Nanoparticles of indirubin, derivatives thereof and methods of making and using same

Abstract

The disclosure provides nanoparticles of indirubin and methods of making and using these particles for the treatment of cancer, neurodegenerative disorders and inflammatory diseases. The effective average particle size of the nanoparticles is less than 2000 nm.

1 . A nanoparticulate indirubin composition comprising:
 (a) particles of indirubin or derivatives thereof, wherein the indirubin particles have an effective average particle size of less than 2 microns; and   (b) at least one surface stabilizer.   
     
     
         2 . The composition of  claim 1 , wherein the effective average particle size of the nanoparticulate indirubin particles is less than 1000 nm. 
     
     
         3 . The composition of  claim 1 , wherein the effective average particle size of the nanoparticulate indirubin particles is less than 500 nm. 
     
     
         4 . The composition of  claim 1 , wherein at least about 70% of the indirubin particles have a particle size less than the effective average particle size. 
     
     
         5 . The composition of  claim 1 , wherein the composition is formulated for oral or intravenous administration. 
     
     
         6 . The composition of  claim 1 , wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof. 
     
     
         7 . The composition of  claim 1 , wherein the indirubin is present from about 80% to about 99.9999% by weight, based on the total combined dry weight of the indirubin and at least one surface stabilizer, not including other excipients. 
     
     
         8 . The composition of  claim 1 , wherein the at least one surface stabilizer is present in an amount of from about 0.0001% to about 20% by weight, based on the total combined dry weight of the indirubin and at least one surface stabilizer, not including other excipients. 
     
     
         9 . The composition of  claim 1 , comprising at least two surface stabilizers. 
     
     
         10 . The composition of  claim 1 , wherein the surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and a non-ionic surface stabilizer. 
     
     
         11 . The composition of  claim 1 , wherein the at least one surface stabilizer is a poloxamer. 
     
     
         12 . The composition of  claim 11 , wherein the poloxamer is selected from the group consisting of block copolymers of ethylene oxide and propylene oxide. 
     
     
         13 . The composition of  claim 11 , wherein the poloxamer is a block copolymer of ethylene oxide. 
     
     
         14 . The composition of  claim 1 , further comprising an indirubin composition having an effective average particle size of greater than 2 microns. 
     
     
         15 . The composition of  claim 1 , further comprising at least one additional nanoparticulate indirubin composition having an effective average particle size of less than 2 microns, wherein said additional nanoparticulate indirubin composition has an effective average particle size which is different than the effective average particle size of the nanoparticulate indirubin composition of  claim 1 . 
     
     
         16 . The composition of  claim 1 , further comprising at least one non-indirubin active agent. 
     
     
         17 . The composition of  claim 1  formulated into a liquid dosage form, wherein the dosage form has a viscosity of less than 2000 mPas at a shear rate of 0.1 (l/s). 
     
     
         18 . The composition of  claim 1 , wherein upon administration the composition redisperses such that the indirubin particles have an effective average particle size of less than 2 microns. 
     
     
         19 . The composition of  claim 1 , wherein the composition redisperses in a biorelevant media such that the indirubin particles have an effective average particle size of less than 2 microns. 
     
     
         20 . A method of making the nanoparticulate indirubin composition of  claim 1 , comprising contacting indirubin particles with at least one surface stabilizer for a time and under conditions sufficient to provide a nanoparticulate indirubin composition having an effective average particle size of less than 2 microns. 
     
     
         21 . The method of  claim 20 , wherein said contacting comprises grinding. 
     
     
         22 . The method of  claim 21 , wherein said grinding comprises wet grinding. 
     
     
         23 . The method of  claim 20 , wherein said contacting comprises homogenizing and emulsification. 
     
     
         24 . The method of  claim 20 , wherein said contacting comprises:
 (a) dissolving the indirubin particles in a solvent;   (b) adding the resulting indirubin solution to a solution comprising at least one surface stabilizer; and   (c) precipitating the solubilized indirubin and at least one surface stabilizer.   
     
     
         25 . A method of treating cancer in a subject in need thereof comprising administering an effective amount of the nanoparticulate indirubin composition of  claim 1 . 
     
     
         26 . The method of  claim 25 , wherein the cancer is glioblastoma or leukemia. 
     
     
         27 . The method of  claim 25 , wherein said subject is a human. 
     
     
         28 . A method of treating an inflammatory disease in a subject in need thereof comprising administering an effective amount of the nanoparticulate indirubin composition of  claim 1 . 
     
     
         29 . The method of  claim 28 , wherein the inflammatory disease is psoriasis. 
     
     
         30 . The method of  claim 28 , wherein said subject is a human. 
     
     
         31 . A method of treating a neurodegenerative disorder in a subject in need thereof comprising administering an effective amount of the nanoparticulate indirubin composition of  claim 1 . 
     
     
         32 . The method of  claim 31 , wherein the neurodegenerative disorder is Alzheimer's disease. 
     
     
         33 . The method of  claim 31 , wherein said subject is a human. 
     
     
         34 . The method of  claim 31 , further comprising administering an agent that enhances the permeability of the blood brain barrier to the subject in need thereof.