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 - 79 . (canceled) 
     
     
         80 . A formulation comprising nanoparticles comprising paclitaxel and albumin which is free of cremophor, wherein the average size of the nanoparticles is no greater than about 200 nm, and wherein upon intravenous administration of said formulation the area under curve of paclitaxel increases proportionally with the dose of paclitaxel between about 55 mg/m 2  and about 158 mg/m 2 . 
     
     
         81 . The formulation of  claim 80 , wherein upon administration of said formulation the area under curve of paclitaxel increases proportionally with the dose of paclitaxel between about 55 mg/m 2  and about 700 mg/m 2 . 
     
     
         82 . The formulation of  claim 80 , wherein the nanoparticles have diameter of less than 200 nm. 
     
     
         83 . The formulation of  claim 80 , wherein the nanoparticles are sterile filterable. 
     
     
         84 . The formulation of  claim 80 , wherein the nanoparticles have a core that is substantially free of a polymeric matrix. 
     
     
         85 . The formulation of  claim 80 , wherein the nanoparticles comprise paclitaxel coated with albumin. 
     
     
         86 . The formulation of  claim 85 , wherein the albumin is cross-linked by way of disulfide bonds. 
     
     
         87 . The formulation of  claim 80 , wherein paclitaxel in the nanoparticles is substantially amorphous. 
     
     
         88 . The formulation of  claim 80 , wherein the formulation is lyophilized. 
     
     
         89 . The formulation of  claim 80 , wherein the nanoparticles are suspended in a biocompatible aqueous liquid. 
     
     
         90 . The formulation of  claim 89 , wherein the formulation is stable for at least three days under at least one of room temperature or refrigerated conditions. 
     
     
         91 . The formulation of  claim 80 , wherein the albumin is human serum albumin. 
     
     
         92 . A method of intravenously administering to an individual a formulation comprising nanoparticles comprising paclitaxel and albumin which is free of cremophor, wherein the average size of the nanoparticles is no greater than about 200 nm, and wherein upon administration of said formulation the area under curve of paclitaxel increases proportionally with the dose of paclitaxel between about 55 mg/m 2  and about 158 mg/m 2 . 
     
     
         93 . The method of  claim 92 , wherein upon administration of said formulation the area under curve of paclitaxel increases proportionally with the dose of paclitaxel between about 55 mg/m 2  and about 700 mg/m 2 . 
     
     
         94 . The method of  claim 92 , wherein the nanoparticles are sterile filterable. 
     
     
         95 . The method of  claim 92 , wherein the nanoparticles have a core that is substantially free of a polymeric matrix. 
     
     
         96 . The method of  claim 92 , wherein the nanoparticles comprise paclitaxel coated with albumin. 
     
     
         97 . The method of  claim 92 , wherein the individual is human. 
     
     
         98 . A method of treating cancer in an individual comprising administering to the individual an effective amount of the formulation of  claim 80 . 
     
     
         99 . The method of  claim 98 , wherein the cancer is breast cancer.