US2016039800A1PendingUtilityA1
Dosage units of 3-(6-(1-(2,2-difluorobenzo[d] [1,3] dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid

Assignee: VERTEX PHARMAPriority: Sep 29, 2008Filed: Oct 22, 2015Published: Feb 11, 2016
Est. expirySep 29, 2028(~2.2 yrs left)· nominal 20-yr term from priority
A61P 43/00A61P 3/00A61P 1/00A61K 31/47A61K 9/2059C07D 405/12A61K 9/4858A61K 45/06A61K 9/4866A61K 9/2018A61K 31/443A61K 9/2054A61K 31/36A61K 31/4418A61K 9/48
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References
Claims
Abstract

The present invention relates to formulations of 3-(6-(1-(2,2-difluorobenzo [d][1,3 ]dioxol-5 -yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid in Form I, pharmaceutical packs or kits thereof, and methods of treatment therewith.
Claims

exact text as granted — not AI-modified
1 . A dosage unit comprising 25 to 400 mg of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid characterized as Form I. 
     
     
         2 . The dosage unit of  claim 1 , wherein the amount of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid is 100 to 300 mg. 
     
     
         3 . The dosage unit of  claim 1 , wherein the amount of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid is 200 mg. 
     
     
         4 - 19 . (canceled) 
     
     
         20 . The dosage unit of  claim 1 , wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid has a monoclinic crystal system, a P2 1 /n space group, and the following unit cell dimensions:
   a=4.9626 (7) Å α=90°
     b=12.2994 (18) Å β=93.938 (9)°
     c=33.075 (4) Å γ=90°.
   
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . The dosage unit of  claim 1 , wherein the dosage unit is an oral dosage unit. 
     
     
         24 . The dosage unit of  claim 1 , wherein the dosage unit is a solid oral dosage unit. 
     
     
         25 . The dosage unit of  claim 1 , wherein the dosage unit is in the form of a tablet or capsule. 
     
     
         26 . The dosage unit of  claim 1 , wherein the dosage unit is in the form of a capsule. 
     
     
         27 . The dosage unit of  claim 1 , wherein the dosage unit comprises more than one capsule. 
     
     
         28 . The dosage unit of  claim 1 , wherein the dosage unit comprises 4 capsules of 50 mg of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid each. 
     
     
         29 . The dosage unit of  claim 1 , further comprising a filler. 
     
     
         30 . The dosage unit of  claim 29 , wherein the filler is selected from the group consisting of lactose, microcrystalline cellulose, calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate, calcium phosphate tribasic, cellulose powder, magnesium carbonate, calcium sulfate, starch, talc, sucrose, dextrose, mannitol, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, fructose, xylitol, sorbitol, and combinations thereof. 
     
     
         31 . The dosage unit of  claim 29 , wherein the filler is lactose and microcrystalline cellulose. 
     
     
         32 . The dosage unit of  claim 29 , wherein the amount of filler is 40 to 80 percent by weight. 
     
     
         33 . The dosage unit of  claims 29 , wherein the amount of filler is 50 to 70 percent by weight. 
     
     
         34 . The dosage unit of  claim 29 , wherein the amount of filler is 60 percent by weight. 
     
     
         35 . The dosage unit of  claim 1 , further comprising a disintegrant. 
     
     
         36 . The dosage unit of  claim 35 , wherein the disintegrant is selected from the group consisting of sodium starch glycolate, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, cellulose powder, croscarmellose sodium, crosspovidone, chitin, bicarbonate salt, gellan gum, and combinations thereof. 
     
     
         37 . The dosage unit of  claim 35 , wherein the disintegrant is sodium starch glycolate. 
     
     
         38 . The dosage unit of  claim 35 , wherein the amount of disintegrant is 1 to 20 percent by weight. 
     
     
         39 . The dosage unit of  claim 35 , wherein the amount of disintegrant is 5 to 15 percent by weight. 
     
     
         40 . The dosage unit of  claim 35 , wherein the amount of disintegrant is 10 percent by weight. 
     
     
         41 . The dosage unit of  claim 1  further comprising a surfactant. 
     
     
         42 . The dosage unit of  claim 41 , wherein the surfactant is an anionic, cationic, or nonionic surfactant. 
     
     
         43 . The dosage unit of  claim 41 , wherein the surfactant is an anionic surfactant selected from the group consisting of salts of lauryl sulfate, laureth sulfate, alkyl benzene sulfonates, butanoic acid, hexanoic acid, octanoic acid, decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, and docosahexaenoic acid. 
     
     
         44 . The dosage unit of  claim 41 , wherein the surfactant is sodium lauryl sulfate. 
     
     
         45 . The dosage unit of  claim 41 , wherein the surfactant is a cationic surfactant selected from the group consisting of cetyl trimethylammonium bromide, cetylpyridinium chloride, polethoxylated tallow amine, benzalkonium chloride, and benzethonium chloride. 
     
