# US RE46,234 E1 · Tissue adhesive and sealant comprising polyglycerol aldehyde > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US RE46,234 E1 - Document ID: USRE46234E1 - Status: Granted - Kind: E1 - Application number: 14/628,909 - Filed: 2015-02-23 - Granted: 2016-12-13 - Earliest claimed: 2009-03-27 - Assignees: Actamax Surgical Materials, LLC - Applicants: Actamax Surgical Materials, LLC - Inventors: Henry Keith Chenault - Web page: https://patentgrep.com/patent/USRE46234E1 ## CPC - A61L 24/0031: {Hydrogels or hydrocolloids} - A61L 24/043: {Mixtures of macromolecular materials} - A61L 24/046: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds (A61L24/043 takes precedence)} - C08G 65/323: containing halogens - C08G 65/329: with organic compounds - C08G 65/33306: {acyclic} - C08L 71/02: Polyalkylene oxides - C09J 171/02: Polyalkylene oxides - C08G 2650/50: containing nitrogen, e.g. polyetheramines or Jeffamines(r) - C08L 2203/02: for biomedical use - C08L 2666/22: Macromolecular compounds not provided for in C08L2666/16 - C08L2666/20 - 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) - C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS - C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06) - C09J: ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES (preparation of glue or gelatine C09H) ## Abstract A tissue adhesives and sealant formed by reacting a polyglycerol aldehyde with a water-dispersible, multi-arm amine is described. The tissue adhesive and sealant may be useful for medical and veterinary applications, including, but not limited to, wound closure, supplementing or replacing sutures or staples in internal surgical procedures such as intestinal anastomosis and vascular anastomosis, tissue repair, preventing leakage of fluids such as blood, bile, gastrointestinal fluid and cerebrospinal fluid, ophthalmic procedures, drug delivery, and to prevent post-surgical adhesions. ## Claims ### Claim 1 A kit comprising: a) at least one polyglycerol aldehyde having aldehyde groups, said polyglycerol aldehyde having a number-average molecular weight of about 400 1,000 to about 20,000 Daltons and the general formula: wherein; A is either (a) a hydrocarbyl group derived by removing on one or more hydroxyl groups from an alcohol or polyol containing 1 to 20 carbon atoms and 1 to 8 hydroxyl groups or (b) an oxahydrocarbyl or polyoxahydrocarbyl group derived by removing or or more hydroxyl groups from the reaction product of (I) an alcohol or polyol containing 1 to 20 carbon atoms and 1 to 8 hydroxyl groups and (II) one or more cyclic ethers, wherein the Mn of the reaction product is less than or equal to 5,000 Da; R1 is a hydrogen atom, a 1 to 8-carbon hydrocarbyl group, R2—O—[R3—CHO]p R2—[O—R3—CHO]p, or R3—CHO; R2 is a polymeric segment comprising 1 to 270 glycerol units connected by ether linkages, wherein each —[O—R3—CHO]p, or —[O—R3—CHO]m group is attached directly to R2 by a carbon-oxygen single bond, and wherein no carbon atom that bears an —[O—R3—CHO]p, or —[O—R3—CHO]m group also bears a hydroxyl group, a second —[O—R3—CHO]p, or —[O—R3—CHO]m group, or a bond to a second oxygen atom; R3 is a hydrocarbylene group containing 1 to 8 carbon atoms; n=1 to 8; m*n=3 to 170; and p=1 to 40, wherein n, m and p are intergers; and an equivalent weight per aldehyde group of about 100 to about 3,000 Daltons; and b) at least one water-dispersible, multi-arm amine wherein at least three of the arms are terminated by at least one primary amine group, wherein the multi-arm amine has a number-average molecular weight of about 450 to about 200,000 Daltons. ### Claim 2 (depends on 1) The kit according to claim 1 wherein the polyglycerol aldehyde is contained in a first aqueous solution or dispersion and the water-dispersible, multi-arm amine is contained in a second aqueous solution or dispersion. ### Claim 3 (depends on 2) The kit according to claim 2 wherein the first aqueous solution or dispersion contains the polyglycerol aldehyde at a concentration of about 5% to about 40% by weight relative to