FORMULATIONS OF AN LSD1 INHIBITOR

• US 20170304282A1
• Filed: 04/21/2017
• Published: 10/26/2017
• Est. Priority Date: 04/22/2016
• Status: Active Grant

• Current Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Original Assignee: Incyte Corporation
• Inventors: Rocco, William L., Liu, Ying, Li, Mei, Shah, Tanvi, Wu, Huifang
• Granted Patent: US 10,166,221 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61K 9/4833 Encapsulating processes; Filling of capsules mechanical aspects A61J3/07
• CPC Class Codes: A61K 9/485 Inorganic compounds
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present application relates to pharmaceutical formulations and dosage forms of a lysine specific demethylase-1 (LSD1) inhibitor, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, including methods of preparation thereof, which are useful in the treatment of LSD1 mediated diseases such as cancer.

Claims

1. A pharmaceutical formulation in solid oral dosage form comprising:

(a) an inhibitor of LSD1 which is Compound 1 di-tosylate salt of the formula;

2. The pharmaceutical formulation of claim 1, further comprising a diluent.

3. The pharmaceutical formulation of claim 1, wherein the organic acid is fumaric acid or citric acid.

4. The pharmaceutical formulation of claim 3, wherein the organic acid is fumaric acid.

5. The pharmaceutical formulation of claim 4, comprising about 1 wt % to about 50 wt % of fumaric acid.

6. The pharmaceutical formulation of claim 4, comprising about 1 wt % to about 15 wt % of fumaric acid.

7. The pharmaceutical formulation of claim 4, comprising about 5 wt % to about 15 wt % of fumaric acid.

8. The pharmaceutical formulation of claim 4, comprising about 9 wt % to about 11 wt % of fumaric acid.

9. The pharmaceutical formulation of claim 4, comprising about 10 wt % of fumaric acid.

10. The pharmaceutical formulation of claim 1, comprising about 1 wt % to about 5 wt % of the LSD1 inhibitor.

11. The pharmaceutical formulation of claim 1, comprising about 2 wt % to about 4 wt % of the LSD1 inhibitor.

12. The pharmaceutical formulation of claim 1, comprising about 3 wt % of the LSD1 inhibitor.

13. The pharmaceutical formulation of claim 2, wherein the diluent is lactose or mannitol.

14. The pharmaceutical formulation of claim 13, wherein the lactose is lactose monohydrate or lactose-316 Fast Flo®

.

15. The pharmaceutical formulation of claim 14, comprising about 80 wt % to about 97 wt % of lactose monohydrate.

16. The pharmaceutical formulation of claim 14, comprising about 85 wt % to about 97 wt % of lactose monohydrate.

17. The pharmaceutical formulation of claim 1 further comprising a lubricant, glidant, or both.

18. The pharmaceutical formulation of claim 17, wherein the lubricant is sodium stearyl fumarate or stearic acid.

19. The pharmaceutical formulation of claim 18, wherein the lubricant is sodium stearyl fumarate.

20. The pharmaceutical formulation of claim 19, comprising about 1 wt % to about 5 wt % of sodium stearyl fumarate.

21. The pharmaceutical formulation of claim 20, comprising about 2 wt % of sodium stearyl fumarate.

22. The pharmaceutical formulation of claim 18, wherein the lubricant is stearic acid.

23. The pharmaceutical formulation of claim 22, comprising about 1 wt % to about 5 wt % of stearic acid.

24. The pharmaceutical formulation of claim 22, comprising about 2 wt % of stearic acid.

25. The pharmaceutical formulation of claim 17, wherein the glidant is colloidal silica.

32. The pharmaceutical formulation of claim 1, further comprising a disintegrant.

33. The pharmaceutical formulation of claim 32, wherein the disintegrant is croscarmellose sodium, sodium starch glycolate or crospovidone.

34. The pharmaceutical formulation of claim 1, wherein the Compound 1 di-tosylate salt, or hydrate or solvate thereof, is in crystalline form.

