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Last Updated: January 22, 2020

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Claims for Patent: 9,387,208

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Summary for Patent: 9,387,208
Title:Pharmaceutical formulations of (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-- pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate
Abstract: This invention relates to solid oral pharmaceutical formulations of (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-- pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (COMPOUND A) and the use of the formulations for treating proliferative diseases, such as solid tumor diseases.
Inventor(s): Verma; Daya (Edison, NJ), Krishnamachan; Yogita (Springfield, NJ), Shen; Xiaohong (Livingston, NJ), Lee; Hanchen (Teaneck, NJ), Li; Ping (Basking Ridge, NJ), Singh; Rajinder (Sewaren, NJ), Tan; LayChoo (Bridgewater, NJ)
Assignee: Novartis AG (Basel, CH)
Application Number:14/359,121
Patent Claims: 1. A solid oral pharmaceutical formulation, which comprises: an inner phase which is a solid dispersion comprising amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methyl sulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)prop- an-2-yl)carbamate (COMPOUND A); copovidone; and poloxamer 188 or sorbitol; and an external phase which comprises succinic acid, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate.

2. The solid oral pharmaceutical formulation of claim 1, wherein the inner phase comprises from 5% to 40% by weight of amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methyl sulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)prop- an-2-yl)carbamate (Compound A), from 50% to 80% by weight of copovidone, and from 5% to 20% by weight of poloxamer 188 or sorbitol.

3. The solid oral pharmaceutical formulation of claim 2, wherein the external phase comprises from 2% to 60% by weight of succinic acid, from 30% to 70% by weight of microcrystalline cellulose, from 5% to 20% by weight of crospovidone, from 0.5% to 5% by weight of colloidal silicon dioxide, and from 0.5% to 5% by weight of magnesium stearate.

4. The solid oral pharmaceutical formulation of claim 1, comprising a blend of the internal and external phases in a ratio of from 80:20 to 40:60.

5. The solid oral pharmaceutical formulation of claim 4, comprising a blend of the internal and external phases in a ratio of from 75:25 to 50:50.

6. The solid oral pharmaceutical formulation of claim 1, comprising 10 mg, 25 mg, 50 mg, or 100 mg of amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-- pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (Compound A).

7. The solid oral pharmaceutical formulation of claim 6, wherein the formulation comprises 15% by weight of amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methyl sulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)prop- an-2-yl)carbamate (Compound A).

8. The solid oral pharmaceutical formulation of claim 1, wherein the formulation is selected from the group consisting of: A) TABLE-US-00012 Ingredient % w/w Internal Phase amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3- 15 (methylsulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (Compound A) copovidone 45 Poloxamer 188 5 External Phase Succinic acid 13 Microcrystalline cellulose 16 Crosspovidone 5 magnesium Stearate 0.5 Colloidal silicon dioxide 0.5 Total 100

and B) TABLE-US-00013 Ingredient % w/w Internal amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3- 17 (methylsulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (Compound A) PVP-K30 51 Sorbitol 5 External Succinic Acid 9 Microcrystalline cellulose 12 Crosspovidone 5 Mg Stearate 0.5 Colloidal silicon dioxide 0.5 Total 100.

9. The solid oral formulation of claim 1, wherein the formulation is selected from the group consisting of: TABLE-US-00014 Ingredient Internal Phase (mg) amorphous (S)-methyl (1-((4-(3-(5- 10.0 chloro-2-fluoro-3- (methylsulfonamido)phenyl)-1- isopropyl-1H-pyrazol-4-yl)pyrimidin- 2-yl)amino)propan-2-yl)carbamate (Compound A) Copovidone 29.9 Poloxamer 188 3.3 External Phase (mg) Succinic acid 8.7 Cellulose microcrystalline 10.7 Crospovidone 3.3 Colloidal silicon dioxide 0.3 Magnesium Stearate 0.3 Total (mg) 66.6,

TABLE-US-00015 Ingredient Internal Phase (mg) amorphous (S)-methyl (1-((4(-3(5-chloro-2-fluoro-3- 25.0 (methylsulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (Compound A) Copovidone 74.8 Poloxamer 188 8.4 External Phase (mg) Succinic acid 21.7 Cellulose microcrystalline 26.7 Crospovidone 8.4 Colloidal silicon dioxide 0.9 Magnesium Stearate 0.9 Total (mg) 166.5,

