# US 12,758,496 B2 · Polyfunctional radical scavenger hydrogel formulation > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,758,496 B2 - Document ID: US12758496B2 - Status: Granted - Kind: B2 - Application number: 18/675,072 - Filed: 2024-05-27 - Published: 2024-10-24 - Granted: 2026-10-13 - Earliest claimed: 2015-01-02 - Assignees: RXOS Medical, Inc. - Applicants: RXOS Medical Inc. - Inventors: Richard M Millis; Jeffrey A Niezgoda; Rajagopalan Sridhar - Web page: https://patentgrep.com/patent/US12758496B2 ## CPC - A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)} - A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)} - A61K 31/13: Amines {(A61K31/04 takes precedence)} - A61K 31/15: Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) {; Imines (C—N=C)} - A61K 31/216: of acids having aromatic rings, e.g. benactizyne, clofibrate - A61K 31/445: Non condensed piperidines, e.g. piperocaine - A61K 33/38: Silver; Compounds thereof - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61K 47/32: Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone} - A61L 15/325: {Collagen} - A61L 15/44: Medicaments - A61L 15/60: Liquid-swellable gel-forming materials, e.g. super-absorbents - A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K) ## Abstract A polyfunctional radical scavenger hydrogel formulation providing extended protection of the extracellular space within a wound site. The polyfunctional radical scavenger hydrogel formulation is generally formed from a hydrogel, a first radical scavenger and a second radical scavenger differing from the first radical scavenger with respect to at least one property. A portion of the first radical scavenger included with the formation and/or second radical scavenger included within the formulation may be dissolved, suspended and/or bonded to a polymer of the hydrogel. ## Claims ### Claim 1 A method comprising the step of: contacting a polyfunctional free radical scavenger hydrogel composition with a wounded tissue; and wherein the polyfunctional free radical scavenger hydrogel composition comprises: a hydrogel; a first free radical scavenger, and a second free radical scavenger and wherein the first free radical scavenger comprises a sterically hindered amine of the general formula: wherein R1-1 is a carbon chain having a length of C1 to C12, wherein the carbon chain is linear, branched, cyclic, aromatic portion, or a combination thereof, wherein R2-1 is a carbon chain having a length of C1 to C12, wherein the carbon chain is linear, branched, cyclic, aromatic portion, or a combination thereof, wherein R3-1 is selected from the group consisting of H and a carbon chain having a length of C1 to C12, wherein the carbon chain is linear, branched, cyclic, aromatic portion, or a combination thereof, wherein R4-1 is selected from the group consisting of H and a carbon chain having a length of C1 to C12, wherein the carbon chain is linear, branched, cyclic, aromatic portion, or a combination thereof, wherein X1-1 is selected from the group consisting of H, OH, acrylate, methacrylate, N-(alkylcarboxyl)-acrylamide, and N-(alkyl carboxyl)-methacrylamide, wherein X2-1 is selected from the group consisting of H, OH, acrylate, methacrylate, N-(alkylcarboxyl)-acrylamide, and N-(alkyl carboxyl)-methacrylamide, wherein X3-1 is selected from the group consisting of H, OH, acrylate, methacrylate, N-(alkylcarboxyl)-acrylamide, and N-(alkyl carboxyl)-methacrylamide, wherein X4-1 is selected from the group consisting of H, OH, {dot over (O)} and O; and the second free radical scavenger is lipid soluble and wherein the second free radical scavenger is present in an amount to provide protection against reactive oxygen species within the wounded tissue, the second free radical scavenger comprising a sterically hindered nitrone of the general formula: wherein R1-4 is a carbon chain having a length of C1 to C12, wherein the carbon chain is linear, branched, cyclic, aromatic portion, or a combination thereof, wherein R2-4 is a carbon chain having a length of C1 to C12, wherein the carbon chain is linear, branched, cyclic, aromatic portion, or a combination thereof, wherein R3-4 is a carbon chain having a length of C1 to C12, wherein the carbon chain is linear, branched, cyclic, aromatic portion, or a combination thereof, wherein