35. The pharmaceutical formulation of claim 34, wherein the crystalline form comprises Form I.

36. The pharmaceutical formulation of claim 34, wherein the crystalline form comprises Form HI.

37. The pharmaceutical formulation of claim 1, wherein the dosage form is a tablet or capsule.

38. A method of treating a disease associated with LSD1 activity comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical formulation of claim 1.

39. A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical formulation of claim 1.

40. The method of claim 39, wherein the cancer is selected from hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

41. The method of claim 40, wherein the hematological cancer is selected from acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), or multiple myeloma.

48. The pharmaceutical formulation of claim 2, prepared by the method of claim 42.

26. A pharmaceutical formulation comprising:

(a) 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid di-tosylate salt (Compound 1 di-tosylate salt), or a solvate or hydrate thereof;

(b) fumaric acid; and

(c) lactose or mannitol, or a solvate or hydrate thereof.

28. The pharmaceutical formulation of claim 26 further comprising sodium stearyl fumarate.

29. The pharmaceutical formulation of claim 26 further comprising stearic acid.

27. A pharmaceutical formulation comprising:

(a) about 1 wt % to about 5 wt % of 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid di-tosylate salt (Compound 1 di-tosylate salt), or a solvate or hydrate thereof;

(b) about 1 wt % to about 15 wt % of fumaric acid; and

(c) about 80 wt % to about 97 wt % of lactose, or a solvate or hydrate thereof.

30. A pharmaceutical formulation comprising:

(a) about 1 wt % to about 5 wt % of 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid di-tosylate salt (Compound 1 di-tosylate salt), or a solvate or hydrate thereof;

(b) about 1 wt % to about 15 wt % of fumaric acid;

(c) about 80 wt % to about 97 wt % of monohydrate lactose; and

(d) about 1 wt % to about 5 wt % of sodium stearyl fumarate.

31. A pharmaceutical formulation comprising:

(a) about 1 wt % to about 5 wt % of 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid di-tosylate salt (Compound 1 di-tosylate salt), or a solvate or hydrate thereof;

(b) about 1 wt % to about 15 wt % of fumaric acid;

(c) about 80 wt % to about 97 wt % of monohydrate lactose; and

(d) about 1 wt % to about 5 wt % of stearic acid.

42. A method for preparing a pharmaceutical formulation suitable for oral administration comprising 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid di-tosylate salt, said method comprising blending 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid di-tosylate salt, an organic acid and one or more portions of a diluent to form the pharmaceutical formulation suitable for oral administration.

46. The method of claim 42, wherein the organic acid is fumaric acid, the diluent is lactose monohydrate and the lubricant is sodium stearyl fumarate or steric acid.

47. The method of claim 42, further comprising compressing the pharmaceutical formulation to afford a tablet.

43. A method for preparing a pharmaceutical formulation suitable for oral administration comprising 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid di-tosylate salt, said method comprising:

a) blending 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid di-tosylate salt with one or more portions of a diluent to form a first homogeneous mixture;

b) blending the first mixture with an organic acid to form a second homogeneous mixture; and

c) blending the second mixture with a lubricant to form the pharmaceutical formulation suitable for oral administration.

44. A method for preparing a pharmaceutical formulation suitable for oral administration comprising 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid di-tosylate salt, said method comprising:

a) blending 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid di-tosylate salt, an organic acid and one or more portions of a diluent to form a homogeneous mixture;

b) blending the homogeneous mixture with a lubricant to form the pharmaceutical formulation suitable for oral administration.

45. A method for preparing a pharmaceutical formulation suitable for oral administration comprising 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid di-tosylate salt, said method comprising:

a) blending an organic acid and a diluent to form a first homogeneous mixture;

b) wet granulating the first mixture and drying to afford a dried mixture;

c) blending the dried mixture with 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid di-tosylate salt form a second homogeneous mixture; and

d) blending the second mixture with a lubricant to form the pharmaceutical formulation suitable for oral administration.