TABLE-US-00016 Ingredient Internal Phase (mg) amorphous(S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3- 50.0 (methylsulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (Compound A) Copovidone 150.0 Poloxamer 188 16.7 External Phase (mg) Succinic acid 43.3 Cellulose microcrystalline 53.3 Crospovidone 16.7 Colloidal silicon dioxide 1.7 Magnesium Stearate 1.7 Total (mg) 333.4,

and TABLE-US-00017 Ingredient Internal Phase (mg) amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3- 100.0 (methylsulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (Compound A) Copovidone 300.0 Poloxamer 188 33.3 External Phase (mg) Succinic acid 86.7 Cellulose microcrystalline 106.7 Crospovidone 33.3 Colloidal silicon dioxide 3.3 Magnesium Stearate 3.3 Total (mg) 666.6.

10. The solid oral pharmaceutical formulation of claim 8, comprising a blend of the internal and external phases in a ratio of from 75:25 to 50:50.

11. The solid oral pharmaceutical formulation of claim 8, formulated as a capsule or a tablet.

12. The solid oral pharmaceutical formulation of claim 8, wherein the formulation is prepared by a process comprising: (i) blending a mixture comprising amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-- pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (COMPOUND A); copovidone; and poloxamer 188 or sorbitol to provide a first blend; (ii) extruding the first blend to provide an extrudate; (iii) milling the extrudate to provide a milled extrudate; (iv) blending the milled extrudate with at least one of succinic acid, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate to provide a second blend; (v) optionally repeating step (iv) as needed to provide a third blend comprising the succinic acid, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate, and the milled extrudate; and (vi) optionally tableting or encapsulating the third blend.

13. The solid oral pharmaceutical formulation of claim 8, wherein the formulation is formulation A) and reaches a maximum plasma concentration (Cmax) of amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-- pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (compound A) compound A at 4 hours (Tmax) after administration.

14. The solid oral pharmaceutical formulation of claim 8, wherein the formulation is formulation A), and the formulation reaches a mean maximum plasma concentration (Cmax) of 11,833 ng/mL and produces a mean area under the plasma concentration versus time curve (AUC) of 32,686 ng*hr/ml when orally dosed to a monkey, wherein a dose of amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-- pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (Compound A) is 200 mg.

15. The solid oral pharmaceutical formulation of claim 8, wherein the formulation provides a mean maximum plasma concentration (Cmax) of amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-- pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (Compound A) that is about five times greater than the mean maximum plasma concentration of amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-- pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (Compound A) administered as microemulsion formulation when orally dosed to a monkey, wherein a dose of amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-- pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (Compound A) as a solid oral pharmaceutical formulation is 200 mg and a dose of amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-- pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (Compound A) as a microemulsion formulation is 50 mg/kg.

16. The solid oral pharmaceutical formulation of claim 15, wherein the formulation provides a plasma concentration versus time curve (AUC) of amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methyl sulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)prop- an-2-yl)carbamate (Compound A) that is greater than the plasma concentration versus time curve (AUC) produced by amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methyl sulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)prop- an-2-yl)carbamate (Compound A) administered as microemulsion formulation when orally dosed to a monkey, wherein a dose of Compound A as a solid oral pharmaceutical formulation is 200 mg and a dose of amorphous (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methyl sulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)prop- an-2-yl)carbamate (Compound A) as a microemulsion formulation is 50 mg/kg.

17. The solid oral pharmaceutical formulation of claim 8, wherein the formulation has a physical stability of at least four weeks upon storage under accelerated stability conditions of 40.degree. C./75% RH.

18. The solid oral pharmaceutical formulation of claim 17, wherein the formulation is formulation A), and wherein: in-vitro 2-stage dissolution studies indicate no change in dissolution kinetics of the solid dispersion between initial (0 week) and 4-week time points under accelerated stability conditions; and/or the formulation is free of crystalline (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropyl-1H-- pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (Compound A) at the 4-week time point upon storage at accelerated stability conditions of 40.degree. C./75% RH for 4 weeks; and/or the formulation is free of degradation products and 100% assay content results for (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methyl sulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)prop- an-2-yl)carbamate (Compound A) upon storage at accelerated stability conditions at 40.degree. C./75% RH.

19. The solid oral pharmaceutical formulation of claim 8, wherein the formulation exhibits a glass transition temperature (Tg) of 97.degree. C. or 109.degree. C.

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