Novel methods

Abstract

The present invention relates to the field of methods for providing components of pharmaceutical compositions comprising poorly water-soluble drugs. In particular the present invention relates to methods for providing stable, amorphous hybrid nanoparticles, comprising at least one protein kinase inhibitor and at least one polymeric stabilizing and matrix-forming component, useful in pharmaceutical compositions.

1 . A method of producing stable, amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one polymeric stabilizing and matrix-forming component, comprising
 a) providing a first pressurized stream of said protein kinase inhibitor dissolved in a solvent;   b) providing a second pressurized stream of antisolvent;
 wherein said at least one polymeric stabilizing and matrix-forming component is present in either said first or second stream; and 
   c) mixing said first and second streams, and spraying the mixed stream at the outlet of a nozzle, whereby said hybrid nanoparticles are formed; followed by collecting said hybrid nanoparticles.   
     
     
         2 . The method of  claim 1 , wherein said polymeric stabilizing and matrix-forming component is present in said solvent. 
     
     
         3 . The method of  claim 1 , wherein said polymeric stabilizing and matrix-forming component is present in said antisolvent. 
     
     
         4 . The method according to  claim 1 , wherein at least one of said fluid streams is a supercritical fluid stream, preferably a super- or subcritical CO 2  fluid stream. 
     
     
         5 . The method according to  claim 1 , wherein said stream of antisolvent is a super- or subcritical CO 2  fluid stream. 
     
     
         6 . The method according to  claim 1 , wherein said stream of solvent is a super- or subcritical CO 2  fluid stream. 
     
     
         7 . The method according to  claim 1 , wherein said at least one polymeric stabilizing and matrix-forming component is present in a super- or subcritical CO 2  fluid stream. 
     
     
         8 . The method according to  claim 1 , wherein said first stream or said second stream is comprised of a super- or subcritical CO 2  fluid stream is provided at a temperature of about 25° C. or lower, at a pressure of from about 100 to about 150 bar. 
     
     
         9 . The method according to  claim 1 , wherein said at least one polymeric stabilizing and matrix-forming component is selected from methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinylpyrrolidone, polyvinyl acetate phthalate, copolyvidone, crospovidon, methacrylic acid and ethylacrylate copolymer, methacrylate acid and methyl methacrylate copolymer, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer, DL lactide/glycolide copolymer, poly DL-lactide, cellulose acetate phthalate, carbomer homopolymer Type A, carbomer homopolymer Type B, aminoalkyl methacrylate copolymers and polaxamers. 
     
     
         10 . The method according to  claim 1 , wherein said at least one polymeric stabilizing and matrix-forming component is selected from hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose, copolyvidone, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate phthalate and polyvinylpyrrolidone. 
     
     
         11 . The method according to  claim 1 , wherein a solubilizer is added to the hybrid nanoparticles obtained in step c. 
     
     
         12 . The method of  claim 11 , wherein said solubilizer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer, d-α-tocopherol acid polyethylene glycol 1000 succinate and a hydrogenated castor oil. 
     
     
         13 . The method according to  claim 1 , wherein said hybrid nanoparticles comprising said protein kinase inhibitor provide an increased dissolution rate, compared to the dissolution rate of said protein kinase inhibitor in raw, crystalline form. 
     
     
         14 . The method of  claim 13 , wherein said dissolution rate is measured by a flow through cell system. 
     
     
         15 . The method of  claim 13 ,  claim 13 , wherein said dissolution rate is measured within the initial 0 to 10 minutes of dissolution. 
     
     
         16 . The method according to  claim 13 , wherein said increased dissolution rate is measured in a solution as a dissolution rate ratio of said hybrid nanoparticles comprising said protein kinase inhibitor and said protein kinase inhibitor in raw, crystalline form. 
     
     
         17 . The method of  claim 16 , wherein said ratio is from about 1.5:1 to about 500:1. 
     
     
         18 . The method according to  claim 13 , wherein said dissolution rate is measured in a solution with a gastric pH. 
     
     
         19 . The method according to  claim 13 , wherein said dissolution rate is measured in a solution with an intestinal pH. 
     
     
         20 . The method according to  claim 1 , which produces hybrid nanoparticles that provide a solubility increase of said protein kinase inhibitor in a solution, said increase measured as the area under the curve (AUC) during about from 40 minutes to about 90 minutes, in said solution as compared with the AUC of said protein kinase inhibitor in raw, crystalline form. 
     
     
         21 . The method of  claim 20 , wherein said increase is from about 2:1 to about 10 000:1, wherein 1 represents the AUC of said protein kinase inhibitor in raw, crystalline form. 
     
     
         22 . The method of  claim 20 , wherein said increase is measured in a solution with gastric pH. 
     
     
         23 . The method according to  claim 20 , wherein said increase is measured in a solution with an intestinal pH. 
     
     
         24 . The method according to  claim 1 , wherein said amorphous hybrid nanoparticles are characterized by providing an amorphous powder X-ray diffraction pattern. 
     
     
         25 . The method according to  claim 1 , wherein the dissolution rate of said stable, amorphous hybrid nanoparticles remain stable to at least about 90%, after 9 months of storage or more, at room temperature. 
     
     
         26 . The method according to  claim 1 , wherein said protein kinase inhibitor is a tyrosine kinase inhibitor selected from the group consisting of lapatinib, pazopanib, nilotinib, erlotinib, dasatinib, gefitinib, sorafenib, crizotinib, axitinib, vemurafenib salts thereof, hydrates thereof, solvates thereof, and combinations thereof. 
     
     
         27 . The method according to  claim 1 , wherein said hybrid nanoparticles have an average particle diameter size of less than about 1000 nm. 
     
     
         28 . The method according to  claim 1 , wherein said hybrid nanoparticles have an average diameter size is less than about 500 nm. 
     
     
         29 . The method according to  claim 1 , wherein said solvent is an organic solvent selected from DMSO and trifluoroethanol, or a mixture thereof. 
     
     
         30 . The method according to  claim 1 , wherein said hybrid nanoparticles further comprise a solubilizer. 
     
     
         31 . The method of  claim 30 , wherein said solubilizer is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer, d-α-tocopherol acid polyethylene glycol 1000 succinate or a hydrogenated castor oil. 
     
     
         32 . (canceled) 
     
     
         33 . The method according to  claim 1 , further comprising
 formulating said hybrid nanoparticles obtained from step (c) as a pharmaceutical composition,   wherein said pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient.