Lapatinib particles and uses thereof

Abstract

The disclosure provides particles of at least 95% by weight of lapatinib, or a pharmaceutically acceptable salt thereof, wherein the particles have a specific surface area (SSA) of at least 10 m2/g and have a mean particle size by volume distribution of between about 0.7 μm and about 8 μm.

We claim: 
     
         1 . A composition, comprising particles comprising at least 95% by weight of lapatinib, or a pharmaceutically acceptable salt thereof, wherein the particles have a specific surface area (SSA) of at least 10 m 2 /g and have a mean particle size by volume distribution of between about 0.7 μm and about 8 μm. 
     
     
         2 . The composition of  claim 1 , wherein the particles have a SSA of at least 15 m 2 /g. 
     
     
         3 . The composition of  claim 1 , wherein the particles have a SSA of at least 18 m 2 /g. 
     
     
         4 . The composition of  claim 1 , wherein the particles have a SSA of between 10 m 2 /g and 50 m 2 /g, between 15 m 2 /g and 50 m 2 /g, or between 18 m 2 /g and 50 m 2 /g. 
     
     
         5 . The composition of  claim 1 , wherein the particles have a mean particle size by volume distribution of between about 1 μm and about 8 μm. 
     
     
         6 . The composition of  claim 1 , wherein the particles comprise at least 96%, 97%, 98%, 99%, or 100% of lapatinib, or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The composition of  claim 1 , wherein the particles are uncoated and exclude polymer, protein, polyethoxylated castor oil and polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol. 
     
     
         8 . The composition of  claim 1 , wherein the composition comprises a suspension further comprising a pharmaceutically acceptable liquid carrier. 
     
     
         9 . The composition of  claim 1 , further comprising one or more components selected from the group consisting of polysorbate, methylcellulose, polyvinylpyrrolidone, mannitol, and hydroxypropyl methylcellulose. 
     
     
         10 . The composition of  claim 1 , wherein
 (a) the particles have a mean bulk density between about 0.005 g/cm 3  and about 0.100 g/cm 3 , between about 0.010 g/cm 3  and about 0.075 g/cm 3 , between about 0.010 g/cm 3  and about 0.050 g/cm 3 , or between about between about 0.015 g/cm 3  and about 0.040 g/cm 3 , tapped or not tapped; and/or   (b) the particles have a mean bulk density less than about 0.100 g/cm 3 , 0.090 g/cm 3 , 0.080 g/cm 3 , 0.070 g/cm 3 , 0.060 g/cm 3 ′, 0.050 g/cm 3 , 0.040 g/cm 3 , or 0.030 g/cm 3 , tapped or not tapped.   
     
     
         11 . The composition of  claim 1 , wherein the pharmaceutically acceptable salt of lapatinib comprises lapatinib ditosylate monohydrate. 
     
     
         12 . A method for treating a tumor, comprising administering to a subject with a tumor an amount effective to treat the tumor of the composition of  claim 1 . 
     
     
         13 . The method of  12 , wherein the tumor is a breast tumor, pancreatic carcinoma, prostate carcinoma, bladder carcinoma, lung carcinoma, ovarian carcinoma, gastrointestinal tumor, or renal cell tumor. 
     
     
         14 . The method of  claim 13 , wherein the tumor is a breast tumor, and wherein the breast tumor is an advanced or metastatic breast tumor that overexpresses human epidermal growth factor 2 (HER2), or a hormone receptor positive metastatic breast tumor that overexpresses the HER2 receptor. 
     
     
         15 . The method of  claim 13 , wherein the method further comprises administering capecitabine and/or letrozole to the subject. 
     
     
         16 . The method of  claim 12 , wherein the subject is a human subject, including but not limited to a female human subject, including but not limited to a post-menopausal female human subject. 
     
     
         17 . The method of  claim 12 , wherein the composition is administered by intra-tumoral injection, peri-tumoral injection, intra-peritoneal injection, or is administered into a mammary fat pad. 
     
     
         18 . A method for making lapatinib particles, comprising:
 (a) introducing (i) a solution comprising at least one solvent selected from the group consisting of acetone and DCM, or combinations thereof, and at least one solute comprising lapatinib or a pharmaceutically acceptable salt thereof into a nozzle inlet, and (ii) a compressed fluid into an inlet of a vessel defining a pressurizable chamber;   (b) passing the solution out of a nozzle orifice and into the pressurizable chamber to produce an output stream of atomized droplets, wherein the nozzle orifice is located between 2 mm and 20 mm from a sonic energy source located within the output stream, wherein the sonic energy source produces sonic energy with an amplitude between 10% and 100% during the passing, and wherein the nozzle orifice has a diameter of between 20 μm and 125 μm;   (c) contacting the atomized droplets with the compressed fluid, to cause depletion of the solvent from the atomized droplets, to produce compound particles comprising at least 95% lapatinib or a pharmaceutically acceptable salt thereof, wherein the particles have a specific surface area (SSA) of at least 10 m 2 /g and have a mean particle size by volume distribution of between about 0.7 μm and about 8 μm,   wherein steps (a), (b), and (c) are carried out under supercritical temperature and pressure for the compressed fluid.   
     
     
         19 . The method of  claim 18 , further comprising:
 (d) contacting the compound particles produced in step (c) with an anti-solvent to cause further depletion of the solvent from the compound particles, wherein step (d) is carried out under supercritical temperature and pressure for the anti-solvent.   
     
     
         20 . The method of  claim 18 , wherein a flow rate of the solution through the nozzle has a range from about 0.5 mL/min to about 30 mL/min. 
     
     
         21 . The method of  claim 18 , wherein the sonic energy source comprises one of a sonic horn, a sonic probe, or a sonic plate. 
     
     
         22 . The method of  claim 18 , wherein the sonic energy source has a frequency between about 18 kHz and about 22 kHz, or about 20 kHz. 
     
     
         23 . The method of  claim 18 , further comprising:
 (e) receiving the plurality of particles through the outlet of the pressurizable chamber; and   (f) collecting the plurality of particles in a collection device.   
     
     
         24 . The method of  claim 18 , wherein the compressed fluid is super critical carbon dioxide. 
     
     
         25 . The method  claim 19 , wherein the anti-solvent is super critical carbon dioxide. 
     
     
         26 . The method of  claim 18 , wherein the method is carried out between 31.1° C. to about 60° C., and at between about 1071 psi and about 1800 psi. 
     
     
         27 . The method of  claim 18 , wherein the particles have a SSA of at least 15 m 2 /g or at least 18 m 2 /g. 
     
     
         28 . Compound particles prepared by the method of  claim 18 .