X1-4 is selected from the group consisting of H, OH, acrylate, methacrylate, N-(alkylcarboxyl)-acrylamide, and N-(alkyl carboxyl)-methacrylamide, wherein X2-4 is selected from the group consisting of H, OH, acrylate, methacrylate, N-(alkylcarboxyl)-acrylamide, and N-(alkyl carboxyl)-methacrylamide, wherein X3-4 is selected from the group consisting of H, OH, acrylate, methacrylate, N-(alkylcarboxyl)-acrylamide, and N-(alkyl carboxyl)-methacrylamide, and wherein Y is an aromatic moiety Y comprising one or more substituents that (1) increases lipid solubility; (2) limits cellular uptake across at least one cellular member within a wound site; or (3) both increases lipid solubility and limits cellular uptake across at least one cellular member within a wound site. ### Claim 2 (depends on 1) The method of claim 1, wherein the aromatic moiety Y is an aromatic ring having a substituent containing a carbon that is bonded to the nitrogen by the double bond and the lipid soluble aromatic moiety inhibits transfer of the sterically hindered nitrone across a cellular membrane; and wherein the first free radical scavenger slows degradation of the second free radical scavenger when: all or a portion of the first free radical scavenger is incorporated into the polyfunctional free radical scavenger hydrogel composition, the second free radical scavenger is incorporated into the polyfunctional free radical scavenger hydrogel composition or bonded to a polymer of the polyfunctional free radical scavenger hydrogel composition or another molecule, or the first free radical scavenger is incorporated into the polyfunctional free radical scavenger hydrogel composition and the second free radical scavenger is incorporated into the polyfunctional free radical scavenger hydrogel composition or bonded to a polymer of the polyfunctional free radical scavenger hydrogel composition or another molecule. ### Claim 3 (depends on 1) The method of claim 1, wherein the first free radical scavenger and the second free radical scavenger are suspended or dissolved within the hydrogel and wherein the aromatic moiety Y is fused with another aromatic ring, conjugated with another aromatic ring or both fused with another aromatic ring and conjugated with another aromatic ring. ### Claim 4 (depends on 1) The method of claim 1, wherein the wounded tissue includes a wound that has already been incurred prior to being contacted with the polyfunctional free radical scavenger hydrogel composition or a wound that has been surgically repaired. ### Claim 5 (depends on 1) The method of claim 1, wherein the lipid soluble aromatic moiety is not subject to cellular uptake across at least one cellular membrane within a wound and wherein the aromatic moiety Y comprises a halide containing substituent. ### Claim 6 (depends on 5) The method of claim 5, wherein the second free radical scavenger has a higher molecular weight than the first free radical scavenger. ### Claim 7 (depends on 1) The method of claim 1, wherein the wounded tissue is a surgical wound and the first free radical scavenger is present in an amount that provides protection of the surgical wound against free radicals. ### Claim 8 (depends on 1) The method of claim 1, wherein the first free radical scavenger and the second free radical scavenger are suspended in the hydrogel and wherein the aromatic moiety Y is lipid soluble and not subject to cellular uptake across at least one cellular membrane within the wounded tissue. ### Claim 9 (depends on 1) The method of claim 1, wherein the first free radical scavenger and the second free radical scavenger are dissolved in the hydrogel and wherein the aromatic moiety Y is lipid soluble and not subject to cellular uptake across at least one cellular membrane within the wounded tissue. ### Claim 10 (depends on 1) The method of claim 1, wherein the step of contacting the polyfunctional free radical scavenger hydrogel composition with the wounded tissue provides protection of an extracellular space and assists the wounded tissue in transitioning from an inflammation phase to a proliferation phase of wound healing and wherein the hydrogel is a polymer chosen from the group consisting of: polymers of collagen, triblock ethylene oxide, triblock propylene oxide, 2-hydroxyethyl methacrylate, acrylate, keratin, pectins, and