Polysaccharide-based polymer tissue adhesive for medical use
View Patent ↗Tissue adhesives formed by reacting an oxidized polysaccharide with a water-dispersible multi-arm polyether amine, wherein at least three of the arms are terminated by primary amine groups, are disclosed. The use of the tissue adhesives for medical and veterinary applications such as topical wound closure; and surgical procedures, such as intestinal anastomosis, vascular anastomosis, tissue repair, and ophthalmic procedures; drug delivery; anti-adhesive applications; and as a bulking agent to treat urinary incontinence are described.
1. A kit comprising:
a) a first aqueous solution comprising an oxidized polysaccharide containing aldehyde groups, having a molecular weight of about 1,000 to about 1,000,000 Daltons, said oxidized polysaccharide having an equivalent weight per aldehyde group of about 90 to about 1500 Daltons, said solution containing from about 5% to about 40% by weight of the oxidized polysaccharide; and
b) a second aqueous solution comprising a water-dispersible, multi-arm polyether amine wherein at least three of the arms are terminated by a primary amine group, wherein the multi-arm polyether amine has a molecular weight of about 450 to about 200,000 Daltons, said solution containing from about 5% to about 70% by weight of the multi-arm polyether amine.
2. The kit according to claim 1 wherein the molecular weight of the oxidized polysaccharide is from about 3,000 to about 250,000 Daltons.
3. The kit according to claim 1 wherein the molecular weight of the multi-arm polyether amine is from about 2,000 to about 40,000 Daltons.
4. The kit according to claim 1 wherein the oxidized polysaccharide is selected from the group consisting of dextran, chitin, starch, agar, cellulose, and hyaluronic acid.
5. The kit according to claim 1 wherein the aldehyde groups on the oxidized polysaccharide of the first aqueous solution are in a stoichiometric excess relative to the amine groups on the multi-arm polyether amine of the second aqueous solution.
6. The kit according to claim 1 wherein the first and second aqueous solutions are sterilized.
7. The kit according to claim 1 wherein the first or second aqueous solution further comprises an additive selected from the group consisting of pH modifiers, viscosity modifiers, antimicrobials, colorants, healing promoters, surfactants, anti-inflammatory agents, thrombogenic agents, and radio-opaque compounds.
8. The kit according to claim 7 wherein said colorants are selected from the group consisting of FD&C Violet No. 2, D&C Green No. 6, D&C Green No. 5, and D&C Violet No. 2.
9. The kit according to claim 7 wherein said antimicrobial is triclosan.
10. The kit according to claim 1 wherein the first or second aqueous solution further comprises a pharmaceutical drug or therapeutic agent.
11. The kit according to claim 1 wherein the concentration of the oxidized polysaccharide in the first aqueous solution is from about 15% to about 30% by weight.
12. The kit according to claim 1 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, amino-terminated dendritic polyamidoamines, and polyoxyalkylene triamines.
13. The kit according to claim 1 wherein the multi-arm polyether amine is a star polyethylene glycol comprising eight arms terminated by a primary amine group and having a molecular weight of 10,000 Daltons.
14. The kit according to claim 1 wherein the concentration of the multi-arm polyether amine in the second aqueous solution is from about 20% to about 50% by weight.
15. The kit according to claim 1 wherein the second aqueous solution further comprises at least one other multi-functional amine having one or more primary amine groups, said multi-functional amine being present at a concentration of about 5% to about 1000% by weight relative to the amount of the multi-arm polyether amine in the solution.
16. The kit according to claim 15 wherein the multi-functional amine is selected from the group consisting of water-dispersible multi-arm polyether amines, linear and branched diamines, branched polyamines, cyclic diamines, aminoalkyltrialkoxysilanes, aminoalkyldialkoxyalkylsilanes, dihydrazides, linear polymeric diamines, comb polyamines, dihydrazides and polyhydrazides.
17. The kit according to claim 1 further comprising a third solution comprising at least one other multi-functional amine having one or more primary amine groups, said solution containing about 5% to about 100% by weight of the multi-functional amine relative to the total weight of the solution.
18. The kit according to claim 17 wherein the multi-functional amine is selected from the group consisting of water-dispersible multi-arm polyether amines, linear diamines, branched diamines, branched polyamines, cyclic diamines, aminoalkyltrialkoxysilanes, dihydrazides, linear polymeric diamines, comb polyamines, dihydrazides and polyhydrazides.
19. The kit according to claim 17 wherein the third solution is sterilized.
20. A method for applying a coating to an anatomical site on tissue of a living organism comprising: applying to the site a) a first aqueous solution comprising an oxidized polysaccharide containing aldehyde groups, having a molecular weight of about 1,000 to about 1,000,000 Daltons, said oxidized polysaccharide having an equivalent weight per aldehyde group of about 90 to about 1500 Daltons, said solution containing from about 5% to about 40% by weight of the oxidized polysaccharide, followed by b) a second aqueous solution comprising a water-dispersible, multi-arm polyether amine wherein at least three of the arms are terminated by a primary amine group, wherein the multi-arm polyether amine has a molecular weight of about 450 to about 200,000 Daltons, said solution containing from about 5% to about 70% by weight of the multi-arm polyether amine, or the aqueous solution of (b) followed by the aqueous solution of (a), or premixing the aqueous solutions of (a) and (b) and applying the resulting mixture to the site before the resulting mixture completely cures.
