Claims for Patent: 11,504,333

Summary for Patent: 11,504,333

Title:	Pharmaceutical composition
Abstract:	The invention pertains to dispersible tablets comprising as active ingredient N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, methanesulfonate salt, processes for preparing the same, and processes for using the same.
Inventor(s):	Nikos KARANIKOLOPOULOS, Paul Anthony GOULDING
Assignee:	Novartis AG
Application Number:	US16/628,463
Patent Claims:	1. A dispersible tablet comprising an inner phase and an outer phase, wherein (a) the inner phase comprises: (i) N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, methanesulfonate salt; (ii) microcrystalline cellulose; (iii) mannitol; (iv) hypromellose; (v) acesulfame potassium; (vi) crospovidone; (vii) colloidal silicon dioxide; (viii) magnesium stearate; and (b) the outer phase comprises: (i) microcrystalline cellulose; (ii) mannitol; (iii) hypromellose; (iv) crospovidone; (v) magnesium stearate; and wherein (I) N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, methanesulfonate salt is present in an amount of from 5% to 40% in weight based on the total weight of the tablet, wherein the tablet contains 10 mg to 25 mg of N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, methanesulfonate salt, (II) hypromellose is present in an amount of from 1% to 13% in weight based on the total weight of the tablet, and (III) mannitol and microcrystalline cellulose are present in an amount of from 35% to 70% in weight based on the total weight of the tablet, wherein mannitol and microcrystalline cellulose are present in a weight by weight ratio of about 2.5:1 to 2:1. 2. The dispersible tablet of claim 1, wherein hypromellose is present in about 5% to about 10% in weight based on the total weight of the tablet. 3. The dispersible tablet of claim 1, wherein hypromellose has nominal viscosity between 4 mPa s to 6 mPa s, as measured at 20° C. for a 2% by weight in water, and a 28% to 30% methoxyl substitution. 4. The dispersible tablet of claim 1, wherein hypromellose has viscosity of between 80 mPa s to 120 mPa s, as measured at 20° C. for a 2% by weight in water, and 19% to 24% methoxyl substitution. 5. The dispersible tablet of claim 1, wherein the tablet has a disintegration time, measured according to the disintegration test of the European Pharmacopoeia 2.9.1, disintegration time of tablets in water at 15° C. to 25° C., of 3 minutes or less. 6. The dispersible tablet of claim 1, wherein the tablet has a hardness of mean value, measured according to the resistance to crushing of tablets test of the European Pharmacopoeia 2.9.8, of not more than 55N. 7. The dispersible tablet of claim 1, wherein crospovidone is present in about 5% to 10% in weight based on the total weight of the tablet. 8. The dispersible tablet of claim 3, wherein: (a) the inner phase comprises, by percent weight by total weight (% w/w) of said tablet: (i) 14.81% w/w N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, methanesulfonate salt; (ii) 8.13% w/w microcrystalline cellulose; (iii) 12.00% w/w mannitol; (iv) 2.50% w/w hypromellose; (v) 3.31% w/w acesulfame potassium; (vi) 6.69% w/w crospovidone; (vii) 0.19% w/w colloidal silicon dioxide; (viii) 0.31% w/w magnesium stearate; and (b) the outer phase comprises, by percent weight by total weight (% w/w) of said tablet: (i) 11.44% w/w microcrystalline cellulose; (ii) 33.25% w/w mannitol; (iii) 2.50% w/w hypromellose; (iv) 3.31% w/w crospovidone; (v) 1.00% w/w magnesium stearate; and wherein hypromellose has viscosity of 5 mPa s, as measured at 20° C. for a 2% by weight in water, and a 28% to 30% methoxyl substitution. 9. The dispersible tablet of claim 3, wherein: (a) the inner phase comprises, by percent weight by total weight (% w/w) of said tablet: (i) 14.81% w/w N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, methanesulfonate salt; (ii) 10.28% w/w microcrystalline cellulose; (iii) 10.28% w/w mannitol; (iv) 3.75% w/w hypromellose; (v) 3.31% w/w acesulfame potassium; (vi) 5.00% w/w crospovidone; (vii) 0.19% w/w colloidal silicon dioxide; (viii) 0.31% w/w magnesium stearate; and (b) the outer phase comprises, by percent weight by total weight (% w/w) of said tablet: (i) 11.31% w/w microcrystalline cellulose; (ii) 32.94% w/w mannitol; (iii) 3.75% w/w hypromellose; (iv) 2.50% w/w crospovidone; (v) 1.00% w/w magnesium stearate; and wherein hypromellose has viscosity of 5 mPa s, as measured at 20° C. for a 2% by weight in water, and a 28% to 30% methoxyl substitution. 