NZ623628B2 - Solid oral pharmaceutical formulations comprising amorphous (S)-methyl (1- ((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropy1-1H-pyrazo1-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (Compound A) - Google Patents

Abstract

Disclosed is 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 these formulations for treating proliferative diseases, such as solid tumor diseases. A preferred embodiment is where the formulation includes an inner phase which is a solid dispersion comprising amorphous (S)-methyl(1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)pheny1)-1-isopropyl-1H-pyrazol-4-yepyrimidin-2-yeamino)propan-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. iseases. A preferred embodiment is where the formulation includes an inner phase which is a solid dispersion comprising amorphous (S)-methyl(1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)pheny1)-1-isopropyl-1H-pyrazol-4-yepyrimidin-2-yeamino)propan-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.

Description

Solid oral pharmaceutical formulations comprising amorphous (S)-methyl (1- ((4-(3- (5-chlor0fluoro(methylsulfonamido)phenyl)-l-isopropy1-1H-pyrazol yl)pyrimidinyl)amino)propanyl)carbamate (Compound A) BACKGROUND This invention s to solid oral pharmaceutical formulations of thyl (l- ((4—(3 -(5-chlorofluoro—3 ~(methylsulfonamido)phenyl)— l —isopropyl- l H-pyrazol—4— imidin—2—yl)amino)propan-2—yl)carbamate (COMPOUND A) and the use of these formulations for treating proliferative diseases, such as solid tumor diseases.

The COMPOUND A has the chemical structure: YD c.

Its preparation and its use as an tor of B-RAF for the treatment of proliferative diseases, such as solid tumor diseases, like melanoma and colorectal cancer, are described in , which is here incorporated by reference in its entirety.

COMPOUND A is a BCS class 11 compound exhibiting poor aqueous solubility at weakly acidic and neutral pH which poses a challenge for oral bioavailability and therapeutic effect. The compound exhibits typical weak base solubility characteristics and is highly soluble at low pH, starts to decline at around pH 3.0 and remains low at sic lity level over the range of neutral pH. Upon emptying from the h, COMPOUND A has the tendency to quickly precipitate out of solution due to an abrupt solubility drop in intestinal pH. This significantly reduces COMPOUND A that is available for intestinal absmption. The present invention s to orally bioavailable pharmaceutical solid dispersion formulations of COMPOUND A.

SUMMARY OF THE INVENTION In a first aspect, the present invention provides a solid oral pharmaceutical formulation of claim 1, which comprises: an inner phase which is a solid dispersion comprising amorphous (S)-methyl (1 — ((4-(3 —(5—chloro—2—fluoro~3 — (methylsulfonamido)phenyl)»1-isopropyl-lH—pyrazo 1 yl)pyrimidin—2— yl)amino)propanyl)carbamate (COMPOUND A), a hydrophilic binder, a surfactant and an external phase which comprises an acidifier, a filler, and a ant.

In another aspect, the present invention provides a solid oral pharmaceutical ation, which comprises: an inner phase which is a solid dispersion comprising ous (S)- methyl (1- ((4—(3 —(5—chlorofluoro-3 —(methylsulfonamido)phenyl)- l opy1 - 1 H- pyrazol—4— yl)pyrimidin—2-yl)amino)propan-2—yl)carbamate (COMPOUND A); copovidone; and poloxamer 188 or ol; and an external phase which comprises ic acid, rystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate.

Also provided is the use of the formulations of the invention in the manufacture of a medicament for the treatment of a disease which responds to tion ofB-RAF or for the treatment of a proliferative disease.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 represents the 2 stage dissolution profile of the formulation descfibed in Example 1. (followed by page 2a) Figure 2 ents the 2—Stage (pH 2 first 60 min to 6.8 after 60 min) dissolution of the formulations described in Examples 2-7.

Figure 3 represents the dissolution profile of the tablet formulation described in Example 8.

