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-9387208-B2
Application number	US-201214359121-A
Country	US
Kind code	B2
Filing date	Nov 21, 2012
Priority date	Nov 23, 2011
Publication date	Jul 12, 2016
Grant date	Jul 12, 2016

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.

First claim

We claim:

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)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 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)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.

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)propan-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)

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)

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:

Ingredient

Internal Phase (mg)

amorphous (S)-methyl (1-((4-(3-(5-
10.0

chloro-2-fluoro-3-

(methyl

Assignees

• Verma Daya
• Krishnamachan Yogita
• Shen Xiaohong
• Lee Hanchen
• Li Ping
• Singh Rajinder
• Tan Laychoo
• Novartis Ag

Inventors

• Verma Daya
• Krishnamachan 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

• A61K9/2031

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers · CPC title