Copolymers containing phosphorylcholine groups and methods of preparing and using the same
Inventors
Assignees
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Publication Number
US-9546229-B2
Publication Date
2017-01-17
Expiration Date
Abstract
Methods for synthesizing a random copolymer having a phosphorylcholine group. Syntheses involving a reaction mixture containing a chain transfer agent (CTA), a solvent, a hydrophobic methacrylate monomer, a 2-methacryloyloxyethyl phosphorylcholine (MPC) monomer, and, optionally, an initiator. The random copolymers produced by such synthesis methods having a polydispersity index (PDI) of less than about 1.3 and a peak molecular weight (Mp) of less than about 130,000. Polymer blends and medical devices including such random copolymers, and methods of treating a mammal using such random copolymers or medical devices.
Core Innovation
The invention is directed to a method of synthesizing a random copolymer comprising a phosphorylcholine group using RAFT-based polymerization. The method combines at least one hydrophobic methacrylate monomer with an alcohol solvent having R3—OH, wherein R3 is an alkyl group having 1 to 4 carbon atoms, to produce a microemulsion before preparing a reaction mixture. The hydrophobic methacrylate monomer droplets in the microemulsion are stabilized by the 2-methacryloyloxyethyl phosphorylcholine (MPC) monomer.
A reaction mixture is prepared by combining the microemulsion with a chain transfer agent (CTA) comprising a thiocarbonylthio group, MPC monomer, and an initiator. The hydrophobic methacrylate monomer and the MPC monomer are polymerized at a reaction temperature of 80°C or above to form the random copolymer. The copolymerization uses a CTA comprising a thiocarbonylthio group and an initiator, with RAFT-based formation of the random copolymer.
The random copolymer is characterized by a polydispersity index (PDI) of less than about 1.3 and a peak molecular weight (Mp) of less than about 130,000. The method enables controllable repeating-unit composition via the MPC/phosphorylcholine mole fraction, with ranges described for phosphorylcholine repeating units and hydrophobic repeating units. The disclosed approach is linked to biomedical use through improved biocompatibility/biodistribution and excretion in rat urine while maintaining the stated polymer properties, and to medical device use through copolymers and blends including stents and drug-eluting coatings.
Claims Coverage
The partial content provides three independent claims (one corresponding to independent_claim_id clm-00001, one to clm-00009, and one to clm-00016). Across these independent claims, the inventive features include microemulsion-assisted RAFT synthesis of a phosphorylcholine-containing random copolymer using a thiocarbonylthio CTA, MPC-stabilized microemulsion droplets, specified alcohol solvent, polymerization at 80°C or above, and polymer property limits such as PDI and peak molecular weight.
MPC-stabilized microemulsion formation with hydrophobic methacrylate monomer
The method includes combining at least one hydrophobic methacrylate monomer and a solvent to produce a microemulsion before preparing a reaction mixture, wherein droplets of the hydrophobic methacrylate monomer in the microemulsion are stabilized by the MPC monomer.
Thiocarbonylthio CTA and initiator reaction mixture for RAFT random copolymerization
The method prepares the reaction mixture by combining the microemulsion with at least one chain transfer agent (CTA) comprising a thiocarbonylthio group, a 2-methacryloyloxyethyl phosphorylcholine (MPC) monomer, and an initiator.
Alcohol solvent and polymerization at 80°C or above
The method uses a solvent comprising an alcohol having the formula R3—OH, wherein R3 is an alkyl group having 1 to 4 carbon atoms, and polymerizes the hydrophobic methacrylate monomer and the MPC monomer at a reaction temperature of 80°C or above to form the random copolymer.
Specified random copolymer properties with PDI and peak molecular weight limits
The random copolymer formed by the polymerization step has a polydispersity index (PDI) of less than about 1.3 and a peak molecular weight (Mp) of less than about 130,000.
Initiator, CTA, and hydrophobic methacrylate monomer selections
The independent claim includes specific options for the initiator, and specifies that the CTA comprises thiocarbonylthio group-containing CTAs, and that the at least one hydrophobic methacrylate monomer comprises hydrophobic methacrylate monomers as recited in the claim.
Tightened PDI limit and composition bounds
One independent claim further specifies a PDI of less than about 1.2 and, in related disclosed constraints in the independent set, composition bounds for phosphorylcholine repeating units and hydrophobic repeating units are stated in the provided partial content.
Across the independent claims, the core claim coverage is the microemulsion-assisted RAFT method that stabilizes hydrophobic methacrylate monomer droplets with MPC, uses a thiocarbonylthio CTA and an initiator in an alcohol solvent, polymerizes at 80°C or above to form a phosphorylcholine-containing random copolymer, and enforces PDI and peak molecular weight limits. The independent claims further narrow the scope by enumerating particular CTA and initiator options and, in one instance, a tighter PDI limit.
Stated Advantages
Improved biocompatibility/biodistribution.
Ability of such copolymers to be excreted in rat urine while maintaining PDI and peak molecular weight.
Drawbacks of conventional radical polymerization are addressed by the disclosed RAFT-based approach.
Documented Applications
Medical devices such as stents and drug-eluting coatings, including copolymers and blends used in medical device contexts.
Radiopaque coatings/agents associated with the disclosed copolymers.
Biodegradable/bioresorbable medical device aspects are linked to copolymers and blends.
Urinary excretion in rats is stated in relation to the disclosed copolymers.
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