DETAILED DESCRIPTION OF THE INVENTION COMPOUND A is a BCS class II compound which exhibits typical weak base solubility characteristics: higher solubility at low pH, and limited solubility around neutral pH. Therapeutic compounds with such solubility characteristics typically present ceutical formulation scientists with a challenge while attempting to prepare oral formulations capable of improving oral bioavailability of the therapeutic compound. Such nges in preparing solid oral dosage forms of COMPOUND A are overcome, according to the present invention, by formulating the compound as a solid dispersion.

Solid dispersions are specialized pharmaceutical formulations. The most suitable solid dispersion formulation is the one that enhances lity and dissolution rate and maintains the stability of the drug substance in an amorphous state. In a typical solid dispersion formulation the drug substance is uniformly dispersed in a solid matrix which es dissolution of the drug in the gastrointestinal tract and maintains the drug in a high energy ous state.

[FOLLOWED BY PAGE 3] WO 2013078264 PCT/U52012/066185 Pharmaceutical solid sions are produced by techniques known in the art, for example, solvent evaporation, kneading and melt extrustion.

According to the present ion, an inner phase is prepared. The inner phase is a solid dispersion comprising COMPOUND A in a suitable polymer , which is composed, for example, of a hydrophilic binder, a surfactant and optional additional excipients, which are known in the art, followed by milling to reduce particle size.

Prior to tableting or encapsulation, the inner phase is preferably combined with additional excipients, which are collectively referred to herein as the external phase.

One or more of an acidifier, a , a disintegrant, a flow enhancer and a lubricant are typically included in the external phase.

Thus, the present ion relates to a solid oral pharmaceutical formulation which comprises a solid dispersion comprising COMPOUND A.

In one embodiment, the present ion is a solid oral pharmaceutical formulation which comprises: (a) an inner phase which is a solid dispersion comprising COMPOUND A, and (b) an external phase which comprises additional ents.

Preferably, the internal phase, or, more preferably, the external phase comprises an acidifier.

The present invention further relates to a solid oral pharmaceutical formulation which comprises: (a) an inner phase which is a solid dispersion sing COMPOUND A, a hydrophilic binder and a surfactant; and (b) an external phase which ses additional excipients.

PCT/U52012/066185 In another embodiment, the present invention is a solid oral pharmaceutical formulation which comprises: (a) an inner phase which is a solid dispersion comprising ND A, a hydrophilic binder, a tant and (b) an external phase which comprises one or more of an acidifier, a filler, a disintegrant, a flow enhancer and a lubricant.

The hydrophilic binder should be suitable for complete miscibility with COMPOUND A and upon formulation dissolution, serve as a itation inhibitor of COMPOUND A. Suitable hydmphilic binders for inclusion in the inner phase include copovidone, hydroxypropylmethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, and methacrylate copolymer, polyethylene oxide, HPMC acetate succinate, HPMC phthalate. done is especially useful as the hydrophilic binder. ON VA64, which is a copolymer of l—vinyl-Z- pyrrolidone and vinyl acetate in a ratio of 6:4 by mass and is available from BASF, is highly suitable for use as a hydrophilic binder in the inner phase.

The surfactant should be suitable for use in melt extrusion to enhance ution and solubilization of COMPOUND A. In some cases, the surfactant may help reduce the process temperature through its plasticizing effect. Suitable surfactants for inclusion in the inner phase include poloxamers, such as Poloxamer 188, sodium lauryl sulphate, Tween 80, sorbitol, polysorbate 20, polysorbate 80, Vitamin E TPGS, and polyethylene .

Additional excipients that may optionally be included in the inner phase e acidifiers, and plasticizers.

In the preferred embodiments, the internal phase, or preferably the al phase comprises an acidifier to control the nvironmental pH in the acidic range.

Suitable acidifiers include organic acids such as citric acid, succinic acid, maleic acid, tartaric acid, malic acid and adipic acid PCT/U52012/066185 le fillers, disintegrants, flow enhancers and ants are known to those of Skill in the art.