10. The dispersible tablet of claim 3, wherein: (a) the inner phase comprises, by percent weight by total weight (% w/w) of said tablet: (i) 14.81% w/w N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, methanesulfonate salt; (ii) 7.13% w/w microcrystalline cellulose; (iii) 10.50% w/w mannitol; (iv) 5.00% w/w hypromellose; (v) 3.31% w/w acesulfame potassium; (vi) 6.69% w/w crospovidone; (vii) 0.19% w/w colloidal silicon dioxide; (viii) 0.31% w/w magnesium stearate; and (b) the outer phase comprises, by percent weight by total weight (% w/w) of said tablet: (i) 10.81% w/w microcrystalline cellulose; (ii) 31.38% w/w mannitol; (iii) 5.00% w/w hypromellose; (iv) 3.31% w/w crospovidone; (v) 1.00% w/w magnesium stearate; and wherein hypromellose has viscosity of 5 mPa s, as measured at 20° C. for a 2% by weight in water, and a 28% to 30% methoxyl substitution. 11. The dispersible tablet of claim 4, wherein: (a) the inner phase comprises, by percent weight by total weight (% w/w) of said tablet: (i) 14.81% w/w N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, methanesulfonate salt; (ii) 8.13% w/w microcrystalline cellulose; (iii) 12.00% w/w mannitol; (iv) 2.50% w/w hypromellose; (v) 3.31% w/w acesulfame potassium; (vi) 6.69% w/w crospovidone; (vii) 0.19% w/w colloidal silicon dioxide; (viii) 0.31% w/w magnesium stearate; and (b) the outer phase comprises, by percent weight by total weight (% w/w) of said tablet: (i) 11.44% w/w microcrystalline cellulose; (ii) 33.25% w/w mannitol; (iii) 2.50% w/w hypromellose; (iv) 3.31% w/w crospovidone; (v) 1.00% w/w magnesium stearate; and wherein hypromellose has viscosity of 100 mPa s, as measured at 20° C. for a 2% by weight in water, and 19% to 24% methoxyl substitution. 12. The dispersible tablet of claim 4, wherein: (a) the inner phase comprises, by percent weight by total weight (% w/w) of said tablet: (i) 14.81% w/w N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, methanesulfonate salt; (ii) 10.28% w/w microcrystalline cellulose; (iii) 10.28% w/w mannitol; (iv) 3.75% w/w hypromellose; (v) 3.31% w/w acesulfame potassium; (vi) 5.00% w/w crospovidone; (vii) 0.19% w/w colloidal silicon dioxide; (viii) 0.31% w/w magnesium stearate; and (b) the outer phase comprises, by percent weight by total weight (% w/w) of said tablet: (i) 11.31% w/w microcrystalline cellulose; (ii) 32.94% w/w mannitol; (iii) 3.75% w/w hypromellose; (iv) 2.50% w/w crospovidone; (v) 1.00% w/w magnesium stearate; and wherein hypromellose has viscosity of 100 mPa s, as measured at 20° C. for a 2% by weight in water, and 19% to 24% methoxyl substitution. 13. The dispersible tablet of claim 4, wherein: (a) the inner phase comprises, by percent weight by total weight (% w/w) of said tablet: (i) 14.81% w/w N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, methanesulfonate salt; (ii) 8.44% w/w microcrystalline cellulose; (iii) 12.50% w/w mannitol; (iv) 5.00% w/w hypromellose; (v) 3.31% w/w acesulfame potassium; (vi) 3.38% w/w crospovidone; (vii) 0.19% w/w colloidal silicon dioxide; (viii) 0.31% w/w magnesium stearate; and (b) the outer phase comprises, by percent weight by total weight (% w/w) of said tablet: (i) 11.25% w/w microcrystalline cellulose; (ii) 32.63% w/w mannitol; (iii) 5.00% w/w hypromellose; (iv) 1.63% w/w crospovidone; (v) 1.00% w/w magnesium stearate; and wherein hypromellose has viscosity of 100 mPa s, as measured at 20° C. for a 2% by weight in water, and 19% to 24% methoxyl substitution. 14. The dispersible tablet of claim 3, wherein: (a) the inner phase comprises, by percent weight by total weight (% w/w) of said tablet: (i) 14.81% w/w N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, methanesulfonate salt; (ii) 8.15% w/w microcrystalline cellulose; (iii) 12.05% w/w mannitol; (iv) 2.50% w/w hypromellose; (v) 3.31% w/w acesulfame potassium; (vi) 6.69% w/w crospovidone; (vii) 0.19% w/w colloidal silicon dioxide; (viii) 0.31% w/w magnesium stearate; and (b) the outer phase comprises, by percent weight by total weight (% w/w) of said tablet: (i) 11.44% w/w microcrystalline cellulose; (ii) 33.25% w/w mannitol; (iii) 2.50% w/w hypromellose; (iv) 3.31% w/w crospovidone; (v) 1.00% w/w magnesium stearate; and wherein hypromellose has viscosity of 5 mPa s, as measured at 20° C. for a 2% by weight in water, and a 28% to 30% methoxyl substitution. 15. The dispersible tablet of claim 4, wherein: (a) the inner phase comprises, by percent weight by total weight (% w/w) of said tablet: (i) 14.81% w/w N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, methanesulfonate salt; (ii) 8.15% w/w microcrystalline cellulose; (iii) 12.05% w/w mannitol; (iv) 2.50% w/w hypromellose; (v) 3.31% w/w acesulfame potassium; (vi) 6.69% w/w crospovidone; (vii) 0.19% w/w colloidal silicon dioxide; (viii) 0.31% w/w magnesium stearate; and (b) the outer phase comprises, by percent weight by total weight (% w/w) of said tablet: (i) 11.44% w/w microcrystalline cellulose; (ii) 33.25% w/w mannitol; (iii) 2.50% w/w hypromellose; (iv) 3.31% w/w crospovidone; (v) 1.00% w/w magnesium stearate; and wherein hypromellose has viscosity of 100 mPa s, as measured at 20° C. for a 2% by weight in water, and 19% to 24% methoxyl substitution.