Method of manufacturing a pharmaceutical composition having chelating type complex micelles
Inventors
Wang, Chau-Hui • Chen, Chia-Hung • Lin, Johnson • Chen, Jing-Yi • Liao, Wei-Chuan
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-9211341-B2
Publication Date
2015-12-15
Expiration Date
Abstract
This invention provides Chelating Complex Micelles as a drug carrier. The Chelating Complex Micelles can load drugs without changing their structure, and therefore extend the half-life of drugs in the human body. The chelating complex micelles contain a metal ion core, at least one polymer, and at least one drug molecule. The metal ion is considered as a Lewis acid while polymer chain and drug molecules are referred to as Lewis bases. The drug molecule is linked to the polymer via forming coordinate bonds with metal ion, and then self-assembled to form chelating complex micelles as a drug carrier.
Core Innovation
Chelating complex micelles (CCM) are provided as a drug carrier formed by self-assembly of a ligand-bridged metal-ion core and a Lewis base drug with a Lewis base ligand. The self-assembled structure forms chelating complex micelles in which the Lewis base drug and the Lewis base ligand are linked together due to coordinate bonds with a ligand-free Lewis acid metal ion core at the same time as the assembly proceeds. The Lewis base ligand is poly(ethylene glycol)-b-poly(glutamic acid) (PEG-b-PGA).
A manufacturing method is described in which raw materials containing a Lewis base drug, a Lewis base ligand, and a ligand-free Lewis acid metal ion core are placed in a buffer solution followed by continuous mixing, thereby enabling the Lewis base drug, Lewis base ligand, and metal ion core to self-assemble into chelating complex micelles. In the specific example formulation, the raw materials include amifostine (WR-1065), PEG-b-PGA, and FeCl2, and the amifostine and PEG-b-PGA are linked together due to the forming of coordinate bonds with ferrous ion Fe2+ during self-assembly.
The described chelating complex micelles are characterized as a coordinate-bond linked drug-polymer carrier concept, with coordinate-bond linkage emphasized as preserving the drug structure while allowing loading of both hydrophilic and hydrophobic drugs. The document further describes micelle formation yielding approximately 10–300 nm micelles and reports in vitro dialysis release showing a reduced amifostine release profile under the described formulation conditions, along with extended drug half-life and an aim to reduce toxicity versus free drugs and covalent drug-polymer linkers.
Claims Coverage
The independent claim coverage focuses on two manufacturing methods for a pharmaceutical composition containing chelating type complex micelles. Across the two independent claims, the main inventive features are the self-assembly of a Lewis base drug with PEG-b-PGA mediated by a ligand-free Lewis acid metal ion core via coordinate bonds during continuous mixing, with one independent claim also restricting the components to amifostine, PEG-b-PGA, and FeCl2/Fe2+.
Coordinate-bond self-assembly to form chelating complex micelles with PEG-b-PGA
Providing a raw material containing a Lewis base drug, a Lewis base ligand, and a ligand-free Lewis acid metal ion core; placing the raw materials in a buffer solution followed by continuous mixing so the Lewis base drug, Lewis base ligand, and Lewis acid metal ion core self-assemble to form chelating complex micelles; wherein the Lewis base drug and the Lewis base ligand are linked together due to coordinate bonds with the Lewis acid metal ion core at the same time, wherein the Lewis base ligand is poly(ethylene glycol)-b-poly(glutamic acid) (PEG-b-PGA).
Amifostine/PEG-b-PGA/Fe2+-mediated coordinate-bond chelating micelles
Providing a raw material containing amifostine, a PEG-b-PGA and FeCl2; placing the raw material in a buffer solution followed by continuous mixing such that the amifostine, the PEG-b-PGA, and the ferrous ion Fe2+ self-assemble to form chelating complex micelles, wherein the amifostine and the PEG-b-PGA are linked together due to coordinate bonds with the ferrous ion Fe2+ at the same time.
Both independent claims center on manufacturing pharmaceutical compositions where chelating complex micelles are formed by self-assembly in a buffer with continuous mixing, and where the drug is coordinate-bond linked to PEG-b-PGA through a ligand-free Lewis acid metal ion core.
Stated Advantages
Coordinate-bond linkage is described as enabling the preservation of drug structure.
Chelating complex micelles are described as enabling loading of hydrophilic and hydrophobic drugs.
The document states that the approach extends drug half-life.
The document states an aim to reduce toxicity compared with free drugs and covalent drug-polymer linkers.
Documented Applications
The described imaging/therapy monitoring possibilities are associated with imaging nuclei including Gd(III), Tc-99m, Ga-68, Re-188, and In-111.
A targeting moiety is mentioned as optional (folic acid).
The document describes in vitro dialysis release evaluation for amifostine from the chelating complex micelles formulation.
Interested in licensing this patent?