the total weight of the solution or dispersion. ### Claim 4 (depends on 2) The kit according to claim 2 wherein the second aqueous solution or dispersion contains the water-dispersible, multi-arm amine at a concentration of about 5% to about 70% by weight relative to the total weight of the solution or dispersion. ### Claim 5 (depends on 1) The kit according to claim 1 wherein the cyclic ethers are selected from the group consisting of oxirane, methyloxirane, oxetane and oxolane. ### Claim 6 (depends on 1) The kit according to claim 1 wherein in the general formula A is CH3CH2C(CH2—)3, derived by removing three hydroxyl groups from trimethylolpropane; R2 is a polymeric segment consisting of 1 to 60 glycerol units connected by ether linkages; R3 is —CH2—; R1 is a hydrogen atom, R2—O—[R3—CHO]p R2—[O—R3—CHO]p, or R3—CHO; m=1 to 30; n=3; and p=1 to 30. ### Claim 7 (depends on 1) The kit according to claim 1 wherein the polyglycerol aldehyde has a degree of branching of about 10% to about 99.9%. ### Claim 8 (depends on 1) The kit according to claim 1 wherein the water-dispersible, multi-arm amine is selected from the group consisting of water dispersible multi-arm polyether amines, amino-terminated dendritic polyamidoamines, and multi-arm branched end amines. ### Claim 9 (depends on 1) The kit according to claim 1 wherein the water-dispersible, multi-arm amine is a water dispersible multi-arm polyether amine. ### Claim 10 (depends on 9) The kit according to claim 9 wherein the water dispersible multi-arm polyether amine is selected from the group consisting of amino-terminated star polyethylene oxides, amino-terminated dendritic polyethylene oxides, amino-terminated comb polyethylene oxides, amino-terminated star polypropylene oxides, amino-terminated dendritic polypropylene oxides, amino-terminated comb polypropylene oxides, amino-terminated star polyethylene oxide-polypropylene oxide copolymers, amino-terminated dendritic polyethylene oxide-polypropylene oxide copolymers, amino-terminated comb polyethylene oxide-polypropylene oxide copolymers, and polyoxyalkylene triamines. ### Claim 11 A dried hydrogel formed by a process comprising the steps of: a) combining in a solvent (i) at least one polyglycerol aldehyde having aldehyde groups, said polyglycerol aldehyde having a number-average molecular weight of about 400 1,000 to about 20,000 Daltons and the general formula: wherein: A is either (a) a hydrocarbyl group derived by removing on one or more hydroxyl groups from an alcohol or polyol containing 1 to 20 carbon atoms and 1 to 8 hydroxyl groups or (b) an oxahydrocarbyl or polyoxahydrocarbyl group derived by removing or or more hydroxyl groups from the reaction product of (I) an alcohol or polyol containing 1 to 20 carbon atoms and 1 to 8 hydroxyl groups and (II) one or more cyclic ethers, wherein the Mn of the reaction product is less than or equal to 5,000 Da; R1 is a hydrogen atom, a 1 to 8-carbon hydrocarbyl group, R2—O—[R3—CHO]p R2—[O—R3—CHO]p, or R3—CHO; R2 is a polymeric segment comprising 1 to 270 glycerol units connected by ether linkages, wherein each —[O—R3—CHO]p, or —[O—R3—CHO]m group is attached directly to R2 by a carbon-oxygen single bond, and wherein no carbon atom that bears an —[O—R3—CHO]p, or —[O—R3—CHO]m group also bears a hydroxyl group, a second —[O—R3—CHO]p, or —[O—R3—CHO]m group, or a bond to a second oxygen atom; R3 is a hydrocarbylene group containing 1 to 8 carbon atoms; n=1 to 8; m*n=3 to 170; and p=1 to 40, wherein n, m and p are intergers; and an equivalent weight per aldehyde group of about 100 to about 3,000 Daltons; with (ii) at least one water-dispersible, multi-arm amine, wherein at least three of the arms are terminated by at least one primary amine group, said multi-arm amine having a number-average molecular weight of about 450 to about 200,000 Daltons, to forma hydrogel; and b) treating said hydrogel to remove at least a portion of said solvent to form the dried hydrogel. ### Claim 12 (depends on 11) The dried hydrogel according to claim 11 wherein said dried hydrogel is in