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-10980796-B2
Publication Date
2021-04-20
Expiration Date
Abstract
The present invention relates to a drug delivery system having a double core-shell structure and, specifically, to a double nano-drug delivery system having an inner core-shell containing a poorly soluble camptothecin compound and a water-soluble camptothecin compound inside and an amphiphilic polymer shell, and to a manufacturing method therefor. The double core-shell structured particles manufactured by the present invention form very stable particles and show a mono-distribution of particles before and after freeze-drying. The particles of the present invention show excellent results compared with existing monolayer micelles in animal efficacy tests and pharmacokinetic tests, and do not use a surfactant causing hypersensitivity, and thus the use of the particles of the present invention can provide a pharmaceutical composition or a drug delivery system platform, which are safe for the human body.
Core Innovation
The invention relates to a composition of freeze-dried particles having a particle size of less than 1 μm, comprising inner core-shell particles and an outer shell surrounding the inner core. The inner core-shell particle comprises a hydrophobic camptothecin compound and a hydrophilic camptothecin compound, forming the inner core, and the outer shell is formed of an amphiphilic block copolymer selected from PEG-PBLA, mPEG-PLA, PEG-PCL, PEG-PLA, mPEG-PGA, mPEG-PLGA, PEG-p(Glu), PEG-PLA-PEG, and PEG-p(Asp).
The hydrophobic camptothecin compound is 7-ethyl-10-hydroxylcamptothecin (SN-38), and the hydrophilic camptothecin compound is irinotecan, topotecan, or SN-38 glucuronide. The composition specifies that the proportion of freeze-dried particles with a size more than 200 nm is 11.8% or less as measured by dynamic light scattering (DLS), and it does not contain a surfactant that causes hypersensitivity.
The double core-shell (bilayer micelle) drug delivery system is stable before and after freeze-drying and maintains a mono-distribution with a low fraction of particles larger than 200 nm. The document states improved tumor inhibition and pharmacokinetics compared with monolayer micelles in animal tests and frames the system as a safer pharmaceutical composition platform.
Claims Coverage
The independent claim set centers on one independent claim directed to a freeze-dried composition of double core-shell particles with controlled particle size distribution, specific camptothecin pairings, a selected amphiphilic block copolymer, and exclusion of hypersensitivity-causing surfactants.
Freeze-dried double core-shell particle composition with <1 μm particle size
A composition of freeze-dried particles with particle size of less than 1 μm, comprising an inner core-shell particle and an outer shell surrounding the inner core.
Inner core made from hydrophobic and hydrophilic camptothecin compounds
The inner core-shell particle comprises a hydrophobic camptothecin compound and a hydrophilic camptothecin compound, wherein the hydrophobic camptothecin compound and the hydrophilic camptothecin compound form the inner core.
Outer shell from an amphiphilic block copolymer
An outer shell surrounding the inner core, wherein the outer shell is formed of an amphiphilic block copolymer selected from PEG-PBLA, mPEG-PLA, PEG-PCL, PEG-PLA, mPEG-PGA, mPEG-PLGA, PEG-p(Glu), PEG-PLA-PEG, and PEG-p(Asp).
Specific camptothecin pairing (SN-38 with irinotecan/topotecan/SN-38 glucuronide)
The hydrophobic camptothecin compound is 7-ethyl-10-hydroxylcamptothecin (SN-38) and the hydrophilic camptothecin compound is irinotecan, topotecan, or SN-38 glucuronide.
Controlled fraction of particles larger than 200 nm (DLS)
A proportion of the freeze-dried particles with a size more than 200 nm in the composition is 11.8% or less as measured by dynamic light scattering (DLS).
Absence of hypersensitivity-causing surfactant
The composition does not contain a surfactant that causes hypersensitivity.
Overall, the claim coverage is directed to a freeze-dried composition of <1 μm particles in which SN-38 and irinotecan, topotecan, or SN-38 glucuronide form an inner core, that inner core is surrounded by an outer shell formed from a selected amphiphilic block copolymer, and the formulation controls the >200 nm fraction while excluding hypersensitivity-causing surfactants.
Stated Advantages
Improved tumor inhibition and pharmacokinetics versus monolayer micelles in animal tests.
Stable before and after freeze-drying, maintaining a mono-distribution with a low fraction of particles larger than 200 nm.
Avoidance of hypersensitivity-causing surfactants.
Provides a safer pharmaceutical composition platform.
Documented Applications
Drug delivery system for camptothecin, including SN-38 and related camptothecin compounds, used to achieve tumor inhibition and improved pharmacokinetics in animal tests.
Uses animal test models for tumor efficacy, including mouse colorectal and pancreatic models as described in the partial content provided.
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