Especially useful fillers include lactose, maltodextrin, mannitol, microcrystalline cellulose, pregelatinized starch, and sucrose esters.

Useful disintegrants include crospovidone, croscarmeilose sodium, sodium starch glycolate, microcrystalline ose, and pregelatinized .

Useful flow enhancers include colloidal n dioxide, talc, magnesium stearate, and mannitol.

Useful lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, hydrogenated castor oil, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, zinc stearate, talc, microcrystalline ose, and sucrose esters.

In different embodiments ofthe present invention, the inner phase comprises various ranges of %w/w of active agent, hilic binder and surfactant. For instance, the present inner phase can comprise 5-70% Compound A, 10-90% of hydrophilic , and 5-30% surfactant, preferably 5—50% Compound A, 30-80% of hydrophilic , and 5—30% surfactant, more preferably 5—40% Compound A, 50— 80% ofhydrophilic binder, and 5~20% surfactant.

In different embodiments of the present invention, the external phase comprises various ranges of %w/w of acidifier, filler, disintegrant, flow enhancer and ant. For instance, the present external phase can comprise l-70% acidifier, -70% filler, 0-30% disintegrant, 0-10% flow enhancer and 0-10% lubricant, preferably 2-60% acidifier, 30—70% filler, 5—20% disintegrant, 0.5—5% flow 2012/066185 enhancer and 0.5-5% lubricant, more preferably 10-40% acidifier, 20-40% tiller, 1- % disintegrant, 1-S% flow enhancer and 1-5% lubricant.

In different embodiments of the present ion, the solid oral dosage form, for e, capsules or tablets, are a blend of the al and external phases in a ratio of from 100:0 to 30:70, preferably 80:20 to 40:60, most preferably 75:25 to 50:50.

Stabilization of an ous form of COMPOUND A in a solid dispersion ation enhances bioavailabiiity, attributable to a higher dissolution rate and kinetic solubility ofthe ous form in comparison to its crystalline form.

When COMPOUND A stays in ous form, an increase in kinetic solubility and dissolution rate as well as in oral bioavailability is achieved using the solid dispersion formulation.

In one embodiment, the present invention is formulated as a capsule, such as hard gelatin capsule or a soft elastic capsule. Alternatively, the present invention is in the form of a tablet or a pill. In these solid oral formulations the amount of COMPOUND A can be present in the ranges of 1-1500 mg, 25-800 mg, or 5—400 mg, with preferred examples including 10 mg, 20 mg, 25 mg, 50 mg 100 mg, 200 mg, 400 mg and 500 mg.

The solid oral formulations of the present invention can be administered to treat diseases which respond to inhibition of B~RAF, particularly es that are characterzed by a mutation in B-RAF, particularly melanoma and colorectal cancer.

Thus, the present invention further relates to the use of a solid oral pharmaceutical formulation described above for the preparation of a medicament for the treatment of a proliferative disease, especially wherein the proliferative disease is a solid tumor disease characterized by a mutation in B—RAF, such as melanoma or ctal cancer.

PCT/U820121066185 The present invention further relates to a method of treating a proliferative disease which comprises administering to a patient in need of ent a therapeutically effective amount of a formulation bed herein, especially wherein the proliferative disease is a solid tumor e characterized by a mutation in B—RAF, such as melanoma or colorectal cancer.

The following Examples are intended to illustrate, but not to limit, the invention.

Example 1 The following composition is prepared at constant drug g of 15% and formulated into 10, 25, 50 mg and 100 mg capsules.