     
         46 . The dosage unit of  claim 41 , wherein the surfactant is a nonionic surfactant selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, alkyl poly(ethylene oxide), poloxamine, alkyl polyglucosides, octyl glucoside, decyl maltoside, fatty alcohol, cetyl alcohol, oleyl alcohol, cocamide MEA, cocamide DEA, and cocamide TEA. 
     
     
         47 . The dosage unit of  claim 41 , wherein the amount of surfactant is 0.5 to 15 percent by weight. 
     
     
         48 . The dosage unit of  claim 41 , wherein the amount of surfactant is 1 to 10 percent by weight. 
     
     
         49 . The dosage unit of  claim 41 , wherein the amount of surfactant is 5 perecent by weight. 
     
     
         50 . The dosage unit of  claim 1 , further comprising a glidant or viscosity agent. 
     
     
         51 . The dosage unit of  claim 50 , wherein the glidant or viscosity agent is selected from the group consisting of colloidal silicon dioxide, magnesium aluminum silicate, xanthan gum, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, carageenan, carboxymethyl cellulose, polyvinylpyrrolidone, sodium alginate, povidone, acacia, guar gum, tragacanth, magnesium aluminum silicate, carbomers, and combinations thereof. 
     
     
         52 . The dosage unit of  claim 50 , wherein the glidant is colloidal silicon dioxide. 
     
     
         53 . The dosage unit of  claim 50 , wherein the amount of glidant or viscosity agent is 0.05 to 2 percent by weight. 
     
     
         54 . The dosage unit of  claim 50 , wherein the amount of glidant or viscosity agent is 0.1 to 1 percent by weight. 
     
     
         55 . The dosage unit of  claim 50 , wherein the amount of glidant or viscosity agent is 0.5 percent by weight. 
     
     
         56 . The dosage unit of  claim 1 , further comprising a lubricant. 
     
     
         57 . The dosage unit of  claim 56 , wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, magnesium trisilicate, sodium stearyl fumarate, stearic acid, zinc stearate, and combinations thereof. 
     
     
         58 . The dosage unit of  claim 56 , wherein the lubricant is magnesium stearate. 
     
     
         59 . The dosage unit of  claim 56 , wherein the amount of lubricant is 0.05 to 2 percent by weight. 
     
     
         60 . The dosage unit of  claim 56 , wherein the amount of lubricant is 0.1 to 1 percent by weight. 
     
     
         61 . The dosage unit of  claim 56 , wherein the amount of lubricant is 0.5 percent by weight. 
     
     
         62 . The dosage unit of  claim 1 , wherein the dosage unit comprises a capsule comprising 50 mg of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid characterized as Form I, 40 to 44 percent by weight lactose, 15 to 20 percent by weight microcrystalline cellulose, 10 percent by weight sodium starch glycolate, 5 to 6 percent by weight sodium lauryl sulfate, 0.5 to 0.6 percent by weight colloidal silicon dioxide, and 0.5 percent by weight magnesium stearate. 
     
     
         63 . The dosage unit of  claim 1 , wherein the dosage unit comprises a capsule comprising 25 mg of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid characterized as Form I. 
     
     
         64 . The dosage unit of  claim 63 , wherein the dosage unit further comprises 40 or 44 percent by weight lactose, 15 to 20 percent by weight microcrystalline cellulose, 10 percent by weight sodium starch glycolate, 5 to 6 percent by weight sodium lauryl sulfate, 0.5 to 0.6 percent by weight colloidal silicon dioxide, and 0.5 percent by weight magnesium stearate. 
     
     
         65 . The dosage unit of  claim 1 , wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid characterized as Form I has a particle size of 0.1 microns to 50 microns. 
     
     
         66 . The dosage unit of  claim 1 , wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid characterized as Form I has a particle size of 0.1 microns to 20 microns. 
     
     
         67 . The dosage unit of  claim 1 , wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid characterized as Form I has a particle size of 0.1 microns to 10 microns. 
     
     
         68 . The dosage unit of  claim 1 , wherein the 3-(6(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid characterized as Form I has a particle size of 1.0 microns to 5 microns. 
     
     
         69 . The dosage unit of  claim 1 , wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid characterized as Form I has a particle size D50 of 2.0 microns. 
     
     
         70 . A method of treating cystic fibrosis in a subject comprising administering to a subject in need thereof an effective amount of the dosage unit of  claim 1 . 
     
     
         71 . The method of  claim 70 , wherein the method comprises administering an additional therapeutic agent. 
     
     
         72 . The method of  claim 71 , wherein the additional therapeutic agent is slected from the group consisting of mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than a compound of the present invention, and a nutritional agent. 
     
     
         73 - 75 . (canceled) 
     
     
         76 . The method of  claim 70 , wherein the dosage unit is administered to the subject once a day. 
     
     
         77 . A pharmaceutical pack or kit comprising the dosage unit of  claim 1  and instructions for use thereof.
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