Method of treating melanoma by administration of 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

Patent metadata

Field	Value
Publication number	US-9763941-B2
Application number	US-201615179190-A
Country	US
Kind code	B2
Filing date	Jun 10, 2016
Priority date	Nov 23, 2011
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

This invention relates to solid oral pharmaceutical formulations of (S)-methyl (1-((4-(3-(5-chloro-2-fluoro-3-(methyl -sulfonamido)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.

First claim

We claim:

1. A method for treating melanoma, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a solid oral pharmaceutical formulation, wherein the formulation 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-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)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.

2. The method of claim 1 , wherein the melanoma is characterized by a mutation in B-RAF.

3. The method 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-(methylsulfonamido)phenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-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.

4. The method of claim 1 , 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.

5. The method of claim 1 , comprising a blend of the internal and external phases in a ratio of from 80:20 to 40:60.

6. The method of claim 5 , comprising a blend of the internal and external phases in a ratio of from 75:25 to 50:50.

7. The method of claim 1 , wherein the formulation comprises 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).

8. The method of claim 7 , wherein the formulation comprises 50 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).

9. The method of claim 7 , wherein the formulation comprises 15% by weight 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).

10. The method of claim 1 , wherein the formulation is selected from the group consisting of:
A)

Ingredient
% w/w

Internal Phase

amorphous (S)-methyl (1-((4-(3-(5-chloro-2-
15

fluoro-3-(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)

Ingredient
% w/w

Internal

amorphous (S)-methyl (1-((4-(3-(5-chloro-2-
17

fluoro-3-(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.

11. The method of claim 10 , wherein the melanoma is characterized by a mutation in B-RAF.

12. The method of claim 1 , wherein the formulation is

Assignees

• Array Biopharma Inc

Inventors

• Verma Daya
• Krishnamachari Yogita
• Shen Xiaohong
• Lee Hanchen
• Li Ping
• Singh Rajinder
• Tan Laychoo

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• A61K9/2027

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates · CPC title