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 - 48 . (canceled) 
     
     
         49 . A method of treating or lessening the severity of a disease in a subject comprising administering to the subject a tablet for oral administration comprising:
 a. Compound 1, Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A;   b. a filler;   c. a diluent;   d. a disintegrant;   e. a surfactant;   f. a lubricant; and   g. at least one of a binder and a glidant,   
       wherein the disease is selected from pancreatic insufficiency or male infertility. 
     
     
         50 - 55 . (canceled) 
     
     
         56 . The method of  claim 49 , wherein Compound 1, Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A is present in the tablet in an amount ranging from about 25 mg to about 250 mg. 
     
     
         57 . The method of  claim 49 , wherein the amount of Compound 1, Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A in the tablet ranges from about 15 wt % to about 75 wt % by weight of the tablet. 
     
     
         58 . The method of  claim 49 , wherein the amount of Compound 1, Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A in the tablet ranges from about 40 wt % to about 60 wt % by weight of the tablet. 
     
     
         59 . The method of  claim 49 , 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, or any combination thereof. 
     
     
         60 . The method of  claim 49 , wherein the filler is microcrystalline cellulose (MCC) and is present in the tablet in an amount ranging from about 20 wt % to about 50 wt % by weight of the tablet. 
     
     
         61 . The method of  claim 49 , wherein the diluent is selected from lactose, mannitol, sorbitol, cellulose, calcium phosphate, starch, sugar or any combination thereof. 
     
     
         62 . The method of  claim 49 , wherein the diluent is mannitol and is present in the tablet in an amount ranging from about 1 wt % to about 30 wt % by weight of the tablet. 
     
     
         63 . The method of  claim 49 , wherein the disintegrant is selected from agar-agar, algins, calcium carbonate, carboxymethylcellulose, cellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose, clays, croscarmellose sodium, crospovidone, gums, magnesium aluminum silicate, methylcellulose, polacrilin potassium, sodium alginate, sodium starch glycolate, maize starch, potato starch, tapioca starch, or any combination thereof. 
     
     
         64 . The method of  claim 49 , wherein the disintegrant is croscarmellose sodium and is present in the tablet at a concentration of 5 wt % or less by weight of the tablet. 
     
     
         65 . The method of  claim 49 , wherein the surfactant is selected from sodium lauryl sulfate, sodium stearyl fumerate, polyoxyethylene 20 sorbitan mono-oleate, or any combination thereof. 
     
     
         66 . The method of  claim 49 , wherein the surfactant is sodium lauryl sulfate at a concentration of about 5 wt % or less by weight of the tablet. 
     
     
         67 . The method of  claim 49 , wherein the glidant is selected from colloidal silicon dioxide, talc, corn starch, or a combination thereof. 
     
     
         68 . The method of  claim 49 , wherein the glidant is colloidal silicon dioxide at a concentration of 5 wt % or less by weight of the tablet. 
     
     
         69 . The method of  claim 49 , wherein the binder is selected from polyvinylpyrrolidone, dibasic calcium phosphate, sucrose, corn starch, modified cellulose, or any combination thereof. 
     
     
         70 . The method of  claim 49 , wherein the binder is polyvinylpyrrolidone at a concentration of less than 10 wt % by weight of the tablet. 
     
     
         71 . The method of  claim 49 , wherein the lubricant is selected from magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil or any combination thereof. 
     
     
         72 . The method of  claim 49 , wherein the lubricant is magnesium stearate at a concentration of less than 5 wt % by weight of the tablet. 
     
     
         73 . The method of  claim 49  wherein the tablet has the following formulation:
 99.5% w/w of a roller compaction granule blend and 0.5% w/w magnesium stearate; wherein the roller compaction granule blend comprises 30% w/w 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid Form I, 42.3% w/w microcrystalline cellulose, 21.2% w/w mannitol, 3% w/w croscarmellose sodium, 1% w/w sodium lauryl sulfate, 0.5% w/w colloidal silica, and 2% w/w magnesium stearate. 
 
     
     
         74 . The method of  claim 49  wherein the tablet has the following formulation:
 97.5% w/w of a high shear granule blend, 2.0% w/w croscarmellose sodium, and 0.5% w/w magnesium stearate; wherein the high shear granule blend comprises 50% w/w 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid Form I, 30% w/w microcrystalline cellulose, 13% w/w mannitol, 2% w/w croscarmellose sodium, 4% w/w polyvinylpyrrolidone, and 1% w/w sodium lauryl sulfate. 
 
