Sustained release of bioactive factors from zwitterionic hydrogels
Inventors
Krebs, Melissa D. • Sener Yildirim, Gulsu
Assignees
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Publication Number
US-10653783-B2
Publication Date
2020-05-19
Expiration Date
Abstract
Methods of producing microporous zwitterionic cryogels are described, wherein the cryogels are useful for sustaining release of therapeutic agents. The disclosed cryogels overcome several limitations associated with existing compositions, for example the disclosed cryogels have high loading efficiencies and a sustained release profile with minimal burst of up to 4 months or more. The characteristics of the disclosed cryogels can be varied by altering monomer (e.g. zwitterion) and crosslinker selection. The amount of monomer contained in the hydrogel may also be varied to aid in controlling the cryogel's chemistry.
Core Innovation
The invention relates to microporous zwitterionic cryogels for sustained therapeutic protein release. The problem addressed is improved protein loading efficiency while reducing burst release and providing sustained release over an extended period.
The disclosed cryogel is formed from a zwitterionic monomer identified as 2-(methylacryloyloxy)ethyl]dimethyl-(3-sulfoproplyl)ammonium hydroxide (SBMA) combined with a crosslinking agent selected from glycerol dimethyacrylate, N,N′-methylbis(acrylamide), and polyethylene glycol, and one or more initiator compounds in an aqueous solution. The aqueous solution is cooled to at least −20 °C to crosslink the monomers to form the cryogel, followed by thawing to room temperature and washing to remove unreacted monomers, crosslinking agents, and initiator compounds.
The cryogel produced has an average pore size greater than about 50 μm and less than about 100 μm. The microporous cryogel structure promotes higher protein encapsulation and steadier release, including reduced burst release and sustained release for about four months or more, with release behavior described as dependent on pH.
Claims Coverage
The independent claim set centers on a cryogel-making method that defines specific zwitterionic monomer chemistry, a selected crosslinking agent set, cryogelation by cooling to at least −20 °C, post-thaw washing, and a microporous cryogel having an average pore size greater than about 50 μm and less than about 100 μm. Dependent claims mainly refine crosslinker selection and add optional therapeutic-agent loading and additional processing steps.
Cryogel method using SBMA zwitterionic monomer with selected crosslinker and initiators in aqueous solution
Mixing a zwitterionic monomer of 2-(methylacryloyloxy)ethyl]dimethyl-(3-sulfoproplyl)ammonium hydroxide and a crosslinking agent selected from glycerol dimethyacrylate, N,N′-methylbis(acrylamide), and polyethylene glycol, with one or more initiator compounds in an aqueous solution.
Cryogelation by cooling to at least −20 °C followed by thawing
Cooling the aqueous solution to at least −20 °C while the monomers are crosslinked to form the cryogel, and thawing the cryogel to room temperature.
Washing to remove unreacted components to yield microporous cryogel with defined pore size
Washing the cryogel to remove unreacted monomers, crosslinking agents, and initiator compounds, wherein the cryogel has an average pore size greater than about 50 μm and less than about 100 μm.
Optional therapeutic-agent loading and protein therapeutic agents
Adding a therapeutic agent to the aqueous solution before cooling; wherein the therapeutic agent is a protein.
Optional rehydration of a dried cryogel
Further comprising the step of rehydrating the dried cryogel.
Overall, the claim coverage is focused on a specific SBMA-based zwitterionic cryogel preparation that uses cooling-based cryogelation, post-thaw washing, and produces a microporous cryogel with an average pore size between about 50 μm and about 100 μm, with dependent claims refining crosslinking-agent options and adding optional therapeutic-agent loading, including proteins, and optional rehydration.
Stated Advantages
Improved loading efficiency and reduced burst release, while providing sustained release continuing for about four months or more.
Cryogelation yields interconnected macropores and results in higher protein encapsulation and steadier release.
Reduced burst release and sustained protein release over an extended time.
Documented Applications
Implants and coatings for therapeutic delivery.
Ophthalmic contact lenses or ophthalmic contact lens cases.
Subcutaneous delivery.
Antiviral or microbicide concepts, including vaginal ring concepts.
Hormone delivery concepts.
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