Novel formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof

Abstract

In accordance with the present invention, there are provided compositions and methods useful for the in vivo delivery of substantially water insoluble pharmacologically active agents (such as the anticancer drug paclitaxel) in which the pharmacologically active agent is delivered in the form of suspended particles coated with protein (which acts as a stabilizing agent). In particular, protein and pharmacologically active agent in a biocompatible dispersing medium are subjected to high shear, in the absence of any conventional surfactants, and also in the absence of any polymeric core material for the particles. The procedure yields particles with a diameter of less than about 1 micron. The use of specific composition and preparation conditions (e.g., addition of a polar solvent to the organic phase), and careful selection of the proper organic phase and phase fraction, enables the reproducible production of unusually small nanoparticles of less than 200 nm diameter, which can be sterile-filtered. The particulate system produced according to the invention can be converted into a redispersible dry powder comprising nanoparticles of water-insoluble drug coated with a protein, and free protein to which molecules of the pharmacological agent are bound. This results in a unique delivery system, in which part of the pharmacologically active agent is readily bioavailable (in the form of molecules bound to the protein), and part of the agent is present within particles without any polymeric matrix therein.

1 - 65 . (canceled) 
     
     
         66 . A method of treating cancer comprising administering a composition comprising nanoparticles comprising a taxane and a coating comprising a protein, wherein the cancer is selected from the group consisting of prostate, bone, kidney, heart, and spleen, and wherein the composition is free of cremophor. 
     
     
         67 . The method of  claim 66 , wherein the composition is administered orally, intramuscularly, intravenously, intraperitoneally, intraarterially, intraurethrally, intrathecally, or by inhalation. 
     
     
         68 . The method of  claim 66 , wherein the taxane is paclitaxel. 
     
     
         69 . The method of  claim 66 , wherein the protein is albumin. 
     
     
         70 . A method of treating restenosis or retinopathy comprising administering a composition comprising nanoparticles comprising a taxane and a coating comprising a protein, wherein the composition is free of cremophor. 
     
     
         71 . The method of  claim 70 , wherein the composition is administered orally, intramuscularly, intravenously, intraperitoneally, intraarterially, intraurethrally, intrathecally, or by inhalation. 
     
     
         72 . The method of  claim 70 , wherein the taxane is paclitaxel. 
     
     
         73 . The method of  claim 70 , wherein the protein is albumin. 
     
     
         74 . A composition comprising nanoparticles comprising a substantially water insoluble pharmacologically active agent and a coating comprising a protein and polyethylene glycol. 
     
     
         75 . A composition comprising nanoparticles comprising a substantially water insoluble pharmacologically active agent and a coating comprising a protein, and wherein said nanoparticles are attached to an RGD (arginine-glycine-aspartic acid) peptide.