In redient %wlw Internal Comeound A 15 Kollidon VA64 45 Pluronic F 68 5 PCT/U52012/066185 100 mg ca sule Internal Phase (mg) Compound A 10.0 25.0 50.0 100.0 Kollidon VA64 29.9 74.8 150.0 300.0 Poloxamer 188 3.3 8.4 16.7 (Pluronic F68) External Phase (mg) Cellulose 106.7 0.3 0,9 Total (mg) 66.6 166.5 333.4 Manufacturing process: The processing is performed by hot—melt extrusion using a 18 mm twin—screw Leistriez extruder, followed by milling the extrudates, blending with the external phase and screening. Following blending, the blend is ulated into pink hard gelatin capsules of size 0 and 00 for drug doses of 50 and 100 mg respectively. A step—by step approach is shown below: Weigh the required amount of nd A, Kollidon VA64 and Poloxamer 188 Blend the mixture Extrude the blend on a 18 mm Leistreiz twin—screw er at a feed rate of 1kg/hour maintaining temperatures of 50 to 160 °C in the extruder.

Mill the extrudate Add ed succinic acid and cellulose rystalline Add and blend the milled extrudates, succinic acid and cellulose microcrystalline PCT/U82012/066185 Add vidone and aerosil Blend the mixture Add prescreen magnesium stearate Blend the mixture Encapsulation using H&K encapsulator ln—vivo monkey PK data with the resulting capsules show bioavailability le for oral administration with a mean Cmax of 11833 rig/ml, Tmax at 4 hours and an AUC of32686 ng*hr/ml.

XRPD data indicate physical stability of the amorphous solid dispersion formulation (no indication of conversion to the crystalline drug, substance) upon storage at rated ity conditions of40 °C/ 75 % RH for 4 weeks.

In-vitro 2—stage dissolution studies indicate no change in dissolution kinetics of the solid dispersion between initial (0 week) and 4-week time point at accelerated stability storage conditions indicating no change in physical ity of the solid dispersion.

The present formulation exhibits a glass transition temperature (Tg) of 97 °C which is above the recommended drug product storage temperature of no greater than °C, demonstrating physical stability without conversion of the amorphous drug substance into the poorly water soluble crystalline drug substance.

The t formulation shows excellent chemical ity upon storage at accelerated stability conditions at 40 ° C/75 % RH with no evidence of any degradation products and 100% assay content results for COMPOUND A.

Example 2 The ing formulation is prepared in a manner similar to that bed in Example 1.

Ingredient %wlw Internal LGX818 17 PVP-K30 51 Sorbitol 5 _| External Succinic Acid 9 Cellulose MKGR 12 ovidone 5 Mg Stearate 0.5 Aerosil 0.5 Total 100 This formulation exhibits a glass transition temperature (Tg) of 109°C demonstrating physical stability Without conversion of the amorphous drug nce into the poorly water soluble lline drug substance.

Example 3 The following table described the results of a pharmacokinetic study in monkeys of Compound A formulated as a microemulsion dosed at 50 mg/kg and the formulations of Example 1 (Solid Dispersion 1) and Example 2 (Solid Dispersion 2) at a dose of 200 mg of Compound A.

Treatment__lD Subject. Tmax Cmax AUClast Tlast h / L *h/ Microemulsion (early) monkey 2 4 3410 25400 30 1 monkey 3 4 727 8820 30 Mean 3.3 2216 18407 SD 12 1366 8589 Solid Dispersion_1 (Kollidon) mon ey monkey 3 10600 24626 30 Showed emesis monkey 4 271 1037 8 monkev 5 13400 27924 24 Mean 11833 32686 S 1894 7986 Solid sion_2 (PVP-KBO) m n ey monkey 3 2 2220 5804 30 monkey 4 1 14500 33177 30 monkey 5 1 12900 21390 30 Mean 12144 26691 SD 5933 14076 PCT/U82012/066 185 Examples 2—7 The following ations are prepared by tehniques r to those described in Example 1, but with a single phase. The dissolution profiles ofthe formulations are reported in Figure 2.

