INJECTABLE FORMULATIONS FOR TREATING CANCER
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.
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-((((1r,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 0.1 54 % (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.