Particle and pharmaceutical composition comprising an insoluble camptothecin compound with double core-shell structure and method for manufacturing the same
Inventors
Park, Young Hwan • LEE, Il Hyun
Assignees
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Publication Number
US-11793804-B2
Publication Date
2023-10-24
Expiration Date
Abstract
A drug delivery system having an inner core-shell like structure containing a poorly soluble camptothecin compound and a water-soluble camptothecin compound, and an outer amphiphilic polymer shell surrounding the inner core-shell like structure, a manufacturing method therefor, and uses of the drug delivery system in treating cancer are disclosed. The core-shell structured particles form very stable particles and show a mono-distribution of particles before and after freeze-drying. The particles show excellent results compared with existing particles which do not contain the inner core-shell like structure, in animal efficacy tests and pharmacokinetic tests.
Core Innovation
The invention relates to double core-shell particles as bilayer micelles for camptothecin delivery, including an inner core and an outer shell surrounding the inner core. The inner core comprises a hydrophobic camptothecin compound and a hydrophilic camptothecin compound, and the outer shell is formed of an amphiphilic block copolymer having a hydrophobic block and a hydrophilic block in a same chain.
A population of freeze-dried particles is provided with particle size less than 1 μm, and with a controlled proportion of particles larger than 200 nm as measured by dynamic light scattering (DLS). The document describes manufacturing by mixing and solvent processing to form particles comprising the inner core and the outer shell, followed by freeze-drying to yield the freeze-dried population.
The problem addressed is to improve freeze-drying stability and minimize particle growth and the fraction of particles above 200 nm, while maintaining performance compared with monolayer micelles. The document reports comparative and in vivo evidence that bilayer micelles show improved stability and enhanced tumor inhibition and pharmacokinetics/bioavailability, including improved SN-38 glucuronide bioavailability in dogs, without surfactant hypersensitivity.
Claims Coverage
The partial content identifies two independent claims, both directed to manufacturing freeze-dried particles with an inner core containing hydrophobic and hydrophilic camptothecin compounds and an outer amphiphilic block copolymer shell, while controlling particle size and the proportion of particles larger than 200 nm by DLS. The independent claims share the same core particle structure and DLS-based size/distribution constraint, with differences in the order of mixing steps and component incorporation details.
Freeze-dried camptothecin bilayer micelles with hydrophobic/hydrophilic inner core and amphiphilic block copolymer outer shell
A method for manufacturing a population of freeze-dried particles with particle size of less than 1 μm, the freeze-dried particles comprising an inner core with a hydrophobic camptothecin compound and a hydrophilic camptothecin compound, and an outer shell surrounding the inner core formed of an amphiphilic block copolymer having a hydrophobic block and a hydrophilic block in a same chain.
Solvent formation of inner core and aqueous shell formation followed by freeze-drying to control >200 nm fraction
A method comprising mixing the hydrophobic and hydrophilic camptothecin compounds in an organic solvent, removing the organic solvent and mixing the solvent-free mixture with an aqueous solvent to form the inner core, then mixing the inner core with an amphiphilic block copolymer in an aqueous solvent to form particles with the inner core and outer shell, and freeze-drying the particles to obtain the freeze-dried population with the proportion of particles with size more than 200 nm being 11.8% or less by DLS.
Simultaneous mixing of camptothecin compounds and amphiphilic block copolymer in an organic solvent followed by solvent removal, aqueous mixing, and freeze-drying
A method for manufacturing a population of freeze-dried particles with particle size of less than 1 μm, comprising mixing the hydrophobic camptothecin compound, the hydrophilic camptothecin compound, and an amphiphilic block copolymer in an organic solvent, removing the organic solvent, mixing the resulting solvent-free mixture with an aqueous solvent to form particles comprising the inner core and outer shell, and freeze-drying to obtain the freeze-dried population with the proportion of particles with size more than 200 nm being 11.8% or less by DLS.
Across the two independent claims, the manufacturing is centered on producing freeze-dried particles below 1 μm that include an inner core with hydrophobic and hydrophilic camptothecin compounds and an outer shell of an amphiphilic block copolymer with hydrophobic and hydrophilic blocks in the same chain. Both claims additionally require a DLS-measured constraint that the proportion of freeze-dried particles larger than 200 nm is 11.8% or less.
Stated Advantages
Improved stability compared with monolayer micelles after freeze-drying (reported improved stability over 6 months).
Minimal particle growth with low fractions of particles ≥200 nm after freeze-drying (as reported by DLS).
Enhanced tumor inhibition and improved pharmacokinetics/bioavailability in animal studies (including reported improved SN-38 glucuronide bioavailability in dogs).
No surfactant hypersensitivity is reported for the bilayer micelles.
Documented Applications
Drug delivery for camptothecin using double core-shell particles (bilayer micelles), including enhanced tumor inhibition and animal pharmacokinetics/bioavailability evaluation (including SN-38 glucuronide bioavailability in dogs).
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