Formulations of an lsd1 inhibitor

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.

What is claimed is: 
     
         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:   
       
         
           
           
               
               
           
         
       
       or a solvate or hydrate thereof, and
 (b) an organic acid. 
 
     
     
         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. 
     
     
         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.   
     
     
         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.   
     
     
         28 . The pharmaceutical formulation of  claim 26  further comprising sodium stearyl fumarate. 
     
     
         29 . The pharmaceutical formulation of  claim 26  further comprising stearic acid. 
     
     
         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.   
     
     
         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. 
     
     
         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. 
     
     
         43 . A method for preparing a pharmaceutical formulation suitable for oral administration comprising 1-{[4-(methoxymethyl)-4-({[(1R,2 S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid di-tosylate salt, said method comprising:
 a) blending 1-{[4-(methoxymethyl)-4-({[(1R,2 S)-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.   
     
     
         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. 
     
     
         48 . The pharmaceutical formulation of  claim 2 , prepared by the method of  claim 42 .