Hydrogels with biodegradable crosslinking
Inventors
Ashley, Gary W. • Santi, Daniel V. • Henise, Jeffrey C.
Assignees
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Publication Number
US-11179470-B2
Publication Date
2021-11-23
Expiration Date
Abstract
Hydrogels that degrade under appropriate conditions of pH and temperature by virtue of crosslinking compounds that cleave through an elimination reaction are described. The hydrogels may be used for delivery of various agents, such as pharmaceuticals.
Core Innovation
The invention provides a biodegradable hydrogel under physiological conditions. The hydrogel comprises one or more multi-armed PEG polymers crosslinked by a linker that decomposes by a beta elimination reaction. The linker is defined by Formula (1), with defined ranges and structural features for substituents X, z, Y, and Z2, and with coupling functionality that connects to multi-armed PEG polymers.
In the hydrogel, each linker of Formula (1) includes a first functional group, Z2, that is coupled to a first cognate group of a first multi-armed PEG polymer. The linker also includes one of R1, R2, or R5 comprising a second functional group that is coupled to a second cognate group of a second multi-armed PEG polymer. The possible functional groups on the linker and the manner in which they couple to PEG cognate groups are enumerated, with provisos governing the remaining R5 groups.
The disclosure further specifies structural and substituent constraints for the biodegradable, beta elimination-decomposing linker, including that R1, R2, and R5 are selected from defined classes and that particular ring-forming options and group selections apply. The claims are framed to cover hydrogels whose degradation behavior is linked to the beta elimination decomposition of the specified linker architecture.
Claims Coverage
The independent claim provides coverage for a biodegradable hydrogel under physiological conditions formed from multi-armed PEG polymers crosslinked by a beta elimination-decomposing linker defined by Formula (1), including enumerated first and second functional-group and cognate-group coupling options and defined linker substituent constraints. Dependent claims refine the coupling chemistry and linker parameters.
Biodegradable PEG hydrogel crosslinked by beta elimination linker
A hydrogel biodegradable under physiological conditions that comprises one or more multi-armed PEG polymers crosslinked by a linker that decomposes by a beta elimination reaction, wherein the linker is of Formula (1) with defined substituent features and with coupling to first and second multi-armed PEG polymers via functional groups and cognate groups.
Formula (1) linker coupling to first and second multi-armed PEG polymers
For each linker of Formula (1), a first functional group, Z2, is coupled to a first cognate group of a first multi-armed PEG polymer, and one of R1, R2, or R5 comprises a second functional group coupled to a second cognate group of a second multi-armed PEG polymer, where each said first and second functional group independently comprises N3, NH2, NH—CO2tBu, SH, StBu, maleimide, CO2H, CO2tBu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctyne, acrylate, or acrylamide, subject to the specified proviso regarding remaining R5 groups.
Defined R1, R2, and R5 substituent classes in the beta elimination linker
The linker of Formula (1) includes substituent selections where R3 and R4 are selected from the recited groups, and where R1 and R2, and/or R5 depending on the proviso scenarios, are independently selected from CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4, together with the specified alternatives governing which R group bears the second functional group and the associated constraints on the remaining R5 groups.
Overall, the claim coverage centers on a biodegradable hydrogel under physiological conditions made from multi-armed PEG polymers crosslinked using a beta elimination-decomposing linker defined by Formula (1), with explicit coupling via first and second functional-group pairs to PEG cognate groups and defined substituent and ring constraints for R1, R2, R3, R4, and R5.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Drug-loaded hydrogels where drugs are entrapped or covalently attached through elimination-releasable linkers (including examples involving exenatide/exendin-4).
Assessment of degradation and drug (or surrogate) release-time dependencies versus pH and substituent selection, including degelation time/half-life relationships.
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