Endoxifen methods and compositions in the treatment of psychiatric and neurodegenerative diseases

Abstract

The present invention provides compositions containing endoxifen, formulations and liposomes of endoxifen, methods of preparation of such agents and formulations, and use of such agents and formulations for the treatment of a subject having or at risk for psychiatric and neurodegenerative diseases. Specifically, the present invention relates to the composition comprising endoxifen in the treatment of bipolar disorder, schizophrenia, multiple sclerosis (MS), Alzheimer disease, Parkinson disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and/or epilepsy by administrating formulations or compositions comprising an effective amount of endoxifen.

We claim: 
     
         1 . A method of treating a cell, comprising exposing said cell to a composition comprising an effective amount of a complex comprising endoxifen, wherein said endoxifen is a free base or is in the form of a salt. 
     
     
         2 . The method of  claim 1 , wherein the cell is in vivo in a host. 
     
     
         3 . The method of  claim 2 , wherein said exposing comprises administering said composition to a subject, wherein said administering comprises oral, intravenous, subcutaneous, percutaneous, parenteral, intraperitoneal, rectal, vaginal, and/or topical delivery said composition to said subject. 
     
     
         4 . The method of  claim 2 , wherein said subject is a mammal. 
     
     
         5 . The method of  claim 4 , wherein said subject is human. 
     
     
         6 . The method of  claim 3 , wherein said subject is at risk for a disease or suffers from a disease. 
     
     
         7 . The method of  claim 6 , wherein said disease is bipolar disorder. 
     
     
         8 . The method of  claim 6 , wherein said disease is selected from the group consisting of multiple sclerosis, schizophrenia, Alzheimer disease, Parkinson disease, Huntington's disease, amyotrophic lateral sclerosis, and epilepsy. 
     
     
         9 . The method of  claim 1 , wherein said composition comprising endoxifen is formulated in a hydroalcoholic gel, a hydroalcoholic solution, a patch, a cream, an emulsion, a lotion, an ointment, a powder, a tablet, a capsule, an enteric-coated capsule, an enteric coated tablet, a lozenge, or an oil. 
     
     
         10 . The method of  claim 1 , wherein said composition comprising endoxifen is formulated in a hydroalcoholic composition containing a penetration enhancer, an aqueous vehicle, an alcoholic vehicle and a gelling agent. 
     
     
         11 . The method of  claim 10 , wherein said hydroalcoholic composition comprises a neutralizing agent, wherein said neutralizing agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonium hydroxide, aminomethylpropanol, arginine, trolamine, and tromethamine, and wherein said neutralizing agent exists at a neutralizing agent/gelling agent ratio of about 1:1 to about 4:1. 
     
     
         12 . The method of  claim 10 , wherein said hydroalcoholic composition comprises:
 (i) endoxifen at about 0.01% to 0.20% by weight;   (ii) isopropyl myristate at about 0.1% to 2.0%, preferably 0.5% to 2.0% by weight;   (iii) alcohol at about 50.0% to 80.0%, preferably about 60.0% to 75.0% by weight   (iv) aqueous vehicle at about 20.0% to 60.0%, preferably 25.0% to 50.0% by weight; and   (v) gelling agent at about 1.0% to 10.0%, preferably about 0.5% to 5.0% by weight.   wherein the percentage of components is weight to weight of the composition.   
     
     
         13 . The method of  claim 1 , wherein in said composition, endoxifen is predominantly in a form selected from a group consisting of Z-isomer, E-isomer, and a mixture of Z- and E-isomer. 
     
     
         14 . The method of  claim 1  or  claim 13  wherein said endoxifen is in the form of a salt selected from the group of salts consisting of citrate, acetate, formate, oxalate, succinate, tartarate, trifluoroacetate, methane sulfonate, phosphate, sulfate, chloride, bromide, iodide, lactate, and formate salts. 
     
     
         15 . The method of  claim 1 , wherein said composition comprising endoxifen comprises at least one lipid selected from the group consisting of egg phosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), soy phosphatidylcholine (SPC), hydrogenated soy phosphatidylcholine (HSPC), dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosohatidylcholine (DPPC), disteroylphosphatidylglycerol (DSPG), dipalmitoylphosphatidylglycerol (DMPG), cholesterol (Chol), cholesterol sulfate and its salts (CS), cholesterol hemisuccinate and its salts (Chems), cholesterol phosphate and its salts (CP), cholesterylphosphocholine and other hydroxycholesterol or amino cholesterol derivatives, cholesteryl succinate, cholesteryl oleate, polyethylene glycol derivatives of cholesterol (cholesterol-PEG), coprostanol, cholestanol, cholestane, cholic acid, cortisol, corticosterone, hydrocortisone, and calciferol, E-guggulsterone, Z-guggulsterone, mixture of E- and Z-guggulsterone, monoglycerides, diglycerides, triglycerides, carbohydrate-based lipids selected from a group consisting of galactolipid, mannolipid, galactolecithin, β-sitosterol, stigmasterol, stigmastanol, lanosterol, α-spinasterol, lathosterol, campesterol, phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylserine, phosphatdylinositol, phosphatidic acid, and pegylated derivatives of distearoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, dimyristoylphosphatidylglycerol, and dioleoylphosphatidylglycerol. 
     
     
         16 . The method of  claim 1 , wherein said composition comprises endoxifen, cholesterol and/or a cholesterol derivative, and one or more phospholipids. 
     
     
         17 . The method of  claim 16 , wherein at least one of said one or more phospholipids is hydrogenated soy phosphatidylcholine or soy phosphatidylcholine. 
     
     
         18 . The composition of  claim 1 , wherein said composition comprising endoxifen comprises a form selected from the group consisting of powder, solution, emulsion, micelle, liposome, lipidic particle, gel, paste form, a lyophilized form, and a tablet or a filled capsule, wherein said tablet or filled capsule optionally comprises an enteric coating material. 
     
     
         19 . The method of  claim 1 , wherein said composition is in a lyophilized form comprising a cryoprotectant, wherein said cryoprotectant comprises one or more sugars selected from the group consisting of trehalose, maltose, lactose, sucrose, glucose, and dextran.