Injectable formulations for treating cancer

Patent metadata

Field	Value
Publication number	US-2019350959-A1
Application number	US-201916396017-A
Country	US
Kind code	A1
Filing date	Apr 26, 2019
Priority date	Mar 15, 2013
Publication date	Nov 21, 2019
Grant date	—

Abstract

The present invention provides injectable formulations of (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol and hydrates thereof and methods for treating disorders in which DOT1-mediated protein methylation plays a part, such as cancer and neurological disorders.

First claim

1 . An injectable formulation, comprising 2-(6-amino-9H-purin-9-yl)-5-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol:

or hydrate, or salt thereof, a solubilizer, and a pH adjustment reagent.

2 . The injectable formulation of claim 1 , comprising (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1 r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol:

or hydrate, or salt thereof, a solubilizer, and a pH adjustment reagent.

3 . The injectable formulation of claim 2 , comprising about 0.5-10% (w/v) (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol.

4 . The injectable formulation of claim 1 , comprising about 1-10% (w/v) solubilizer.

5 . The injectable formulation of claim 4 , comprising about 2-6% (w/v), about 3-5% (w/v), or about 4% (w/v) solubilizer.

6 .- 7 . (canceled)

8 . The injectable formulation of claim 4 , wherein the solubilizer is a cyclodextrin.

9 . The injectable formulation of claim 8 , wherein the cyclodextrin is Hydroxypropyl Betadex.

10 . The injectable formulation of claim 1 , comprising about 0.01-0.5 (w/v) pH adjustment reagent.

11 . The injectable formulation of claim 10 , comprising about 0.1-0.2% (w/v), about 0.1-0.16% (w/v), or about 0.154% (w/v) pH adjustment reagent.

12 .- 13 . (canceled)

14 . The injectable formulation of claim 1 , wherein the pH adjustment reagent is citric acid.

15 . The injectable formulation of claim 14 , wherein the citric acid is anhydrous citric acid.

16 . The injectable formulation of claim 1 , further comprising an isotonic reagent.

17 . The injectable formulation of claim 16 , wherein the isotonic reagent is selected from sodium chloride and dextrose.

18 . The injectable formulation of claim 1 , wherein the pH of the formulation is adjusted to about 4.0-8.0, about 4.5-7.0, or about 5.0-6.5.

19 .- 20 . (canceled)

21 . The injectable formulation of claim 18 , wherein the pH of the formulation is adjusted with sodium hydroxide or hydrochloric acid.

22 . The injectable formulation of claim 1 , wherein the formulation is prepared using water.

23 . The injectable formulation of claim 1 , comprising about 0.5-10% (w/v) (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol, about 1-10% (w/v) solubilizer, and about 0.01-0.5% (w/v) pH adjustment reagent.

24 . The injectable formulation of claim 23 , comprising about 1.00% (w/v) (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol, about 4.00% (w/v) solubilizer, and about 0.154% (w/v) pH adjustment reagent.

25 . The injectable formulation of claim 1 , comprising about 0.5-10% (w/v) (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol, about 1-10% (w/v) Hydroxypropyl Betadex, and about 0.01-0.5% (w/v) citric acid.

26 . The injectable formulation of claim 25 , comprising about 1.00% (w/v) (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol, about 4.00% (w/v) Hydroxypropyl Betadex, and about 0.154% (w/v) citric acid.

Assignees

• Epizyme Inc

Inventors

• Olhava Edward James
• Dovletoglou Angelos
• Rehlaender Bruce

Classifications

• A61K9/08

  Solutions {(composition of solutions A61K47/00)} · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61K47/40

  Cyclodextrins; Derivatives thereof · CPC title

• A61K31/7076 Primary

  containing purines, e.g. adenosine, adenylic acid · CPC title