polyvinylpyrrolidones; and wherein the aromatic moiety Y is a methyl phenyl aromatic moiety such that the sterically hindered nitrone is of the general formula: ### Claim 11 (depends on 1) The method of claim 1, wherein polyfunctional free radical scavenger hydrogel composition is a coating on a medical device chosen from the group consisting of: catheters, stents, artificial valves, organs, and organ parts, pulmonary filters and atrial appendage occlusions devices. ### Claim 12 (depends on 1) The method of claim 1, wherein step of contacting a polyfunctional free radical scavenger hydrogel composition with the wounded tissue comprises either applying the polyfunctional free radical scavenger hydrogel composition to tissues during surgical procedures where wounds are incurred or repaired or by contacting the wounded tissue with a medical device or a dental device coated with the polyfunctional free radical scavenger hydrogel composition. ### Claim 13 (depends on 1) The method of claim 1, wherein the polyfunctional free radical scavenger hydrogel composition is in the form of an ointment or a composition applied to a wound dressing. ### Claim 14 (depends on 1) The method of claim 1, wherein the polyfunctional free radical scavenger composition comprises a plurality of polyfunctional free radical scavengers and wherein the wounded tissue is surgically wounded tissue. ### Claim 15 (depends on 14) The method of claim 14, wherein the polyfunctional free radical scavengers consist of the first free radical scavenger and the second free radical scavenger and wherein the wounded tissue is surgically wounded tissue. ### Claim 16 A method of treating a wound site comprising wounded tissue in a human comprising the step of: applying a hydrogel composition to the wounded tissue; and wherein the hydrogel composition comprises: a hydrogel, a plurality of free radical scavengers comprising a hydroxylamine and a sterically hindered nitrone; wherein the hydroxylamine and the sterically hindered nitrone extend the protection of an extracellular space of the wound site by either: (1) the hydroxylamine kinetically protecting the sterically hindered nitrone from degradation or (2) the hydroxylamine and the sterically hindered nitrone are both bonded to a polymer of the hydrogel composition or another molecule such that the hydroxylamine has a zone of influence and the sterically hindered nitrone has a zone of influence and the zone of Influence of the hydroxylamine and the zone of influence of the nitrone are partially overlapping so that a first portion of the zone of influence of the sterically hindered nitrone is unaffected by the presence of the hydroxylamine while at the same time a second portion of the zone of influence of the sterically hindered nitrone is kinetically protected by the hydroxylamine from being degraded by at least one reactive oxygen species within the wound site; and wherein the sterically hindered nitrone is of the general formula: wherein R1-4 is a carbon chain having a length of C1 to C12, wherein the carbon chain is linear, branched, cyclic, aromatic portion, or a combination thereof, wherein R2-4 is a carbon chain having a length of C1 to C12, wherein the carbon chain is linear, branched, cyclic, aromatic portion, or a combination thereof, wherein R3-4 is a carbon chain having a length of C1 to C12, wherein the carbon chain is linear, branched, cyclic, aromatic portion, or a combination thereof, wherein X1-4 is selected from the group consisting of H, OH, acrylate, methacrylate, N-(alkylcarboxyl)-acrylamide, and N-(alkyl carboxyl)-methacrylamide, wherein X2-4 is selected from the group consisting of H, OH, acrylate, methacrylate, N-(alkylcarboxyl)-acrylamide, and N-(alkyl carboxyl)-methacrylamide, wherein X3-4 is selected from the group consisting of H, OH, acrylate, methacrylate, N-(alkylcarboxyl)-acrylamide, and N-(alkyl carboxyl)-methacrylamide, and wherein Y is an aromatic moiety Y comprising one or more substituents that (1) increases lipid solubility; (2) limits cellular uptake across at least one cellular member within a wound site; or (3) both increases lipid solubility and limits cellular uptake across at least one cellular member within a wound site. ### Claim 17 (depends on 16) The method of claim 16, wherein the hydrogel is