Formulation 2: Hydroxypropylmethyl cellulose Talc Formulation 3: Ingredients Compound A \fitamin E TPGS 41.67 _-4000 16.33 Hydroxypropylmethyl- Talc 2.00 Formulation 4: Ingredients Compound A 25.00 Vitamin E TPGS 41.67 Polyethylene glycol - 4000 5.92 Hydroxypropylmethyl cellulose 15.00 Eudrait L100—55 Formulation 5: ients Compound A 25.00 Vitamin E TPGS 41.67 —-4000 5.92 Hydroxypropylmethyl cellulose 5.00 Eudragit L100-55 15.00 Talc 2.00 PCT/USZOIZ/066185 Formulation 6: Compound A Vitamin E TPGS 40.00 Hydroxypropylmethyl cellulose 14.40 Eudragit L100-55 14.40 Talc 2.00 Formulation 7: nd A 24.00 Vitamin E TPGS 40.00 Polyethylene glycol 4000 1.20 Hydroxypropylmethyl cellulose 14.40 Lactic acid 4.00 Eudralt moo—55 14.40 2-00 Example 8 The following formulation is prepared by tehniques similar to those described in Example 1, but in a tablet dosage form. The dissolution profile ofthe formulation in 0.1N HCl medium is reported in Figure 3. ation 8: Ingredient %wlw Internal Compound A 10.0 Kollldon VA64 Pluronic F 68 Kollidon VA64 Cellulose MKGR Crossovidone 15.0 M . Stearate 1.0 Total 100

Claims (39)

