Pharmaceutical compositions of albumin and rapamycin
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Publication Number
US-11497737-B2
Publication Date
2022-11-15
Expiration Date
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).
Core Innovation
The invention relates to a commercial batch of a pharmaceutical composition comprising nanoparticles comprising rapamycin and albumin, and a non-nanoparticle portion comprising albumin and rapamycin. The batch is defined by the fraction of albumin in the nanoparticles that is in the form of polymeric albumin other than oligomeric albumin, with 42% to about 60% of the albumin in the nanoparticles in that form. This fraction is determined by separating the nanoparticles from the non-nanoparticle portion, dissolving the nanoparticles, and subjecting the dissolved nanoparticles to size-exclusion chromatography.
The disclosure further characterizes the nanoparticle-associated and non-nanoparticle albumin and rapamycin distribution and describes albumin molecular forms including monomer, dimer, trimer, oligomeric albumin, and polymeric albumin other than oligomeric albumin. It also includes rapamycin forms including seco-rapamycin and characterizes nanoparticle physical attributes such as particle size distributions, polydispersity, zeta potential, particle size distribution span, and morphology.
Additional characterization is described for amorphous rapamycin and batch stability. DSC and mDSC are described as establishing amorphous rapamycin by the absence of crystalline melting endotherm and by glass transition temperature behavior, while FTIR and solid-state 13C NMR are described as showing lack of crystalline rapamycin peak features and evidence of molecular-level hydrogen bonding or interaction between rapamycin and human albumin. Cryo-TEM, PIDS-LD, DLS, and X-ray diffraction are also described in the context of morphology, particle size, stability, and crystallinity.
Claims Coverage
The document provides one independent claim defining a commercial batch by a specified polymeric-albumin-other-than-oligomeric-albumin fraction in nanoparticles, with dependent claims adding oligomeric albumin percentage, nanoparticle composition, particle size distribution span, amorphous morphology/crystallinity characterization, and non-spherical nanoparticle fraction. The core inventive measurement is based on separating nanoparticles from the non-nanoparticle portion, dissolving, and using size-exclusion chromatography.
Commercial batch with nanoparticle-associated polymeric albumin other than oligomeric albumin measured by SEC after separating from non-nanoparticle portion
A commercial batch of a pharmaceutical composition with nanoparticles comprising rapamycin and albumin and a non-nanoparticle portion comprising albumin and rapamycin, wherein 42% to about 60% of the albumin in the nanoparticles is polymeric albumin other than oligomeric albumin, determined by separating the nanoparticles from the non-nanoparticle portion, dissolving the nanoparticles, and subjecting the dissolved nanoparticles to size-exclusion chromatography.
Oligomeric albumin percentage range in nanoparticles determined by SEC after separating from non-nanoparticle portion
About 1% to about 4.5% of the albumin in the nanoparticles is oligomeric albumin, determined by separating nanoparticles from the non-nanoparticle material, dissolving the nanoparticles, and analyzing by size-exclusion chromatography.
Albumin and rapamycin weight percentage ranges within nanoparticles
The nanoparticles contain about 25% to about 45% albumin by weight and about 55% to about 75% rapamycin by weight.
Nanoparticle particle size distribution span constraint
A commercial batch of the nanoparticles is characterized by a particle size distribution span of about 0.8 to about 1.2 defined by (Dv95−Dv5)/Dv50.
Amorphous morphology determined by crystallinity measurement via X-ray diffraction after lyophilization of separated nanoparticles
The commercial batch has an amorphous morphology determined by separating the nanoparticles from the composition, lyophilizing the separated nanoparticles, and measuring their crystallinity via X-ray diffraction.
Fraction of non-spherical nanoparticles measured by cryo-TEM
A commercial batch has at least 20% of its nanoparticles that are non-spherical, as determined by cryogenic transmission electron microscopy (cryo-TEM).
The claims focus on defining a commercial batch by a nanoparticle-associated polymeric albumin other than oligomeric albumin fraction measured by size-exclusion chromatography after separating nanoparticles from the non-nanoparticle portion, with dependent features constraining oligomeric albumin percentage, nanoparticle albumin/rapamycin weight composition, particle size distribution span, amorphous morphology/crystallinity assessment by X-ray diffraction, and a non-spherical nanoparticle fraction measured by cryo-TEM.
Stated Advantages
Supports that the formulation maintains amorphous rapamycin and consistent nanoparticle/albumin properties during storage and stresses.
Documented Applications
Treating cancer.
Used for characterizing and supporting stability of a lyophilized pharmaceutical composition comprising albumin/rapamycin nanoparticles, including stability over storage conditions.
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