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-11793803-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 a method for manufacturing a population of freeze-dried particles with particle size of less than 1 μm. The freeze-dried particles comprise an inner core containing a hydrophobic camptothecin compound and a hydrophilic camptothecin compound, and an outer shell surrounding the inner core and formed of an amphiphilic block copolymer comprising a hydrophobic block and a hydrophilic block in a same chain.
The method includes mixing the hydrophobic camptothecin compound and the hydrophilic camptothecin compound in an aqueous solvent, mixing the resulting mixture with the amphiphilic block copolymer in an aqueous solvent to form particles comprising the inner core and the outer shell, and freeze-drying the particles obtained to provide the population of freeze-dried particles with particle size less than 1 μm. A proportion of the freeze-dried particles with a size more than 200 nm in the population obtained is 11.8% or less as measured by dynamic light scattering.
The hydrophobic camptothecin compound is selected from 7-ethyl-10-hydroxycamptothecin (SN-38), camptothecin, 10-hydroxycamptothecin, a pharmaceutical acceptable salt thereof, and a combination thereof. The hydrophilic camptothecin compound is selected from irinotecan, topotecan, belotecan, exatecan, lurtotecan, sinotecan, rubitecan, 9-nitrocamptothecin, 9-aminocamptothecin, gimatecan, 7-t-butyldimethylsilyl-10-hydroxycamptothecin, diflomotecan, elomotecan, a pharmaceutically acceptable salt thereof, a glucuronide metabolite thereof, and a glucuronide metabolite of the hydrophobic camptothecin-based compound, and a combination thereof.
Claims Coverage
The document includes one independent claim. It specifies a freeze-dried particle manufacturing method having an inner core with a hydrophobic and a hydrophilic camptothecin compound, an outer shell made from an amphiphilic block copolymer, and a DLS-based constraint on larger particles.
Freeze-dried particles with inner camptothecin core and outer amphiphilic block copolymer shell
A method for manufacturing a population of freeze-dried particles with particle size of less than 1 μm, wherein the freeze-dried particles comprise an inner core comprising a hydrophobic camptothecin compound and a hydrophilic camptothecin compound, and an outer shell surrounding the inner core, said outer shell being formed of an amphiphilic block copolymer.
Aqueous mixing to form inner core and outer shell before freeze-drying
The method comprises mixing the hydrophobic camptothecin compound and the hydrophilic camptothecin compound in an aqueous solvent, mixing the resulting mixture with the amphiphilic block copolymer in an aqueous solvent to form particles comprising the inner core and the outer shell, and freeze-drying the particles obtained to give the population of freeze-dried particles with particle size less than 1 μm.
Amphiphilic block copolymer hydrophobic and hydrophilic blocks in a same chain
The amphiphilic block copolymer comprises a hydrophobic block and a hydrophilic block in a same chain.
Camptothecin compound selections for hydrophobic and hydrophilic components
The hydrophobic camptothecin compound is selected from 7-ethyl-10-hydroxycamptothecin (SN-38), camptothecin, 10-hydroxycamptothecin, a pharmaceutical acceptable salt thereof, and a combination thereof, and the hydrophilic camptothecin compound is selected from irinotecan, topotecan, belotecan, exatecan, lurtotecan, sinotecan, rubitecan, 9-nitrocamptothecin, 9-aminocamptothecin, gimatecan, 7-t-butyldimethylsilyl-10-hydroxycamptothecin, diflomotecan, elomotecan, a pharmaceutically acceptable salt thereof, a glucuronide metabolite thereof, and a glucuronide metabolite of the hydrophobic camptothecin-based compound, and a combination thereof.
DLS constraint on proportion of particles larger than 200 nm
A proportion of the freeze-dried particles with a size more than 200 nm in the population obtained is 11.8% or less as measured by dynamic light scattering.
Across the independent claim, the core inventive concept is a freeze-dried particle manufacturing method that forms particles with a hydrophobic-and-hydrophilic camptothecin inner core and an outer shell from an amphiphilic block copolymer, followed by freeze-drying, while meeting a DLS-based limit on the proportion of particles larger than 200 nm.
Stated Advantages
Improved aqueous solubility.
Reduced macroparticle and reduced multimodal distributions after freeze-drying.
Enhanced accelerated stability.
Superior tumor inhibition and pharmacokinetics versus monolayer micelles.
Avoids problematic hypersensitivity surfactants.
Documented Applications
Pharmaceutical composition for cancer treatment, including tumor inhibition in HT-29 colorectal and AsPc-1 and MiaPaca-2 pancreatic models.
Use related to pharmacokinetics including increased bioavailability of SN-38 glucuronide compared with monolayer micelles, with pharmacokinetic evaluation in beagle dogs.
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