CLAIMS What is claimed is:
1. l. A solid oral pharmaceutical formulation of claim 1, which comprises: an inner phase which is a solid dispersion comprising amorphous (S)—methyl (1- ((4— (3 ~(5-chloro—2»fluoro-3 -(methylsulfonamido)phenyl)- l opyl—1H—pyrazol yl)pyrimidin—2-yl)amino)propan—2—yl)carbamate (COMPOUND A), a hilic binder, a surfactant and an external phase which comprises an acidifier, a filler, and a lubricant.
2. 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(methylsulfonamido)phenyl)- 1-isopropy1 -1H—pyrazo 1 —4— yl)pyrimidin yl)amino)propanyl)carbamate und A), from 50% to 80% by weight of the hydrophilic , and from 5% to 20% by weight of the surfactant.
3. 3. The solid oral pharmaceutical formulation of claim 1 or 2, wherein the hydrophilic binder is selected from the group consisting of copovidone, hydroxypropylmethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, and methacrylate copolymer, polyethylene oxide, hydroxypropylmethylcellulose HPMC acetate succinate, and hydroxypropylmethylcellulose HPMC phthalate.
4. 4. The solid oral pharmaceutical formulation of claim 3, wherein the hydrophilic binder is copovidone.
5. 5. The solid oral pharmaceutical formulation of any one of claims 1 to 4, wherein the tant is ed from the group consisting of mers, sodium lauryl sulphate, sorbitol, polysorbate 20, polysorbate 80, Vitamin E TPGS, and polyethylene glycol.
6. 6. The solid oral pharmaceutical formulation of claim 5, wherein the tant is a poloxamer.
7. 7. The solid oral pharmaceutical formulation of claim 6, wherein the poloxamer is mer 188.
8. 8. The solid oral pharmaceutical formulation of any one of claims 1 to 7, wherein the external phase comprises from 10% to 40% by weight of the acidifier, from 20% to 40% by weight of the filler, and from 1% to 5% by weight of the lubricant, wherein the external phase optionally filrther comprises from 1% to 15% by weight of a disintegrant and from 1% to 5% by weight of a flow enhancer.
9. 9. The solid oral pharmaceutical formulation of any one of claims 1 to 8, wherein the acidifier is selected from the group ting of citric acid, succinic acid, maleic acid, tartaric acid, malic acid, and adipic acid.
10. 10. The solid oral pharmaceutical formulation of claim 9, wherein the acidifier is succinic acid.
11. 11. The solid oral pharmaceutical formulation of any one of claims 1 to 10, wherein the filler is selected from the group consisting of lactose, extrin, mannitol, microelystalline cellulose, pregelatinized starch, and sucrose esters.
12. 12. The solid oral pharmaceutical formulation of claim 11, wherein the filler is microcrystalline cellulose.
13. 13. The solid oral pharmaceutical formulation of claim 8, wherein the disintegrant is selected from the group consisting of crospovidone, croscalmellose sodium, sodium starch glycolate, rystalline cellulose, and atinized starch.
14. 14. The solid oral pharmaceutical formulation of claim 13, wherein the disintegrant is crospovidone.
15. 15. The solid oral ceutical formulation of claim 8, n the flow er is selected from the group consisting of colloidal silicon dioxide, talc, magnesium stearate, and mannitol.
16. 16. The solid oral pharmaceutical formulation of claim 15, wherein the flow enhancer is colloidal silicon dioxide.
17. 17. The solid oral pharmaceutical formulation of any one of claims 1 to 16, n the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, glyceryl monostearate, enated castor oil, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, zinc stearate, talc, microcrystalline cellulose, and sucrose esters.
18. 18. The solid oral pharmaceutical formulation of claim 17, wherein the lubricant is magnesium stearate,
19. 19. The solid oral pharmaceutical ation of any one of claims 1 to 18, comprising a blend of the internal and external phases in a ratio of from 80:20 to 40:60.
20. 20. The solid oral ceutical formulation of any one of claims 1 to 19, comprising 10 mg, 25 mg, 50 mg or 100 mg of amorphous (S)-methyl (1— ((4—(3-(5- chloro-Z-fluoro(methylsulfonamido)phenyl)- 1 ~isopropy1 — 1 H-pyrazo 1 yl)pyrimidin- 2-yl)amino)propanyl)carbamate (Compound A).