21. A method for bonding at least two anatomical sites together comprising: applying to at least one site a) a first aqueous solution comprising an oxidized polysaccharide containing aldehyde groups, having a molecular weight of about 1,000 to about 1,000,000 Daltons, said oxidized polysaccharide having an equivalent weight per aldehyde group of about 90 to about 1500 Daltons, said solution containing from about 5% to about 40% by weight of the oxidized polysaccharide; applying to a least one of either the same site or one other site b) a second aqueous solution comprising a water-dispersible, multi-arm polyether amine wherein at least three of the arms are terminated by a primary amine group, wherein the multi-arm polyether amine has a molecular weight of about 450 to about 200,000 Daltons, said solution containing from about 5% to about 70% by weight of the multi-arm polyether amine; or premixing the solutions of (a) and (b) and applying the resulting mixture to at least one site before the resulting mixture completely cures; and contacting the at least two anatomical sites together.
22. The method of claim 20 or 21 wherein the molecular weight of the oxidized polysaccharide is from about 3,000 to about 250,000 Daltons.
23. The method of claim 20 or 21 wherein the molecular weight of the multi-arm polyether amine is from about 2,000 to about 40,000 Daltons.
24. The method of claim 20 or 21 wherein the oxidized polysaccharide is selected from the group consisting of dextran, chitin, starch, agar, cellulose, and hyaluronic acid.
25. The method of claim 20 or 21 wherein the aldehyde groups on the oxidized polysaccharide of the first aqueous solution are in a stoichiometric excess relative to the amine groups on the multi-arm polyether amine of the second aqueous solution.
26. The method of claim 20 or 21 wherein the first and second aqueous solutions are sterilized.
27. The method of claim 20 or 21 wherein the first or second aqueous solution further comprises an additive selected from the group consisting of pH modifiers, viscosity modifiers, antimicrobials, colorants, healing promoters, surfactants, anti-inflammatory agents, thrombogenic agents, and radio-opaque compounds.
28. The method of claim 27 wherein said colorants are selected from the group consisting of FD&C Violet No. 2, D&C Green No. 6, D&C Green No. 5, and D&C Violet No. 2.
29. The method of claim 27 wherein said antimicrobial is triclosan.
30. The method of claim 20 or 21 wherein the first or second aqueous solution further comprises a pharmaceutical drug or therapeutic agent.
31. The method of claim 20 or 21 wherein the concentration of the oxidized polysaccharide in the first aqueous solution is from about 15% to about 30% by weight.
32. The method of claim 20 or 21 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, amino-terminated dendritic polyamidoamines, and polyoxyalkylene triamines.
33. The method of claim 20 or 21 wherein the water-dispersible multi-arm polyether amine is a polyethylene glycol comprising eight arms terminated by a primary amine group and having a molecular weight of 10,000 Daltons.
34. The method of claim 20 or 21 wherein the concentration of the multi-arm polyether amine in the second aqueous solution is from about 20% to about 50% by weight.
35. The method of claim 20 or 21 wherein the second aqueous solution further comprises at least one other multi-functional amine having one or more primary amine groups, said multi-functional amine being present at a concentration of about 5% to about 1000% by weight relative to the amount of the multi-arm polyether amine in the solution.
36. The method of claim 35 wherein the multi-functional amine is selected from the group consisting of water-dispersible multi-arm polyether amines, linear diamines, branched diamines, branched polyamines, cyclic diamines, aminoalkyltrialkoxysilanes, dihydrazides, linear polymeric diamines, comb polyamines, dihydrazides and polyhydrazides.
37. The method of claim 20 further comprising applying to the site c) a third solution comprising a multi-functional amine having one or more primary amine groups, wherein the solutions (a), (b), and (c) are applied in any order or premixing the solutions of (a), (b), and (c) and applying the resulting mixture to the site before the resulting mixture completely cures.
38. The method of claim 37 wherein the multi-functional amine is selected from the group consisting of water-dispersible multi-arm polyether amines, linear diamines, branched diamines, branched polyamines, cyclic diamines, aminoalkyltrialkoxysilanes, dihydrazides, linear polymeric diamines, comb polyamines, dihydrazides and polyhydrazides.
39. The method of claim 21 further comprising applying to at least one site c) a third solution comprising a multi-functional amine having one or more primary amine groups, or premixing the solutions of (a), (b), and (c) and applying the resulting mixture to the site before the resulting mixture completely cures, and contacting the at least two anatomical sites together.
40. The method of claim 39 wherein the multi-functional amine is selected from the group consisting of water-dispersible multi-arm polyether amines, linear diamines, branched diamines, branched polyamines, cyclic diamines, aminoalkyltrialkoxysilanes, dihydrazides, linear polymeric diamines, comb polyamines, dihydrazides and polyhydrazides.
41. The method of claim 37 or 39 wherein the third solution is sterilized.
42. The method of claim 20 wherein the anatomical site is a wound on the skin and the method is used for treatment of topical wounds.
43. The method of claim 20 wherein the anatomical site is on an intestine or blood vessel and the method is used in an anastomosis procedure.
44. The method of claim 20 wherein the anatomical site is on the eye and the method is used to seal a corneal incision.
45. The method of claim 20 wherein the method is used to prevent adhesions between adjacent anatomical sites.
46. The method of claim 20 wherein the first or second aqueous solution further comprises a pharmaceutical drug or therapeutic agent and the method is used for drug delivery to the anatomical site.
47. The method of claim 20 wherein the anatomical site is the bladder and the method is used to treat urinary incontinence.