the form of a film. ### Claim 13 (depends on 11) The dried hydrogel according to claim 11 wherein the process further comprises the step of comminuting the dried hydrogel to form finely divided particles. ### Claim 14 A composition comprising the reaction product of: a) at least one polyglycerol aldehyde having aldehyde groups, said polyglycerol aldehyde having a number-average molecular weight of about 400 1,000 to about 20,000 Daltons and the general formula: wherein; A is either (a) a hydrocarbyl group derived by removing on or more hydroxyl groups from an alcohol or polyol containing 1 to 20 carbon atoms and 1 to 8 hydroxyl groups or (b) an oxahydrocarbyl or polyoxahydrocarbyl group derived by removing or or more hydroxyl groups from the reaction product of (I) an alcohol or polyol containing 1 to 20 carbon atoms and 1 to 8 hydroxyl groups and (II) one or more cyclic ethers, wherein the Mn of the reaction product is less than or equal to 5,000 Da; R1 is a hydrogen atom, a 1 to 8-carbon hydrocarbyl group, R2—O—[R3—CHO]p R2—[O—R3—CHO]p, or R3—CHO; R2 is a polymeric segment comprising 1 to 270 glycerol units connected by ether linkages, wherein each —[O—R3—CHO]p, or —[O—R3—CHO]m group is attached directly to R2 by a carbon-oxygen single bond, and wherein no carbon atom that bears an —[O—R3—CHO]p, or —[O—R3—CHO]m group also bears a hydroxyl group, a second —[O—R3—CHO]p, or —[O—R3—CHO]m group, or a bond to a second oxygen atom; R3 is a hydrocarbylene group containing 1 to 8 carbon atoms; n=1 to 8; m*n=3 to 170; and p=1 to 40, wherein n, m and p are intergers; and an equivalent weight per aldehyde group of about 100 to about 3,000 Daltons; and b) at least one water-dispersible, multi-arm amine wherein at least three of the arms are terminated by at least one primary amine group, said multi-arm amine having a number-average molecular weight of about 450 to about 200,000 Daltons. ### Claim 15 A crosslinked hydrogel composition comprising: a) at least one polyglycerol aldehyde having aldehyde groups, said polyglycerol aldehyde having a number-average molecular weight of about 400 1,000 to about 20,000 Daltons and the general formula: wherein: A is either (a) a hydrocarbyl group derived by removing on or more hydroxyl groups from an alcohol or polyol containing 1 to 20 carbon atoms and 1 to 8 hydroxyl groups or (b) an oxahydrocarbyl or polyoxahydrocarbyl group derived by removing or or more hydroxyl groups from the reaction product of (I) an alcohol or polyol containing 1 to 20 carbon atoms and 1 to 8 hydroxyl groups and (II) one or more cyclic ethers, wherein the Mn of the reaction product is less than or equal to 5,000 Da; R1 is a hydrogen atom, a 1 to 8-carbon hydrocarbyl group, R2—O—[R3—CHO]p R2—[O—R3—CHO]p, or R3—CHO; R2 is a polymeric segment comprising 1 to 270 glycerol units connected by ether linkages, wherein each —[O—R3—CHO]p, or —[O—R3—CHO]m group is attached directly to R2 by a carbon-oxygen single bond, and wherein no carbon atom that bears an —[O—R3—CHO]p, or —[O—R3—CHO]m group also bears a hydroxyl group, a second —[O—R3—CHO]p, or —[O—R3—CHO]m group, or a bond to a second oxygen atom; R3 is a hydrocarbylene group containing 1 to 8 carbon atoms; n=1 to 8; m*n=3 to 170; and p=1 to 40, wherein n, m and p are intergers; and an equivalent weight per aldehyde group of about 100 to about 3,000 Daltons; and b) at least one water-dispersible, multi-arm amine wherein at least three of the arms are terminated by at least one primary amine group, said multi-arm amine having a number-average molecular weight of about 450 to about 200,000 Daltons; wherein said at least one polyglycerol aldehyde and said at least one water-dispersible, multi-arm amine are crosslinked through covalent bonds formed between the aldehyde groups of the polyglycerol aldehyde and the primary amine groups of the water-dispersible, multi-arm amine. ### Claim 16 (depends on 15) The crosslinked hydrogel composition according to claim 15 wherein the cyclic ethers are selected from the group consisting of oxirane, methyloxirane, oxetane and