21. 21. The solid oral pharmaceutical formulation of claim 20, wherein the formulation comprises 15% by weight of amorphous (S)—methyl (1- ((4-(3-(5-chlorofluoro (methylsulfonamido)phenyl)-I —isopropy1-1H-pyrazol yl)pyrimidin yl)amino)propanyl)carbamate (Compound A).
22. 22. A solid oral ceutical formulation, which comprises: an inner phase which is a solid dispersion comprising amorphous (S)-methyl (l- ((4-(3 -(5-chloro—2—fluoro-3 —(methylsulfonamido)phenyl)isopropy1-lH—pyrazol—4- y1)pyrimidinyl)amino)propan-2—yl)carbamate (COMPOUND A); copovidone; and poloxamer 188 or sorbitol; and an external phase which comprises ic acid, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and ium stearate.
23. 23. The solid oral pharmaceutical formulation of claim 22, wherein the inner phase comprises from 5% to 40% by weight of amorphous (S)-methyl (l— ((4—(3-(5-chloro 3—(methylsulfonamido)phenyl)— l -isopropyl — lH—pyrazo 1 —4— yl)py1imidin—2- yl)amino)propan—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.
24. 24. The solid oral pharmaceutical formulation of claim 23, 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 ium stearate.
25. 25. The solid oral pharmaceutical formulation of any one of claims 22 to 24, comprising a blend of the internal and external phases in a ratio of from 80:20 to 40:60.
26. 26. The solid oral ceutical formulation of claim 25, comprising a blend of the internal and external phases in a ratio of from 75:25 to 50:50.
27. 27. The solid oral pharmaceutical formulation of any one of claims 22 to 26, comprising 10 mg, 25 mg, 50 mg or 100 mg of amorphous (S)-methyl (1— -(5- chlorofluoro(methylsulfonamido)phenyl)— l -isopropy1 - 1 H-pyrazo 1 yl)pyrimidin- 2-yl)amino)propanyl)carbamate (Compound A).
28. 28. The solid oral pharmaceutical formulation of claim 27, wherein the ation comprises 15% by weight of amorphous (S)—methyl (1- ((4-(3-(5-chlorofluoro (methylsulfonamido)phenyl)—1-isopropy1-lH-pyrazol y1)pyrimidin yl)amino)propanyl)carbamate (Compound A).
29. 29. The solid oral pharmaceutical ation of claim 22, wherein the formulation is selected from the group consisting of: Ingredient %w/w Internal Phase amorphous (S)-methyl (1 - ((4—(3—(5-chloro— 2-fluoro—3-(methylsulfonamido)phenyl)— 1 — isopropyl —lH—pyrazol~4- yl)pyrimidin-2— 15 yl)amino)propanyl)carbamate (Compound A) copovidone 45 Wm188 5 External Phase Succinic acid 13 Microcrystalline cellulose 16 l Crosspovidone 5 ium Stearate 0.5 Colloidal silicon dioxide 0.5 Total 100 Ingredient ‘ %w/w l Internal I I amorphous thyl (1— ((4-(3-(5— chlorofluoro (methylsulfonamido)phenyl) isopropyl - 1 H-pyrazo 1 yl)pyrimidinyl)amino)propan yl)carbamate und A) PVP-K30 51 Sorbitol 5 External Succinic Acid L 9 rystalline cellulose 12 Crosspovidone 5 Mg Stearate 0.5 Colloidal silicon dioxide 0.5 J Total 100
30. 30. The solid oral formulation of claim 22, wherein the formulation is selected from the group consisting of: Ingredient Internal Phase (mg) ous (S)—methyl (1 - ((4-(3- 10.0 (5—chlorofluoro-3 — (methylsulfonamido)phenyl)- l — pyl — 1 H-pyrazo 1—4— yl)pyfimidin—Z—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 m1silicon dioxide 0.3 Magnesium Stearate 0.3 Total (mg) 66.6 Ingredient Internal Phase (mg) amorphous (S)-methyl (1— ((4—(3 - 25 .0 (5-chloro-2—fluoro—3 - (methylsulfonamido)phenyl)— 1 ~ isopropyl — 1 H—pyrazo 1 imidin-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 vidone 8 .4 Colloidal silicon dioxide 0.9 Magnesium Stearate 0.9 Total (mg) 166.5 Ingredient Internal Phase (mg) amorphous (S)-methyl (1~ - 50.0 (5-chlorofluoro-3 - (methylsulfonamido)phenyl) isopropyl - 1 H-pyrazo 1 ~4— yl)pyrimidin—Z—yl)amino)propan- 2—yl)carbamate (Compound A) Copovidone 150.0 Poloxamer 188 16.7 External Phase (mg) ic acid 43 .3 Cellulose microcrystalline 53.3 ___1_______ Crospovidone 16.7 Colloidal silicon dioxide Magnesium Stearate Total (mg) . , Ingredient Internal Phase (mg) ous (S)-methyl (l- ((4—(3- 100.0 oro-2—fluoro—3 - (methylsulfonamido)phenyl)— 1 — isopropyl — 1 H—pyrazo 1—4- yl)py1imidin—2-yl)amin0)propan- 2—yl)carbamate (Compound A) Copovidone 300.0 Poloxamer 188 33.3 W106.7 mm33.3 Colloidal silicon dioxide 3.3 fgnesium te 3.3 Total (mg) 666.6 .
