablet; and   wherein the polyvinylpyrrolidone is present at a concentration of 2 to 5 wt % by weight of the tablet.   
     
     
         78 . The tablet as claimed in  claim 56 ,
 wherein the filler is microcrystalline cellulose (MCC) and is present in the tablet in an amount of 25 wt % by weight of the tablet;   wherein the disintegrant is croscarmellose sodium and is present in the tablet at a concentration of 6 wt % by weight of the tablet;   wherein the surfactant is sodium lauryl sulfate at a concentration of 0.8 wt % by weight of the tablet;   wherein the lubricant is magnesium stearate at a concentration of 1 wt % by weight of the tablet; and   wherein the polyvinylpyrrolidone is present at a concentration of 2 wt % by weight of the tablet.   
     
     
         79 . A method of treating or lessening the severity of cystic fibrosis in a subject, comprising administering to the subject a tablet as claimed in  claim 56 . 
     
     
         80 . The method as claimed in  claim 79 , wherein subject is homozygous for the ΔF508 mutation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. 
     
     
         81 . A method of treating or lessening the severity of cystic fibrosis in a subject, comprising administering to the subject a tablet as claimed in  claim 57 . 
     
     
         82 . The method as claimed in  claim 81 , wherein subject is homozygous for the ΔF508 mutation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. 
     
     
         83 . A method of treating or lessening the severity of cystic fibrosis in a subject, comprising administering to the subject a tablet as claimed in  claim 58 . 
     
     
         84 . The method as claimed in  claim 83 , wherein subject is homozygous for the ΔF508 mutation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. 
     
     
         85 . A method of treating or lessening the severity of cystic fibrosis in a subject, comprising administering to the subject a tablet as claimed in  claim 59 . 
     
     
         86 . The method as claimed in  claim 85 , wherein subject is homozygous for the ΔF508 mutation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. 
     
     
         87 . The tablet as claimed in  claim 56 , wherein the Form I is characterized by at least one peak having a 20 value selected from 15.4±0.2 degrees, 16.3±0.2 degrees, and 14.5±0.2 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation. 
     
     
         88 . The tablet as claimed in  claim 56 , wherein the Form I is characterized by a peak having a 20 value at 15.4±0.2 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation. 
     
     
         89 . The tablet as claimed in  claim 56 , wherein the Form I is characterized by a peak having a 20 value at 16.3±0.2 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation. 
     
     
         90 . The tablet as claimed in  claim 56 , wherein the Form I is characterized by a peak having a 20 value at 14.5±0.2 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation. 
     
     
         91 . The tablet as claimed in  claim 56 , wherein the Form I is characterized by a diffraction pattern substantially similar to that of  FIG. 2 .