     
     
         75 . The method of  claim 49  wherein the tablet has the following formulation:
 97.5% w/w of a high shear granule blend, 2.0% w/w croscarmellose sodium, and 0.5% w/w magnesium stearate; wherein the high shear granule blend comprises 60% w/w 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid Form I, 20% w/w microcrystalline cellulose, 13% w/w mannitol, 2% w/w croscarmellose sodium, 4% w/w polyvinylpyrrolidone, and 1% w/w sodium lauryl sulfate. 
 
     
     
         76 . The method of  claim 49  wherein the tablet has the following formulation:
 83% w/w of a high shear granule blend, 14% w/w microcrystalline cellulose, 2% w/w croscarmellose sodium, and 1.0% w/w magnesium stearate; wherein the high shear granule blend comprises 60% w/w 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid Form I, 20% w/w microcrystalline cellulose, 13% w/w mannitol, 2% w/w croscarmellose sodium, 4% w/w polyvinylpyrrolidone, and 1% w/w sodium lauryl sulfate. 
 
     
     
         77 . The method of  claim 49  wherein the tablet has the following formulation:
 400 mg of a core tablet composition, 12 mg film coat, and 0.04 g wax; wherein the core table composition comprises 332 mg of a high shear granule blend, 56 mg microcrystalline cellulose, 8 mg croscarmellose sodium, and 4 mg of magnesium stearate; wherein the high shear granule blend comprises 200 mg 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid Form I, 66 mg of microcrystalline cellulose, 43 mg of mannitol, 7 mg of croscarmellose sodium, 13 mg of polyvinylpyrrolidone, and 3 mg of sodium lauryl sulfate. 
 
     
     
         78 . The method of  claim 49  wherein the tablet has the following formulation:
 400 mg of a core tablet composition, 12 mg film coat, and 0.04 mg wax; wherein the core tablet composition comprises 332 mg of a high shear granule blend, 56 mg microcrystalline cellulose, 8 mg croscarmellose sodium, and 4 mg magnesium stearate; wherein the high shear granule blend comprises 200 mg 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid Form I, 67 mg microcrystalline cellulose, 45 mg mannitol, 7 mg croscarmellose sodium, 10.4 mg polyvinylpyrrolidone, and 2.6 mg sodium lauryl sulfate. 
 
     
     
         79 . The method of  claim 49  wherein the tablet has the following formulation:
 97.5% w/w of a high shear granule blend, 2.0% w/w croscarmellose sodium, and 0.5% w/w magnesium stearate; wherein the high shear granule blend comprises 70% w/w 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid Form I, 12% w/w microcrystalline cellulose, 11% w/w mannitol, 2% w/w croscarmellose sodium, 4% w/w polyvinylpyrrolidone, and 1% w/w sodium lauryl sulfate. 
 
     
     
         80 . The method of  claim 49  wherein the tablet has the following formulation:
 83% w/w of a high shear granule blend, 14% w/w microcrystalline cellulose, 2% w/w croscarmellose sodium, and 1% w/w magnesium stearate; wherein the high shear granule blend comprises 61% w/w 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid Form I or Form II, 20.3% w/w microcrystalline cellulose, 13.2% w/w mannitol, 2% w/w croscarmellose sodium, and 2.7% w/w polyvinylpyrrolidone. 
 
     
     
         81 . The method of  claim 49  wherein the tablet has the following formulation:
 163.9 mg of a high shear granule blend, 27.6% mg microcrystalline cellulose, 3.9 mg croscarmellose sodium, and 2.0 mg magnesium stearate; wherein the high shear granule blend comprises 100 mg 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid Form I or Form II, 33.3 mg microcrystalline cellulose, 21.7 mg mannitol, 3.3 mg croscarmellose sodium, 4.4 mg polyvinylpyrrolidone, and 1.1 mg sodium lauryl sulfate. 
 
     
     
         82 . The method of  claim 49 , wherein Compound 1 has a particle size of 0.1 microns to 50 microns. 
     
     
         83 . The method of  claim 49 , wherein Compound 1 has a particle size of 0.1 microns to 20 microns. 
     
     
         84 . The method of  claim 49 , wherein Compound 1 has a particle size of 0.1 microns to 10 microns. 
     
     
         85 . The method of  claim 49 , wherein Compound 1 has a particle size of 1.0 microns to 5 microns. 
     
     
         86 . The method of  claim 49 , wherein Compound 1 has a particle size D50 of 2.0 microns.