Pharmaceutical compositions of albumin and rapamycin

Abstract

The present invention provides compositions (such as pharmaceutical compositions), and commercial batches of such compositions, comprising nanoparticles comprising albumin and rapamycin. The compositions (such as pharmaceutical compositions) have specific physicochemical characteristics and are particularly suitable for use in treating diseases such as cancer. Also provided are methods of making and methods of using the compositions (such as pharmaceutical compositions).

1 - 30 . (canceled) 
     
     
         31 . A nanoparticle composition comprising (a) nanoparticles comprising rapamycin and albumin, and (b) a non-nanoparticle portion comprising albumin and rapamycin; wherein the nanoparticle composition comprises seco-rapamycin, and wherein the seco-rapamycin is about 0.2% to about 3% by weight of the sum of seco-rapamycin and rapamycin in the nanoparticle composition. 
     
     
         32 . The method of  claim 31 , wherein the nanoparticle composition further comprises a caprylic acid derivative or a tryptophan derivative. 
     
     
         33 . The pharmaceutical composition of  claim 31 , wherein:
 (a) about 80% to about 95% of the total albumin in the composition is in the form of monomeric albumin,   (b) about 4% to about 15% of the total albumin in the composition is in the form of dimeric albumin,   (c) about 0.3% to about 3% of the total albumin in the composition is in the form of oligomeric albumin, and   (d) about 2% to about 7% of the total albumin in the composition is in the form of polymeric albumin;   wherein the percentage of human albumin in the composition that is in the form of monomeric albumin, dimeric albumin, or polymeric albumin is determined by subjecting the composition to size exclusion chromatography (SEC).   
     
     
         34 . The pharmaceutical composition of  claim 33 , wherein the albumin is human albumin. 
     
     
         35 . The pharmaceutical composition of  claim 31 , wherein the weight ratio of the albumin to the rapamycin in the nanoparticles is about 1:1 to about 1:4. 
     
     
         36 . The pharmaceutical composition of  claim 31 , wherein the weight ratio of the albumin to the rapamycin in the composition is about 1:1 to about 10:1. 
     
     
         37 . The pharmaceutical composition of  claim 31 , wherein 90% or more, by weight, of the rapamycin in the composition is in the nanoparticles. 
     
     
         38 . The pharmaceutical composition of  claim 31 , wherein less than 1% of rapamycin in the composition is free rapamycin. 
     
     
         39 . The pharmaceutical composition of  claim 31 , wherein the Z-average particle size of the nanoparticles is about 200 nm or less. 
     
     
         40 . The pharmaceutical composition of  claim 31 , wherein the polydispersity index of the nanoparticles is less than 0.3. 
     
     
         41 . The pharmaceutical composition of  claim 31 , wherein the span of the particle size distribution (D v 95-D v 5)/D v 50) of the nanoparticles is about 0.8 to about 1.2. 
     
     
         42 . The pharmaceutical composition of  claim 31 , wherein the nanoparticles have an amorphous morphology as determined by separating the nanoparticles from the composition, lyophilizing the separated nanoparticles, and measuring crystallinity of the separated and lyophilized nanoparticles by X-ray diffraction. 
     
     
         43 . The pharmaceutical composition of  claim 31 , wherein at least 20% of the nanoparticles in the composition are non-spherical. 
     
     
         44 . The pharmaceutical composition of  claim 31 , wherein the nanoparticles have a non-smooth surface. 
     
     
         45 . The pharmaceutical composition of  claim 31 , wherein the nanoparticle composition comprises tert-butanol, and wherein the amount of tert-butanol in the nanoparticle composition is less than 10 µg/mL tert-butanol. 
     
     
         46 . The pharmaceutical composition of  claim 31 , wherein the zeta potential of the nanoparticles is about -25 to about -50 mV. 
     
     
         47 . The pharmaceutical composition of  claim 31 , wherein the composition is a nanoparticle suspension. 
     
     
         48 . The pharmaceutical composition of  claim 31 , wherein the nanoparticles are about 25% to about 45% albumin by weight. 
     
     
         49 . The pharmaceutical composition of  claim 31 , wherein the nanoparticles are about 55% to about 75% rapamycin by weight. 
     
     
         50 . A commercial batch of the pharmaceutical composition of  claim 31 .