31. 31. The solid oral pharmaceutical formulation of claim 22, comprising a blend of the internal and external phases in a ratio of from 75:25 to 50:50.
32. 32. The solid oral pharmaceutical formulation of claim 29, formulated as a capsule or a tablet.
33. 33. The solid oral pharmaceutical fonnulation of claim 29, wherein the formulation is ed by a process comprising: (i) blending a mixture comprising amorphous (S)- methyl (1— ((4—(3 —(5-chloro-2—fluoro—3~(methylsulfonamido)phenyl)isopropyl—1H— pyrazol yl)pyrimidinyl)amino)propan—2-yl)carbamate (COMPOUND A); copovidone; and poloxamer 188 or sorbitol to provide a first blend; (ii) extruding the first blend to e an extrudate; (iii) milling the extrudate to provide a milled extrudate; (iv) blending the milled ate 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 ate; and (vi) optionally tableting or encapsulating the third blend.
34. 34. The solid oral pharmaceutical formulation of claim 29, wherein the ation is formulation A) and s a m plasma concentration (Cmax) of amorphous (S)— methyl (1- ((4—(3 —(5~chloro—2—fluoro-3 —(methylsulfonamido)phenyl)-1 —isopropyl -1H- pyrazol imidin-2—yl)amino)propan—2-yl)carbamate (compound A) compound A at 4 hours (Tmax) after administration.
35. 35. The solid oral pharmaceutical formulation of claim 29, wherein the formulation is formulation A), and the formulation reaches a mean maximum plasma concentration (Cmax) of 1 1,833 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—chlorofluoro (methylsulfonamido)phenyl)— l —isopropyl — l zo 1 —4— yl)pyrimidin~2- yl)amino)pr0pan—2-yl)carbamate (Compound A) is 200 mg.
36. 36. The solid oral pharmaceutical formulation of claim 29, wherein the formulation provides a mean m plasma concentration (Cmax) of amorphous (S)-methyl (1- ((4-(3 -(5-chlorofluoro—3—(methylsulfonamido)phenyl)isopropy1-lH-pyrazol~4- yl)pyrimidin-Z-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-chlorofluoro-3—(methylsulfonamido)phenyl)isopropy1-1H-pyrazol y1)pyrimidin—2-yl)amino)propan—Z-yl)carbamate (Compound A) administered as mulsion ation when orally closed to a monkey, wherein a dose of amorphous (S)—methy1 (l - ((4—(3-(5-chloro—2-fluoro(methylsulfonamido)phenyl)— 1 - isopropyl- 1 H—pyrazo 1-4— yl)pyrimidinyl)amino)propanyl)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 - lH— pyrazol-4— yl)pyrimidin—2-yl)amino)propanyl)carbamate (Compound A) as a microemulsion formulation is 50 mg/kg.
37. 37. The solid oral pharmaceutical formulation of claim 29, wherein the formulation provides a plasma concentration versus time curve (AUC) of amorphous (S)-methyl (1— ((4-(3 -(5-chlorofluoro~3 ylsulfonamido)phenyl)isopropyl-lH—pyrazol-4— y1)pyiimidinyl)amino)propan-2—yl)carbamate (Compound A) that is greater than the plasma tration versus time curve (AUC) produced by amorphous thyl (1- ((4-(3 -(5-chloro—2-flu0ro—3—(methylsulfonamido)phenyl)isopropyl—lH-pyrazol —4- yl)pyrimidinyl)amino)propan-Z-yl)carbamate (Compound A) administered as mieroemulsion 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 thyl (l— -(5-chlorofluoro~3—(methylsulfonamido)phenyl)- l- isopropyl - 1 H-pyrazo 1 yl)pyrimidinyl)amino)propan-2—yl)carbamate (Compound A) as a microemulsion formulation is 50 mg/kg.
38. 38. The solid oral ceutical formulation of claim 29, wherein the formulation has a physical stability of at least four weeks upon storage under accelerated stability conditions of 40 °C/ 75 % RH.
39. 39. The solid oral pharmaceutical formulation of claim 38, 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—chlorofluoro—3- (methylsulfonamido)phenyl)isopropy1-1H-pyrazo 1 yl)pyrimidin y1)amino)propanyl)carbamate (Compound A) at the 4-week time point upon e at accelerated stability ions of 40 °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 -(methy1sulfonamido)pheny1)—1—isopropyl-1H— pyrazol—4- imidinyl)amino)propan—2-yl)carbamate (Compound A) upon storage at accelerated stability conditions at 40 ° (