oxolane. ### Claim 17 (depends on 15) The crosslinked hydrogel composition according to claim 15 wherein in the general formula A is CH3CH2C(CH2—)3, derived by removing three hydroxyl groups from trimethylolpropane; R2 is a polymeric segment consisting of 1 to 60 glycerol units connected by ether linkages; R3 is —CH2—; R1 is a hydrogen atom, R2—O—[R3—CHO]p R2—[O—R3—CHO]p, or R3—CHO; m=1 to 30; n=3; and p=1 to 30. ### Claim 18 (depends on 15) The crosslinked hydrogel composition according to claim 15 wherein the water-dispersible, multi-arm amine is selected from the group consisting of water dispersible multi-arm polyether amines, amino-terminated dendritic polyamidoamines, and multi-arm branched end amines. ### Claim 19 (depends on 15) The crosslinked hydrogel composition according to claim 15 wherein the water-dispersible, multi-arm amine is a water dispersible multi-arm polyether amine. ### Claim 20 (depends on 19) The crosslinked hydrogel composition according to claim 19 wherein the water dispersible multi-arm polyether amine is selected from the group consisting of amino-terminated star polyethylene oxides, amino-terminated dendritic polyethylene oxides, amino-terminated comb polyethylene oxides, amino-terminated star polypropylene oxides, amino-terminated dendritic polypropylene oxides, amino-terminated comb polypropylene oxides, amino-terminated star polyethylene oxide-polypropylene oxide copolymers, amino-terminated dendritic polyethylene oxide-polypropylene oxide copolymers, amino-terminated comb polyethylene oxide-polypropylene oxide copolymers, and polyoxyalkylene triamines. ### Claim 21 A method for applying a coating to an anatomical site on tissue of a living organism comprising: applying to the site a) at least one polyglycerol aldehyde having aldehyde groups, said polyglycerol aldehyde having a number-average molecular weight of about 400 1,000 to about 20,000 Daltons and the general formula: wherein: A is either (a) a hydrocarbyl group derived by removing on or more hydroxyl groups from an alcohol or polyol containing 1 to 20 carbon atoms and 1 to 8 hydroxyl groups or (b) an oxahydrocarbyl or polyoxahydrocarbyl group derived by removing or or more hydroxyl groups from the reaction product of (I) an alcohol or polyol containing 1 to 20 carbon atoms and 1 to 8 hydroxyl groups and (II) one or more cyclic ethers, wherein the Mn of the reaction product is less than or equal to 5,000 Da; R1 is a hydrogen atom, a 1 to 8-carbon hydrocarbyl group, R2—O—[R3—CHO]p R2—[O—R3—CHO]p, or R3—CHO; R2 is a polymeric segment comprising 1 to 270 glycerol units connected by ether linkages; wherein each —[O—R3—CHO]p, or —[O—R3—CHO]m group is attached directly to R2 by a carbon-oxygen single bond, and wherein no carbon atom that bears an —[O—R3—CHO]p, or —[O—R3—CHO]m group also bears a hydroxyl group, a second —[O—R3—CHO]p, or —[O—R3—CHO]m group, or a bond to a second oxygen atom; R3 is a hydrocarbylene group containing 1 to 8 carbon atoms; n=1 to 8; m*n=3 to 170; and p=1 to 40, wherein n, m and p are intergers; and an equivalent weight per aldehyde group of about 100 to about 3,000 Daltons; followed by b) at least one water-dispersible, multi-arm amine wherein at least three of the arms are terminated by a primary amine group, said multi-arm amine having a number-average molecular weight of about 450 to about 200,000 Daltons, or (b) followed by (a), or premixing (a) and (b); and applying the resulting mixture to the site before the resulting mixture completely cures. ### Claim 22 (depends on 21) The method according to claim 21 wherein the cyclic ethers are selected from the group consisting of oxirane, methyloxirane, oxetane and oxolane. ### Claim 23 (depends on 21) The method according to claim 21 wherein in the general formula A is CH3CH2C(CH2—)3, derived by removing three hydroxyl groups from trimethylolpropane; R2 is a polymeric segment consisting of 1 to 60 glycerol units connected by ether linkages; R3 is —CH2—; R1 is a hydrogen atom, R2—O—[R3—CHO]p R2—[O—R3—CHO]p, or R3—CHO; m=1 to 30; n=3; and p=1 to 30.