applied to a surface of a medical device chosen from the group consisting of a catheter, a stent, and artificial valve, an organ, an organ parts, a pulmonary filter, and an atrial appendage occlusions device and wherein the aromatic moiety Y comprises a halide containing substituent. ### Claim 18 (depends on 16) The method of claim 16, wherein the hydrogel composition is in the form of an ointment and the step of applying the hydrogel composition to the wounded tissue comprises applying the hydrogel composition to the wounded tissue during surgical procedures and visceral soft tissue repairs. ### Claim 19 A method of treating a wound comprising the step of: applying a polyfunctional free radical scavenger hydrogel composition to a wound; and wherein the polyfunctional free radical scavenger hydrogel composition comprises a hydrogel; and a plurality of free radical scavengers that provide protection against reactive oxygen species within a wound; wherein the plurality of free radical scavengers is suspended or dissolved in the hydrogel and comprise a first free radical scavenger and a second free radical scavenger that is a lipid soluble nitrone comprising an aromatic moiety that (1) increases lipid solubility; (2) limits cellular uptake across at least one cellular member within a wound site; or (3) both increases lipid solubility and limits cellular uptake across at least one cellular member within a wound site; and wherein the first free radical scavenger present in an amount providing protection of the wound against reactive oxygen species within the wound, the first free radical scavenger comprising a sterically hindered amine of the general formula: wherein R1-1 is a carbon chain having a length of C1 to C12, wherein the carbon chain is linear, branched, cyclic, aromatic portion, or a combination thereof, wherein R2-1 is a carbon chain having a length of C1 to C12, wherein the carbon chain is linear, branched, cyclic, aromatic portion, or a combination thereof, wherein R3-1 is selected from the group consisting of H and a carbon chain having a length of C1 to C12, wherein the carbon chain is linear, branched, cyclic, aromatic portion, or a combination thereof, wherein R4-1 is selected from the group consisting of H and a carbon chain having a length of C1 to C12, wherein the carbon chain is linear, branched, cyclic, aromatic portion, or a combination thereof, wherein X1-1 is selected from the group consisting of H, OH, acrylate, methacrylate, N-(alkylcarboxyl)-acrylamide, and N-(alkyl carboxyl)-methacrylamide; wherein X2-1 is selected from the group consisting of H, OH, acrylate, methacrylate, N-(alkylcarboxyl)-acrylamide, and N-(alkyl carboxyl)-methacrylamide; wherein X3-1 is selected from the group consisting of H, OH, acrylate, N-(alkylcarboxyl)-acrylamide, and N-(alkyl carboxyl)-methacrylamide; and wherein X4-1 is selected from the group consisting of H, OH, {dot over (O)} and O—. ### Claim 20 (depends on 19) The method of claim 19, wherein the second free radical scavenger comprises a sterically hindered nitrone of the general formula: wherein R1-4 is a carbon chain having a length of C1 to C12, wherein the carbon chain is linear, branched, cyclic, aromatic portion, or a combination thereof, wherein R2-4 is a carbon chain having a length of C1 to C12, wherein the carbon chain is linear, branched, cyclic, aromatic portion, or a combination thereof, wherein R3-4 is a carbon chain having a length of C1 to C12, wherein the carbon chain is linear, branched, cyclic, aromatic portion, or a combination thereof, wherein X1-4 is selected from the group consisting of H, OH, acrylate, and methacrylate, N-(alkylcarboxyl)-acrylamide, and N-(alkyl carboxyl)-methacrylamide; wherein X2-4 is selected from the group consisting of H, OH, acrylate, and methacrylate, N-(alkylcarboxyl)-acrylamide, and N-(alkyl carboxyl)-methacrylamide; wherein X3-4 is selected from the group consisting of H, OH, acrylate, and methacrylate, N-(alkylcarboxyl)-acrylamide, and N-(alkyl carboxyl)-methacrylamide; and wherein Y is the aromatic moiety that (1) increases lipid solubility; (2) limits cellular uptake across at least one cellular member within a wound site; or (3) both increases lipid solubility and limits cellular uptake across at least one cellular member within a wound site.