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Publication Number
US-11273226-B2
Publication Date
2022-03-15
Expiration Date
Abstract
Aspects of the invention described herein include a hydrogel prodrug and methods of making a hydrogel prodrug for drug delivery. Also contemplated are methods of treating, inhibiting, ameliorating or inhibiting a disease or disorder. Without being limiting, the methods for treatment can be directed to a cancer, HIV, a virus, pain, a bacterial infection, a neurological disorder, hemorrhaging, multiple sclerosis, diabetes, high blood pressure, Alzheimer's, or inhibiting a fungal growth in a subject in need.
Core Innovation
The invention provides hydrogel prodrugs formed by conjugating amine-containing drugs with acrylates to produce polymer prodrugs, followed by polymerization and free-radical cross-linking to form a hydrogel prodrug with a backbone structure. The reacting comprises a polymerization reaction, and the cross-linking is carried out in the presence of a free radical initiator and a catalyst in a reaction mixture. The resulting hydrogel prodrug is made as a backbone polymer that is cross-linked from the polymer prodrug and is described in microparticle form.
In one aspect, a hydrogel prodrug delivery system is formed from amine-containing drugs conjugated to acrylates, including optional chemical spacer units, and the system is cross-linked to generate a hydrogel. The document describes formulations and processing options for producing dosage forms and device-like structures, including films, dressings, scaffolds, tablets, capsules, implants, microparticles, and pills. It also describes multi-drug hydrogel prodrug compositions by blending distinct hydrogel prodrugs prior to cross-linking, thereby forming a cross-linked hydrogel backbone structure.
The disclosure additionally references targeting moieties, different release or degradation time ranges, and examples of initiators and catalysts. It further describes hydrogel prodrugs in microparticle form and mentions flexible geometries including films, microparticles, and implants, along with examples of mesalamine and tranexamic acid hydrogel prodrugs evaluated for release and degradation-coupled release behavior.
Claims Coverage
The independent claim coverage centers on making a hydrogel prodrug in microparticle form via amine–acrylate conjugation to form a polymer prodrug, followed by free-radical cross-linking to form a cross-linked backbone structure. Across the items, the claim set includes 7 inventive features, with dependent refinements that add catalyst and initiator loading ranges, named initiators, defined acrylates, selected drugs or drug classes, and multi-drug hydrogel prodrug compositions.
Hydrogel prodrug in microparticle form manufacturing workflow
Providing at least one drug that comprises at least one amine group; providing at least one acrylate; reacting the at least one acrylate with the at least one amine group of the at least one drug thereby producing at least one polymer prodrug, wherein the reacting comprises a polymerization reaction; and cross-linking the at least one polymer prodrug in the presence of a free radical initiator and a catalyst in a reaction mixture thereby making the hydrogel prodrug, wherein the hydrogel prodrug comprises a backbone structure, wherein the backbone structure comprises polymerized polymer prodrug; wherein the hydrogel prodrug is in microparticle form.
Catalyst loading relative to polymer prodrug
The catalyst is present at 1–10 wt% relative to the at least one polymer prodrug.
Free radical initiator loading relative to polymer prodrug
The free radical initiator is included at 1–10 wt% relative to the at least one polymer prodrug.
Free radical initiator selected from named initiators
The free radical initiator is selected from ammonium persulfate or 2,2-dimethoxy-2-phenylacetophenone.
Acrylate selected from defined acrylates
The at least one acrylate is chosen from a defined group of named acrylates.
Selected drug group for amine-containing drug
The method uses at least one selected drug chosen from a specified group of therapeutic agents and drug classes.
Multi-drug hydrogel prodrug compositions
Distinct hydrogel prodrugs are blended prior to cross-linking to form a cross-linked hydrogel backbone structure.
Overall, the claims are directed to forming a microparticle hydrogel prodrug by polymerizing an amine-containing drug with an acrylate to create a polymer prodrug, then cross-linking the polymer prodrug using a free radical initiator and a catalyst to form a backbone structure. Dependent and related features further narrow initiator and acrylate selections, impose catalyst and initiator wt% ranges, and include multi-drug hydrogel prodrug compositions.
Stated Advantages
Controlled, localized drug delivery.
Constant or zero-order type release synchronized with polymer degradation.
Reduced burst release.
Simplified one-step synthesis.
Flexible fabrication into various geometries including microparticles.
Zero-order/constant-release kinetics.
Synchronized degradation and drug release.
Shelf stability.
Flexible geometries including films, microparticles, and implants.
Documented Applications
Hydrogel prodrug systems for mesalamine, with reported observations related to drug incorporation and drug release kinetics.
Hydrogel prodrug systems for tranexamic acid, with reported observations related to drug incorporation and drug release kinetics.
Hydrogel prodrug systems incorporating targeting moieties such as tumor cell ligands or cancer antigens.
Hydrogel prodrugs formulated in microparticle form, including injectable microparticles and implants.
Hydrogel prodrugs used as thin films, including thin-film geometries.
Hydrogel prodrugs described for wound dressing as an intended geometry/use context.
Hydrogel prodrugs demonstrated with mesalamine and tranexamic acid hydrogel prodrugs and evaluated for release and degradation-coupled release behavior.
cancer
HIV
viral infection
pain
wounds
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